WO2019018752A1 - Methods of attenuating undesirable metabolic adaptations to weight loss induced by caloric restriction - Google Patents

Methods of attenuating undesirable metabolic adaptations to weight loss induced by caloric restriction Download PDF

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Publication number
WO2019018752A1
WO2019018752A1 PCT/US2018/043063 US2018043063W WO2019018752A1 WO 2019018752 A1 WO2019018752 A1 WO 2019018752A1 US 2018043063 W US2018043063 W US 2018043063W WO 2019018752 A1 WO2019018752 A1 WO 2019018752A1
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subject
weight
amount
days
caloric restriction
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PCT/US2018/043063
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French (fr)
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Barbara J. NICKLAS
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Wake Forest University Health Sciences
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Priority to US62/534,796 priority
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Publication of WO2019018752A1 publication Critical patent/WO2019018752A1/en

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    • AHUMAN NECESSITIES
    • A63SPORTS; GAMES; AMUSEMENTS
    • A63BAPPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B21/00Exercising apparatus for developing or strengthening the muscles or joints of the body by working against a counterforce, with or without measuring devices
    • A63B21/06User-manipulated weights
    • A63B21/065User-manipulated weights worn on user's body
    • AHUMAN NECESSITIES
    • A63SPORTS; GAMES; AMUSEMENTS
    • A63BAPPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B21/00Exercising apparatus for developing or strengthening the muscles or joints of the body by working against a counterforce, with or without measuring devices
    • AHUMAN NECESSITIES
    • A63SPORTS; GAMES; AMUSEMENTS
    • A63BAPPARATUS FOR PHYSICAL TRAINING, GYMNASTICS, SWIMMING, CLIMBING, OR FENCING; BALL GAMES; TRAINING EQUIPMENT
    • A63B21/00Exercising apparatus for developing or strengthening the muscles or joints of the body by working against a counterforce, with or without measuring devices
    • A63B21/06User-manipulated weights

Abstract

Described herein are methods of applying a gravitational load or weight to a subject undergoing caloric restriction that can be capable of attenuating a decrease in resting metabolic rate in the subject that can be due to weight loss or caloric restriction in the subject. In some aspects, the change in the resting metabolic rate is not more than 15%, 10%, or 5%.

Description

METHODS OF ATTENUATING UNDESIRABLE METABOLIC ADAPTATIONS TO WEIGHT

LOSS INDUCED BY CALORIC RESTRICTION

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 62/534,796, filed on July 20, 2017, entitled "Use of a Weighted Vest During a Dietary Weight Loss Intervention," the contents of which is incorporated by reference herein in its entirety.

BACKGROUND

Obesity is a world-wide epidemic that has related health complications. Therapeutic treatments for obesity first involve adopting lifestyle changes that incorporate restricting caloric intake to induce loss of body fat and weight. However, traditional weight loss and caloric restriction regimens are not tolerated or are otherwise unsuccessful for a variety of reasons. Weight loss and caloric restriction lead to loss of bone and muscle tissue, as well as body fat. In addition, these treatments lead only to short-term weight loss, as weight regain over time is the norm. Several factors contribute to the inability to prevent weight regain following weight loss. One key factor is the consistent phenomenon that weight loss results in lowered energy expenditure beyond what is needed to maintain the new weight-reduced state. This compensatory decrease in energy output results in an increased appetite, lower satiety, and increased food intake that results in regain of lost weight. Weight regain after weight loss is currently the most substantial problem in obesity therapeutics. As such there exists a need for improved methodologies and techniques for individual's undergoing caloric restriction for treatment of obesity.

SUMMARY

In various aspects, methods are provided that overcome one or more of the aforementioned deficiencies. Applicants have found that, in some aspects, applying an external weight to a subject can result in an attenuation of the decrease in resting metabolic rate even when the weight added is small, e.g. even when the amount of weight added has no discernable impact on the amount of weight lost. For example, in some aspects, a weight loss in the subject is within about 10% of a reference weight loss of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight. The methods can provide for attenuating the decrease in the resting metabolic rate of the subject such that a change in the resting metabolic rate of not more than 15%, 10%, or 5%. In some aspects, a decrease in the resting metabolic rate of the subject is about 50% less than a reference decrease in resting metabolic rate of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.

In some aspects, a method is provided for attenuating a decrease of resting metabolic rate in a subject undergoing caloric restriction, the method comprising: (a) measuring a reference/initial body weight of the subject; (b) administering an amount of external weight to the subject for an amount of time per day for at least one week during the period of caloric restriction, wherein the amount of external weight is added by coupling an external or internal apparatus to the subject; (c) re-measuring the body weight of the subject after at least one week of caloric restriction; and (d) increasing the amount of external weight administered to the subject such that a sum of the body weight of the subject and the external weight is within about ± 20 percent of the reference body weight obtained in step (a).

In some aspects, a method is provided for attenuating a decrease in a resting metabolic rate attributed to weight loss or caloric restriction in a subject undergoing caloric restriction, the method comprising: adding an amount of external weight to the subject for a period of time per day for a number of days, wherein a sum of the bodyweight of the subject and the amount of external weight does not exceed 20 percent of a starting bodyweight of the subject, and wherein the amount of external weight, the period of time per day, and the number of days is effective to attenuate the decrease in the resting metabolic rate in the subject.

The methods can be repeated one or more times, e.g. daily, weekly, or for a set number of times or until a desired amount of weight loss in the subject is achieved.

The methods can be used in a variety of subjects, e.g. those with a body mass index ranging from about 25 kg/m2 to about 40 kg/m2 prior to beginning the methods.

A variety of methods can be employed to apply the weight, e.g. using a vest, a belt, a strap, a cuff, a pair of pants or shorts, an undergarment, a shirt, a jacket, a sock or pair of socks, or a shoe or pair of shoes, or any combination thereof.

Other systems, methods, features, and advantages of the methods will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure will be readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.

FIG. 1 shows a graph that can demonstrate 22 week treatment effects on DXA-acquired regional BMD, adjusted for baseline values of the outcome and gender and presented as means (95% CI).

FIG. 2 shows a graph that can demonstrate 22 week treatment effects on biomarkers of bone turnover, adjusted for baseline values of the outcome and gender and presented as means (95% CI).

FIGS. 3A-3B show graphs that demonstrate the effect of gravitational loading on resting metabolic rate (RMR) and weight maintenance in patients two years post initial vest use.

FIG. 4 shows a graph that = demonstrates the effect of gravitational loading on RMR as compared to initial baseline within in each group. Data were analyzed using a paired Student's t-test * P<0.0001. A significant between-group difference in the change in RMR analyzed with ANCOVA adjusted for age, gender, race, and baseline value (P <0.0001) was observed.

FIGS. 5A-5B show graphs that = demonstrate a correlation in RMR with weight gain during a follow-up period of about two years after initial vest wearing and caloric restriction. FIG. 5A shows the correlation including a -600 kcal/day outlier. FIG. 5B shows the correlation after exclusion of the -600 kcal/day outlier.

DETAILED DESCRIPTION

Despite the plethora of health benefits that can be attributed to weight loss induced by caloric restriction, there can be undesirable effects as well. For example, weight loss induced by caloric restriction reduces muscle mass, bone density, and resting metabolic rate. While in the majority of cases, the health benefits of weight loss and/or caloric restriction outweigh any undesirable effects, it is still desirable to reduce the negative impact of weight loss and/or caloric restriction, particularly in those populations that are at a heightened risk for being impacted by those undesirable effects, such as older individuals (e.g. those above 60 years old) or those with other diseases or disorders.

In various aspects, methods are provided for attenuating and/or eliminating one or more undesirable side effects of weight loss and caloric restriction. For example, the methods are capable of attenuating and/or eliminating one or more of a decreasing metabolic rate and a decreasing bone mineral density in a subject undergoing caloric restriction. Applicants have found that, in some aspects, by applying an external weight to a subject undergoing caloric restriction that the decrease in resting metabolic rate that is associated with caloric restriction can be attenuated or completely eliminated. By attenuating the decrease in resting metabolic rate, in some aspects, the subjects are able to maintain the weight loss for a longer period of time and/or do not gain as much weight back, even more than two years after the cessation of the caloric restriction.

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

All publications and patents cited in this specification are cited to disclose and describe the methods and/or materials in connection with which the publications are cited. All such publications and patents are herein incorporated by references as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and/or materials described in the cited publications and patents and does not extend to any lexicographical definitions from the cited publications and patents. Any lexicographical definition in the publications and patents cited that is not also expressly repeated in the instant application should not be treated as such and should not be read as defining any terms appearing in the accompanying claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of molecular biology, microbiology, nutrition, endocrinology, biochemistry, physiology, cell biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

Definitions

As used herein, "about," "approximately," and the like, when used in connection with a numerical variable, generally refer to the value of the variable and to all values of the variable that are within the experimental error (e.g., within the 95% confidence interval for the mean) or within +/- 10% of the indicated value, whichever is greater.

As used herein, the term "attenuate" can refer to reducing, mitigating, preventing, weaken, or eliminating the effect, intensity, or amount of a condition, physiological response, disease, or attribute.

As used herein, the term "caloric restriction" refers to a decrease in calorie intake by a subject that is anything less than the maintenance caloric intake over a period of time (e.g. day, week, or month) for the subject. "Caloric restriction" can also refer to a decrease in calorie intake as compared to the maintenance caloric intake for the subject that can result in a desired amount of weight loss over a period of time. The amount of weight loss desired can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25 percent or more. Caloric restriction" can also refer to a decrease in caloric intake by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent or more as compared to the maintenance caloric intake for the subject.

As used herein, the terms "reference" and "control" refer to an alternative subject or sample used in an experiment for comparison purpose and included to minimize or distinguish the effect of variables other than an independent variable. As used herein, the term "maintenance caloric intake" refers to the amount of calories that can be consumed by a subject over a period of time (e.g. per day, week, or month) that would, or is calculated to, result in no change in body weight.

As used herein, the term "negative control" refers to a "control" that is designed to produce no effect or result, provided that all reagents are functioning properly and that the experiment is properly conducted. Other terms that are interchangeable with "negative control" include "sham," "placebo," and "mock."

As used herein, the terms "organism", "host", and "subject" refer to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single isolated eukaryotic cell or cultured cell or cell line, or as complex as a mammal, including a human being, and animals (e.g., vertebrates, amphibians, fish, mammals, e.g., cats, dogs, horses, pigs, cows, sheep, rodents, rabbits, squirrels, bears, primates (e.g., chimpanzees, gorillas, and humans).

As used herein, the term "positive control" refers to a "control" that is designed to produce the desired result, provided that all reagents are functioning properly and that the experiment is properly conducted.

As used herein, the term "resting metabolic rate" (RMR) refers to the average daily caloric expenditure in the resting state. RMR is measured in the morning after an overnight fast by indirect calorimetry using the ventilated hood technique. Upon arrival, subjects are asked to lie quietly for 30-45 min before testing. Measurement of oxygen consumption and carbon dioxide production are collected continuously for at least 30 mins and RMR is calculated using the Weir equation.

As used interchangeably herein, the terms "sufficient" and "effective," can refer to an amount (e.g. weight, mass, volume, dosage, concentration, and/or time period) needed to achieve one or more desired result(s). For example, a therapeutically effective amount refers to an amount needed to achieve one or more therapeutic effects.

Discussion

Weight loss and/or caloric restriction has many known health benefits and is prescribed and utilized by medical and fitness practitioners to improve health and quality of life. Weight loss and/or caloric restriction are primary treatment approaches for alleviation of obesity and related conditions, complications, and disorders (e.g. diabetes and cardiovascular disease).

Despite the plethora of health benefits that can be attributed to weight loss, weight loss induced by caloric restriction can have undesirable effects as well. For example, weight loss and/or caloric restriction can reduce muscle mass, bone density, and resting metabolic rate. While in the majority of cases, the health benefits of weight loss and/or caloric restriction outweigh any undesirable effects, it is still desirable to reduce the negative impacts weight loss and/or caloric restriction, Although many fitness, nutrition, and/or behavioral counseling programs are available, these programs can require expensive memberships, equipment, meals, or other supplies, can result in a level of undesirable effects that may not be tolerated, which can result in a failure in compliance in some populations, particularly those that are obese, aged, and/or otherwise afflicted with a disease, condition, disability, or disorder. As such, there exists a need for treatments and methodologies that can reduce the negative impacts of weight loss and/or caloric restriction in a subject, which can improve patient compliance and response to weight loss and/or caloric restriction, and prevent weight regain following weight loss.

With that said, described herein are methods of attenuating an undesirable effect of caloric restriction and/or weight loss in a subject by adding an amount of external weight to the subject for a period of time per day for a number of days, where the amount of external weight does not exceed about 15 percent of the subject's starting body weight and where the amount of external weight, period of time per day, and the number of days can be effective to attenuate the decrease in the undesirable effect of caloric restriction and/or weight loss in the subject. The undesirable effect of caloric restriction and/or weight loss can be, without limitation, a decrease in resting metabolic rate, a decrease in bone mineral density, a decrease in bone formation and bone strength, or any combination thereof. Other methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional methods, features, and advantages be included within this description, and be within the scope of the present disclosure.

Methods of Attenuating an Undesirable Effect of Weight Loss and/or Caloric Restriction

As discussed above, weight loss and/or caloric restriction regimens can result in undesirable effects. Since the loss of RMR, muscle mass and bone during weight loss is partially attributed to the decrease in mechanical stress as weight is reduced, performing exercises that enhance muscle and gravitational loading during the period of caloric restriction usually diminishes the relative amount of muscle and bone loss, and RMR decline, for a given weight loss. However, these exercise regimens do not fully prevent the undesirable effects of weight loss, and for some populations traditional fitness and weight training programs are inappropriate or not tolerated. Further, these require access to specialized equipment and/or trained personnel to safely perform the exercises.

Described herein are methods that include maintaining the gravitational load of the greater body mass during caloric restriction-induced weight loss by applying external loading on a subject that matches their rate of weight loss for a period of time per day for a number of days that can be effective to attenuate the undesirable effects of weight loss in the subject as compared to subjects not undergoing external loading for a period of time per day for a number of days. The undesirable effect of caloric restriction and/or weight loss can be, without limitation, a decrease in resting metabolic rate, a decrease in bone mineral density or bone strength, a decrease in bone formation, or any combination thereof. In some aspects, the undesirable effect that is attenuated is a decrease in resting metabolic rate. In some aspects, the method can be capable of attenuating weight-gain after stopping the application of the mild gravitational load to the subject for a period of time per day for a number of days. The decrease in RMR can be attenuated about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, to 100 percent, with 100 percent attenuation being elimination of the decrease in RMR.

The external load applied to the subject can be correlated with or calculated based on the subject's starting body weight, or can be calculated based on the amount or rate of weight loss. For example, the gravitational load can be an amount of external weight that is applied to the subject to induce a gravitational load on the subject's body that is a percentage of the subject's starting body weight or is equal to, or correlated with, the subject's rate or amount of weight loss during caloric restriction. In some aspects, the weight can be about 1 to about 15 percent of the subject's starting body weight. Caloric restriction can be composed of the subject consuming less calories than the subject's calculated maintenance caloric intake requirement. Caloric restriction can be composed of the subject consuming 1-20% less calories than the subject's calculated maintenance caloric intake requirement.

In some aspects, the gravitational load can be increased after the period of time and the method can be repeated one or more times. After each period of time in each cycle, the subject can be reweighed and the gravitational load for the next cycle can be increased based on the amount of weight lost by the subject. Although the gravitational load can be increased with each cycle, the total load is maintained such that it is still a mild gravitational load. The number of times the method can be repeated can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50 or more times. The period of time per day of applied loading can range from about 2 to about 4, 6, 8, or about 10 hours per day. The number of days can range from 1-365 days. The number of days can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , or more days. In some aspects, the number of days is 7. In some aspects the subject can be greater than 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years old. In some aspects, the subject can be between 60 and 100 years old. The subject can be overweight obese. The subject can have body mass index of about 20 kg/m2, about 25 kg/m2, about 30 kg/m2 or greater as based on the subject's starting body weight prior to the addition of any gravitational load. The subject can have body mass index of about 40 kg/m2 or greater as based on the subject's starting bodyweight prior to the addition of any gravitational load. The subject can be recovering from an injury or illness. The subject can be recovering from a surgical procedure.

Also described herein are methods of attenuating a decrease in resting metabolic rate in a subject undergoing caloric restriction, that can include the step of adding an amount of external weight to the subject for a period of time per day for a number of days, where the amount of external weight does not exceed 10, 15, or 20 percent of the subject's starting bodyweight, and where the amount of external weight, the period of time per day, and the number of days can be effective to attenuate the decrease in resting metabolic rate in the subject.

The decrease in RMR can be attenuated about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, to 100 percent, with 100 percent attenuation being elimination of the decrease in RMR. Caloric restriction can be composed of the subject consuming less calories than the subject's calculated maintenance caloric intake requirement. Caloric restriction can be composed of the subject consuming 1-20% less calories than the subject's calculated maintenance caloric intake requirement.

The period of time per day can range from about 2 to about 4, 6, 8, or about 10 hours. The period of time per day can be about 2, 3, 4, 5, 6, 7, 8, 9, or about 10 hours per day. The number of days can range from 1-365 days. The number of days can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , or more days. In some aspects the number of days is 7. In some aspects the subject is greater than 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years old. In some aspects the subject is between 60 and 100 years old. The subject can be obese. The subject can have body mass index of about 30 kg/m2 or greater. The subject can have body mass index of about 40 kg/m2 or greater. The subject can have an injury or be recovering from an injury or illness. The subject can be recovering from a surgical procedure.

The amount of external weight can range from about 0.1 kg to about 20 kg. The amount of external weight can range from about 1 percent to about 20 percent of the subject's starting bodyweight prior adding any amount of external weight to the subject.

The method can further include the step of increasing the amount of external weight added to the subject after the number of days, wherein the total amount of external weight added (e.g. the amount of external weight initially added and the amount added to increase the amount of external weight) does not exceed 10, 15, or 20 percent of the subject's starting bodyweight. The amount of external weight can be increased by 0.1 to 5.0 kg, 10.0 kg, 15.0 kg, or even 20.0 kg. The amount of external weight can be increased by an amount that can be about 1 to 10%, 15%, or 20 % of the subject's starting bodyweight. The method can be repeated such that the new total amount of external weight is added to the subject for a period of time per day for a number of days, such that the amount of external weight, the period of time per day, and the number of days can be effective to attenuate the decrease in resting metabolic rate in the subject. The number of times the process can be repeated can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50 or more times.

In some aspects, the method can further include the step of weighing the subject after the number of days and increasing the amount of external weight added to the subject by an amount of weight that can be within about 20 percent of the amount of weight lost by the subject over the number of days. The method can then be repeated such that the new total amount of external weight is added to the subject for a period of time per day for a number of days. This process can then be repeated for a number of times. The number of times the process can be repeated can be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50 or more times.

Also described herein are methods of attenuating a decrease resting metabolic rate in a subject undergoing caloric restriction that can include the steps of (a) measuring the body weight of the subject; (b) adding an amount of external weight to the subject for an amount of time per day for at least one day, wherein the amount of external weight can be added by coupling an apparatus to the subject or adding an amount of external weight to an apparatus that can be coupled to the subject; (c) re-measuring the bodyweight of the subject after the at least one day; and (d) increasing the amount of external weight added to the subject, wherein the amount of external weight is increased in an amount that is within about ± 20 percent of the amount of weight lost as calculated from the reference body weight obtained in step (a) and the body weight obtained in step (c). Caloric restriction can be composed of the subject consuming about 800 kcal/day to about 2000 kcal/day or about 1100 kcal/day to about 1300 kcal/day. Caloric restriction can be composed of the subject consuming less calories than the subject's calculated maintenance caloric intake requirement. Caloric restriction can be composed of the subject consuming 1-20% less calories than the subject's calculated maintenance caloric intake requirement. The decrease in RMR can be attenuated about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, to 100 percent, with 100 percent attenuation being elimination of the decrease in RMR.

In some aspects, steps (a)-(d) can be repeated one or more times. Steps (a)-(d) can be repeated daily. Steps (a)-(d) can be repeated 1-365 times. Steps (a)-(d) can be repeated weekly. Steps (a)-(d) can be repeated 1-52 times. Steps (a)-(d) can be repeated until a desired amount of weight loss in the subject is achieved. The desired amount of weight loss can be 1-25 percent or more of the subject's starting bodyweight.

In some aspects the subject is greater than 18, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 years old. In some aspects the subject is between 60 and 100 years old. The subject can be overweight or obese. The subject can have body mass index of about 25 kg/m2 or greater based on starting bodyweight prior to the addition of any external bodyweight. The subject can have body mass index of about 40 kg/m2 or greater based on starting bodyweight prior to the addition of any external weight. The subject can have an injury or be recovering from an injury or illness. The subject can be recovering from a surgical procedure.

The external weight and gravitational load can be added to the body using any desirable method, including or composed of a vest, a belt, a strap, a cuff, a pair of pants or shorts, an undergarment, a shirt, a jacket, a sock or pair of socks, or a shoe or pair of shoes, or any combination thereof. It can also be added surgically or via internal placement of added weight. The method can be configured to receive any amount of added weight. The method can include one or more sleeves, pockets, pouches, or combinations thereof to receive the added weight. The apparatus can weigh about 0.1 to about 2.0 kg. The apparatus can weigh about 0.5 kg.

Also described herein is the use of an apparatus configured to provide a gravitational load or apply an external weight to a subject for an a period of time per day for the attenuation of a decrease in resting metabolic rate attributed to weight loss or caloric restriction in the subject. The methods described herein can be capable of attenuating bone mineral density loss in the subject as compared to a subject that has not undergone the methods described herein or other appropriate control. Bone mineral density loss in the subject can be attenuated about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, to 100 percent, with 100 percent attenuation being elimination of the decrease in bone mineral density loss. Bone mineral density is measured using dual-energy X-ray absorptiometry (DXA) or computed tomography scanning.

The methods can be capable of increasing bone formation in the subject as compared to a subject that has not undergone the methods described herein or other appropriate control. Evidence of an increase in bone formation can be an increase in biomarkers of bone formation such as osteocalcin, bone specific alkaline phosphatase (BALP), and procollagen type 1 N- Terminal Propeptide (P1 NP), and bone resorption marker C-Terminal Telopeptide of Type 1 Collage (CTX). These can be measured using an appropriate assay generally known in the art such as enzyme-linked immunosorbent assays and qPCR methods. In some aspects, the methods described herein can be capable of increasing BALP, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, to 20% or more as compared to a subject not having undergone the methods described herein or an appropriate control.

The methods can be capable of attenuating muscle strength loss in the subject as compared to a subject that has not undergone the methods described herein or other appropriate control.

The methods described herein can result in attenuation of weight-gain after stopping the application of the external weight or gravitational load as described herein to the subject. This can be a result of attenuating the decrease in RMR in the subject that can be associated with caloric restriction and/or weight loss. In some aspects, weight-gain post application of an external weight or gravitational load as described herein can be attenuated 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20 to 25, 30, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, to 100 percent, with 100 percent being elimination of weight gain.

EXAMPLES

Now having described the embodiments of the present disclosure, in general, the following Examples describe some additional embodiments of the present disclosure. While embodiments of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit embodiments of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.

Example 1.

Introduction.

More than one-third of adults in the U.S. over 60 years of age are considered to be obese (body mass index (BMI)≥30 kg/m2) (1), setting the stage for an acceleration of age- and obesity-related diseases and disability (2, 3). Both obesity and aging are strong and independent risk factors for metabolic disturbances such as dyslipidemia and insulin resistance (4), and elevated BMI in older adults is strongly associated with poor physical function and development of disability (5).

There is growing evidence that planned and supervised weight loss in older adults with obesity yields clinically important benefits in metabolic and physical function (6, 7). However, since aging is associated with a loss of muscle mass (sarcopenia), and weight loss results in loss of muscle in addition to fat loss, there may also be undesired effects of weight loss in older adults who are already at a heightened risk for sarcopenia and dynapenia (8, 9). Thus, there is a need to minimize the negative effects of weight loss, while enhancing its health advantages (10).

Obesity treatment guidelines recommend a comprehensive lifestyle program involving behavioral counseling, caloric restriction, and physical activity (11). In addition, exercise during weight loss in older adults is highly recommended to counteract the loss of muscle mass during weight loss; however, conventional exercise training often requires expensive equipment and, ideally, safety supervision by trained leaders. Moreover, the exercises performed are not always tolerated or sustained, especially in adults with obesity (12). Thus, there is a need to identify strategies that are easily adaptable to the environment in which older adults reside. As such, the purpose of this study was to assess the feasibility of daily use of a weighted vest, and to examine the effects of daily vest use on body composition, physical function, resting metabolic rate (RMR), and the lipid profile of older adults undergoing diet-induced weight loss.

Materials and Methods.

Study Design. This 22-week randomized, controlled pilot study (Clinicaltrials.gov; NCT02239939) assessed the feasibility of daily use of a progressively weighted vest and examined the effects of randomization to daily vest use (Diet + Vest, n=20), compared to no vest use (Diet, n=17) during weight loss in older men and women with obesity.

Participant Eligibility. Participants were recruited and enrolled based on the following criteria: 1) 65-79 yrs; 2) sedentary; 3) BMI of 30-40 kg/m2; 4) nonsmoking (<1 cigarette/d or 4/wk within yr); 5) weight stable (<5% weight change in the past 6 months); 6) self-reported physician diagnosed osteoarthritis; 7) willing and able to consume meal replacement products; 8) without insulin-dependent or uncontrolled diabetes, evidence of clinical depression, cognitive impairment, uncontrolled endocrine/metabolic disease, neurological or hematological disease, fibromyalgia, rheumatoid arthritis, cancer, liver or renal disease, chronic pulmonary disease, uncontrolled hypertension, physical impairment (requiring dependency on a cane or walker, osteoporosis, hip fracture, joint replacement or spinal surgery within the last 6 months, or chronic severe back pain) or any contraindication for weight loss. The study was approved by the Wake Forest School of Medicine Institutional Review Board, and all participants provided written informed consent to participate.

A total of 330 individuals were screened by telephone to assess general eligibility. Of these, 56 were invited for in-person screening visits that involved measuring height and weight, a cognition screen (Montreal Cognitive Assessment), physical activity assessment (Physical Activity for the Elderly questionnaire (13)) to insure a sedentary lifestyle, and, if still eligible, a medical history, blood pressure check, and a review of medications. Qualifying participants (n=41) then completed a 3-day run-in period during which they were asked to wear the vest with no weights added, to consume the Medifast® meal replacement products used in the weight loss intervention, and to complete a food record. Four participants withdrew consent during the run- in. Thus, a total of 37 participants met all inclusion and exclusion criteria and were tested on study outcomes before being randomly assigned to an intervention group.

Interventions.

Dietary weight loss intervention. All participants underwent a dietary weight-loss intervention, without a formal exercise program. Caloric deficit was achieved through a combination of meal replacements (MR), conventional foods, and weekly group nutrition/behavioral counseling sessions led by a Registered Dietitian (RD). Participants were instructed to follow the Medifast® 4 & 2 & 1 Plan®, estimated to provide 1100-1300 calories per day. This meal plan includes a total of 4 MR products, with the addition of 2 lean and green meals and 1 healthy snack. The lean and green meals were prepared by the participants and each consisted of 5-7 oz. lean protein, 3 servings of non-starchy vegetables and up to 2 servings of healthy fat. The healthy snack consisted of one serving of fruit, dairy, or grain. The MR from Medifast® each contained 90-1 10 kcals and 1 1-15 g protein. The RD guided participants on their food choices and portion sizes and encouraged participants to consume only what was approved as part of the plan. Daily food logs were collected and reviewed weekly by the RD to verify compliance to the dietary intervention. Compliance was calculated by the RD (based on the self-reported food logs) as the percent of total calories consumed daily relative to the estimated number of calories prescribed (about 1200 calories). In addition, body weight was measured weekly to ensure participants were losing weight at a rate approximating their prescribed energy deficit.

Weighted vest intervention. Participants randomized to the weighted vest group (Diet+Vest) each received an appropriately sized vest (Hyper Vest PRO®, Austin, TX) for the duration of the intervention. The vest's fabric and design fits comfortably under clothing, allowing for full range of motion and movement, and full chest expansion without restricting breathing. The vest firmly and evenly distributes the weight inserts over the body's core; weights come in 1/8th pound increments.

Participants in this group were asked to wear the vest (under their shirts) on a daily basis, progressing to a goal of 10 hrs/day during the most active part of their day. Initially, no extra weight was added to the vest (vest weight alone is about 0.5 kg). The vest weight was then incrementally increased weekly according to each participant's rate of weight loss. As body mass decreased, the weight of the vest was increased to replace the lost weight, up to a maximum amount of 15 % of the participant's baseline weight. Participants also kept a daily log to record the time worn, vest weight, and any problems related to vest use. Staff monitored and discussed these logs and participants' vest use during the weekly group sessions.

Assessments.

All assessments were conducted before and after the interventions. Post-intervention testing occurred during the last week of intervention; participants did not wear the weighted vest during testing.

Body composition and circumferences. Height (Heightronic 235D stadiometer, QuickMedical, Issaquah, WA) and body mass (Detecto scale, Detecto, Webb City, MO) were measured without shoes or outer garments. Whole-body fat mass (FM), lean body mass (LM), and percentage of body fat (%FM) were measured using dual-energy X-ray absorptiometry (Delphi QDR; Hologic, Marlborough, MA). All scans were performed and analyzed by a trained and certified technician. Waist (minimal circumference) and hip (maximal gluteal protuberance) were measured in triplicate with a tape measure; average values are reported and waist-to-hip (WHR) ratio was calculated.

Physical function, mobility and strength. The expanded version of the short physical performance battery (ExSPPB) (12) was used to measure lower-extremity function. The ExSPPB consists of 5 repeated chair stands, standing balance (semi- and full-tandem stands and a single leg stand for 30 seconds), a 4-meter walk at usual pace, and a narrow 4-meter walk test of balance (walking at usual pace within lines of tape spaced 20 cm apart). The continuous scoring system ranges from 0 to 4 with higher scores indicative of better performance. Participants also completed a fast 400-meter walk, which is a measure of aerobic endurance (14). Participants were instructed to complete the 400-meter distance (on a flat indoor surface) as quickly as possible at a maintainable pace. The timed stair climb task assessed the time it took each participant to ascend a standard flight of stairs (12 steps).

Maximal isokinetic knee extensor strength (in Newton meters (Nm)) was measured with a dynamometer (Biodex Medical Systems Inc., Shirley, NY) with the participant sitting and the hips and knees flexed at 90°. Participants were asked to extend the knee and push as hard as possible against the resistance pad. The best of 3 trials was selected for each leg. Lower extremity muscle power was measured using the Nottingham Power Rig (15). Power was averaged for each leg following five trials at maximal effort.

Lipoprotein lipids and resting metabolic rate (RMR). Blood samples were drawn following an overnight fast of at least 8 hours. Triglycerides (TG), total cholesterol (Total chol), very low- density lipoprotein cholesterol (VLDL-chol), low-density lipoprotein cholesterol (LDL-chol), and high-density lipoprotein cholesterol (HDL-chol) were measured in a clinical laboratory (LabCorp, Burlington, NC). RMR was measured by indirect calorimetry (Medgraphics, St. Paul, MN) in the morning after a 12-hour fast.

Statistical Analyses.

All statistical analyses were performed with SPSS software (version 21). An a level of < 0.05 was used to denote significance and all data were analyzed according to randomly assigned group. Baseline descriptive characteristics are reported as mean (± SDs) or frequencies (percentages). Univariate analyses of variance (ANOVAs) were performed to assess between-group differences at baseline. Within-group differences between baseline and follow-up values were determined using a paired t-test. Between-group differences for change values (baseline minus follow-up) were analyzed using ANCOVA with adjustment for baseline age, gender, race and baseline value of the outcome.

Results

Baseline characteristics, retention, and adherence. The average age of the randomized participants was 70.1 ± 3 years, and average BMI was 35.3 ± 2.9 kg/m2, with the majority being female and white. Hypertension was the most prevalent comorbidity. No significant group differences were observed for baseline characteristics (Table 1). Table 1 : Baseline demographic characteristics by treatment group

Diet Only (ISM 7) Diet + Vest (N=20)

Age (yrs) 69.9±2.6 70.3±3.4

Female, N (%) 14 (82%) 15 (75%)

White, N (%) 13 (77%) 16 (80%)

Education (> High School) 17 (100%) 20 (100%)

Weight (kg) 94±12 99±1 1

Height (cm) 163±7 168±9

BMI (kg/m2) 35.3±3.0 35.3±2.8

Systolic blood pressure 134.4±7.7 146.4±16.9

(mmHg)

Diastolic blood pressure (mm 72.3±9.7 72.8±10.7

Hg)

Hypertension 10 (59%) 14 (70%)

Diabetes1 2 (12%) 2 (10%)

Sleep apnea 6 (35%) 7 (35%)

Osteopenia 2 (12%) 1 (5%)

All data are Mean ± SD or # (%)

Non-insulin-treated diabetes

There were no significant differences between groups by using ANOVA at P<0.05

Thirty-three of the 37 randomized participants (89%) completed the study (returned for final data collection). Retention of participants was not different between groups (Diet: 88%; Diet+Vest: 90%). Compliance to the diet intervention was high and did not differ between groups (Diet: 100.3 ± 4.5%; Diet+Vest: 96.3 ± 14.6% of prescribed diet). Over the entire intervention, participants in the Diet+Vest group wore the vest for an average of 6.7 ± 2.2 hours/day (range of 2.0-9.9 hrs/day); four participants wore the vest for an average of less than five hrs/day. Overall, participants reported meeting the vest-wear goal of 10 hrs/day for 67±22% of the total intervention days. Five participants reported adverse events from wearing the vest (all reported back pain or soreness); two of these completely stopped wearing the vest (at weeks 19 and 20), two had interrupted vest use for 2-3 weeks during intervention but resumed vest use for the remainder of the study, and the other one was resolved by decreasing the amount of weight in the vest and not adding additional weight past week 1 1.

Intervention effects on weight and body composition. There were no group differences at baseline for body mass, circumferences, or body composition (Table 2). Both groups experienced similar and significant weight loss (Diet= -1 1.2±4.4 kg; 11.9% and Diet+Vest= - 11.0±6.3 kg; 10.9%; both p<0.001 compared to baseline), with no difference between groups. Waist and hip circumferences significantly decreased in both groups with no difference between groups. WHR did not change in either group. FM, LM and %FM all decreased significantly (p<0.0001) in both groups, with no significant difference between groups. Table 2. Circumference measures and body composition at baseline and changes in those who completed study interventions

Diet Only (n =15) Diet + Vest (n =18)

Baseline Changes Baseline Changes P-between

Relative to Relative to Groups Baseline Baseline

Body mass 93.8 ± 12.5 -1 1.2 ± 4.4* 100.7 ± 8.2 -11.0 ± 6.3* 0.254

(kg)

BMI (kg/m2) 35.0 ± 3.0 -4.1 ± 1.5* 35.4 ± 2.6 -3.8 ± 2.1* 0.464

Waist -7.1 ± 7.2** 105.6 ± 9.9 -7.0 ± 7.2** 0.595 circumference 103.4± 11.4

(cm)

Hip 117.4 ± 9.8 -7.7 ± 3.9* 120.5 ± 9.6 -7.4 ± 4.3* 0.315 circumference

(cm)

Waist to hip 0.89 ± 0.12 -0.01 ± 0.05 0.88 ± 0.09 -0.01 ± 0.04 0.817

ratio

Fat mass (kg) 43.2 ± 7.4 -7.9 ± 3.2* 46.3 ± 8.8 -7.6 ± 4.5* 0.255

Body fat (%) 46.2 ± 5.8 -3.7 ± 1.9* 45.7 ± 7.6 -3.1 ± 2.1* 0.314

Lean body 48.6 ± 9.1 -2.3 ± 1.9* 52.3 ± 8.7 -2.9 ± 1.6* 0.795 mass (kg)

All values are mean ± SD.

BMI, body mass index

Compared to baseline within each group paired t-test;

*P<0.0001 , **P<0.05

Between-group differences for baseline values were analyzed using an ANCOVA adjusted for age, gender, race, and baseline value.

There were no significant differences between groups at baseline.

Intervention effects on resting metabolic rate. The Diet group experienced a significant reduction in RMR (-300 ± 190 kcal/d, p<0.0001) with no change in RMR in the Diet+Vest group (-9.8 ± 119 kcal/d), and there was a significant between group difference (FIG. 6 p<0.0001).

Intervention effects on physical function and lipids. Table 3 shows physical function and muscle strength by treatment group. Wthin the Diet group, usual gait speed (0.08 ± 0.10 m/sec) and ExSPPB score (0.15 ± 0.16) improved (p<0.05), whereas muscle power in the right (-11.1 ± 20.9 W) and left leg (-9.2 ± 15.2 W) decreased (p<0.05). Wthin the Diet+Vest group, usual gait speed improved (0.1 1 ± 0.10 m/sec; p<0.0001). Compared to Diet+Vest, Diet resulted in greater decreases in left and right leg power (p<0.05). There were no between group differences in the other measures of physical function. The intervention effects on lipoprotein lipids are presented in Table 4. None of the lipid values were significantly changed with either intervention. Table 3. Lipoprotein lipids at baseline and changes with intervention by study group

Diet Only (n =15) Diet + Vest (n =18)

Baseline Changes Baseline Changes

between relative to relative to

Groups baseline baseline

HDL- chol 57.8 + 11.1 -3.4 + 9.6 56.5 + 15.8 0.3 + 11.2 0.423

(mg/dl)

VLDL-

16.

chol 25.0 + 9.72 3.5 + 7.8 27.4 + A 2.7 + 10.4 0.533

(mg/dl)

LDL- chol 1 13.7 + 21.8 -2.5 + 29.1 108.8 + 40.3 -5.9 + 33.5 0.596

(mg/dl)

Total

chol 196.5 + 24.3 -9.3 + 27.7 192.7 + 49.2 -8.3 + 36.0 0.945

(mg/dl)

TG

125.1 + 47.5 -17.5 + 38.9 137.2 + 81.9 -13.2 + 52.9 0.516 (mg/dl)

All values are mean ± SD.

HDL-chol, high-density lipoprotein cholesterol; VLDL-chol, very low density lipoprotein cholesterol; TG, triglycerides

There were no significant differences between groups at baseline analyzed using ANOVA There were no significant within group changes using paired t-test

Between-group differences were analyzed with an ANCOVA adjusted for age, gender, race and baseline value.

Table 4. Physical function variables at baseline and changes with intervention by study group

Diet Only (n= = 15) Diet + Vest (n= = 18) P- between

Groups

4-m gait speed 0.98 + 0.1 1 0.98 + 0.13 NS

(m/sec)

Post 1.06 + 0.12 1.09 + 0.10

Change 0.08 + 0.10** 0.1 1 + 0.10* 0.383

Chair rise time (sec) 1 1.8 + 2.23 12.8 + 2.49 NS

Post 1 1.4 + 2.05 12.4 + 2.24

Change -0.37 + 1.16 -0.47 + 1.81 0.523

ExSPPB (score, 0-4) 2.21 + 0.37 2.28 + 0.38 NS

Post 2.37 + 0.26 2.38 + 0.41

Change 0.15 + 0.16** 0.10 + 0.34 0.633

Stair climb time (sec) 7.94 + 2.60 8.23 + 3.1 1 NS

Post 7.90 + 1.68 7.20 + 1.34

Change -0.04 + 2.22 -1.03 + 2.87 0.151

400-m walk time 318.5 + 31.5 335.3 + 37.1 NS

Post 319.7 + 34.9 341.9 + 43.9

Change 1.27 + 16.7 6.67 + 55.0 0.294

Leg Press in W (right) 1 14.0 + 43.2 128.0 + 45.3 NS

Post 102.6 + 37.9 130.5 + 39.6

Change -1 1.4 + 20.9** 2.5 + 29.8 0.022

Leg Press in W (left) 1 14.1 + 44.1 133.5 + 58.0 NS

Post 104.9 + 45.1 132.7 + 49.4

Change -9.2 + 15.2** -0.78 + 22.1 0.007

Leg Strength in Nm 84.7 + 36.9 91.4 + 28.1 NS

(right)

Post 79.3 + 30.4 89.2 + 24.5

Change -5.1 + 12.7 -2.1 + 15.5 0.287

Leg Strength in Nm 80.7 + 30.2 108.4 + 35.4 <0.05

(left)

Post 78.6 + 27.4 99.5 + 31.5

Change -2.2 + 10.7 -5.3 + 12.1 0.590

All values are mean ± SDs. ExSPPB, expanded short physical performance battery; Nm, Newton meters; W, Watts.

Compared to baseline within each group using paired t-test: * PO.0001 , **P<0.05

Between-group differences for baseline values were analyzed using an ANOVA. There were no significant differences between groups at baseline, except for left Leg Strength (p<0.05).

Between-group differences were analyzed with an ANCOVA adjusted for age, gender, race and baseline value.

Discussion.

Results of this study suggest that external replacement of lost weight via daily use of a weighted vest during caloric restriction in obese, older adults is feasible and may have a beneficial impact on health outcomes. Overall, adherence to wearing the vest was good, with average vest wear time of over six hours per day and the daily goal of ten hours of vest use met on 2/3rds of intervention days. In this small pilot, vest use did not differentially affect decreases in body mass, FM or LM, but decreases in RMR and leg muscle power were attenuated with vest use during caloric restriction.

Obesity is a strong predictor of limitations in physical function in older adults (16, 17), and weight loss with exercise results in improved function and mobility in this population (7, 18). In this study, both groups achieved a therapeutic level of weight loss (greater than 10% decrease), moving them closer to the overweight, rather than the obese, BMI range. Weight loss of this magnitude is consistent with that observed in a previous study using meal replacements for weight loss in overweight/obese older adults (19), and is similar to the level of weight loss generally seen in even longer-term (12-18 month) caloric restriction studies in older adults (6, 7).

Even when combined with exercise and higher protein intake, weight loss naturally results in a loss of some muscle mass, in addition to fat loss (9, 20). The loss of muscle during weight loss is partially attributed to the decrease in mechanical stress as weight is reduced (21). Thus, enhancing gravitational load on muscle via weighted vest use during a period of caloric restriction could potentially diminish the amount of muscle lost for a given weight loss (22, 23). In this study, both groups lost a similar and significant amount of both FM and LM, with the majority of total weight lost being fat; however, the added mechanical load from the weighted vest did not result in greater preservation of LM in this small sample. This is contrary to findings from animal studies, where mechanisms regulating skeletal tissue structure and function responded in a similar fashion to increases in actual or externally added body mass (21 , 24). Previous studies of older adults wearing a weighted vest, but just while exercising, did not examine effects on muscle mass per se (25-27), making it difficult to compare the changes in muscle mass we observed with results from other studies. It is possible that a larger sample size would have permitted detection of significant between-group differences in muscle mass changes.

Conservation of muscle mass is a particularly important consideration for older adults as the age-related decreases in muscle strength and power are well characterized and associated with decreased functional capacity in this population. Very little research to date examined effects of weight loss on muscle strength and power in older adults (7). In this study, both groups maintained muscle strength, with no differences between groups. On the other hand, the weighted vest prevented declines in leg muscle power, suggesting this may be a safe and effective method for preserving and potentially improving muscle power during weight loss. These results are similar to a prior study by our group, where we found that, in older women, performing resistance training (RT) during caloric restriction improved leg power, but not knee extensor strength compared to caloric restriction without RT (28). The preservation of lower extremity muscle power we observed in the Diet+Vest group did not transfer into an improvement on power-related functional tasks such as rising from a chair or stair climbing. However, an interesting observation of the results, that is of relevance to the controversy surrounding promoting intentional weight loss in older adults, is that the caloric restriction alone (e.g. without a structured exercise regimen) which resulted in significant reductions in body mass and LM, did not negatively affect key measures of physical function, including chair rise time, global score of physical function (ExSPPB), stair climb time, or 400- meter walk time. In fact, both groups experienced significant improvements in usual gait speed, and the Diet group significantly improved ExSPPB scores.

Body weight, especially the more metabolically active LM, is the major determinant of resting energy expenditure (29). Weight loss is accompanied by a decrease in RMR, with prior studies suggesting an approximate 8 kcal/day decrease per pound lost (30). Interestingly, the use of the weighted vest prevented this decrease in RMR, despite similar decreases in body weight and LM. Since RMR accounts for 60-75% of total daily energy expenditure (31), an intervention that preserves or increases RMR may have a long-term impact on body composition and perhaps reduce propensity for weight regain (32). Thus, the use of an additional external load during caloric restriction may be a viable and promising solution for preserving RMR and is worth further research.

Despite participants in both groups losing more than 10% of total body mass, no significant changes were seen in lipid-related outcomes. This is consistent with previous trials, which examined the effects of caloric restriction on blood lipids in older adults with normal lipid levels at baseline (33, 34). In addition, a high percentage of participants reported using cholesterol-lowering medications (7 in Diet, 1 1 in Diet + Vest group).

The results of this study need to be interpreted within the context that it was an exploratory pilot study with a relatively small number of participants. However, the study provided important insights into the feasibility, practicality and compliance of using a weighted vest during a dietary weight loss intervention in older adults. While, on average, compliance to vest use was good, one-fourth of the participants in this group reported additional back pain and had to disrupt vest use or limit the amount of weight added. Future studies will need to examine the risk: benefit ratio of weighted vest use in this population of older adults with obesity.

In summary, diet-induced weight loss, with or without daily weighted vest use, produced significant decreases in body weight, FM and LM, without impacting physical function in older adults with obesity. Further, use the vest during weight loss appears to help preserve RMR as well as lower extremity muscle power. The implication of these findings are that countering the decreased mechanical load with weight loss by externally replacing lost weight appears to be a promising approach to counteract some aging and obesity-associated conditions; however, future studies using a larger sample size are needed to confirm these findings.

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29. Wang Z, Ying Z, Bosy-Westphal A, Zhang J, Schautz B, Later W, et al. Specific metabolic rates of major organs and tissues across adulthood: evaluation by mechanistic model of resting energy expenditure. Am J Clin Nutr. 2010;92:1369-1377.

30. Seagle HM, Strain GW, Makris A, Reeves RS. Position of the American Dietetic Association: weight management. J Am Diet Assoc. 2009; 109:330-346.

31. Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest. 1986;78:1568-1578.

32. Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WG, et al. Reduced rate of energy expenditure as a risk factor for body-weight gain. N Engl J Med. 1988;318:467- 472.

33. Yassine HN, Marchetti CM, Krishnan RK, Vrobel TR, Gonzalez F, Kirwan J P. Effects of exercise and caloric restriction on insulin resistance and cardiometabolic risk factors in older obese adults-a randomized clinical trial. J Gerontol A Biol Sci Med Sci. 2009;64:90-95.

34. Bouchonville M, Armamento-Villareal R, Shah K, Napoli N, Sinacore DR, Quails C, et al. Weight loss, exercise or both and cardiometabolic risk factors in obese older adults: results of a randomized controlled trial. Int J Obes (Lond). 2014;38:423-431. Example 2.

Introdcution. Recommendation for intentional weight loss in advanced aged individuals (e.g., 65+ years) remains controversial due to weight loss-associated loss of bone mass (1-4) and potential exacerbation of age-related osteoporotic fracture risk (5-8). One potential strategy to preserve bone health during a diet induced weight loss program is to add weight-bearing exercise. The osteogenic effect of exercise in weight stable older adults is well recognized (9) and is attributed to the increased mechanical stress placed on bone tissue (10). However, data from randomized controlled trials (RCTs) specifically designed to assess the effect of exercise on bone mass during weight loss are limited, with mixed findings reported (11-13). Moreover, exercise participation among older adults is strikingly low, with less than 10% of adults over the age of 65 meeting national physical activity guidelines (14). In fact, compliance may be a primary factor explaining discrepant trial findings (15), and speaks to the larger issue of identification of easily translatable weight loss countermeasures to minimize bone loss.

Preventing reductions in mechanical load via use of a weighted vest may offer an alternative to exercise training to attenuate weight loss-associated bone loss in older adults with obesity. Skeletal tissue is highly responsive to mechanical perturbation (16) and most data show that the magnitude of decline in bone density is proportional to the amount of total weight lost, suggesting that reduced mechanical stress is one mechanism underlying the loss of bone in response to weight reduction. Prior clinical studies of weighted vest use are limited, but do provide support for this concept. For instance, walking while wearing a vest weighted with up to 8% of body mass increases loading of the skeletal system, and thus causes increased bone formation and decreased bone resorption in weight stable adults, when compared to sedentary controls (17). Similarly, wearing a weighted vest while strength training and stair climbing for one hour per day, three days per week increased femoral neck bone mineral density in older adults, when compared to controls (18). The effects of weighted vest use during caloric restriction, however, as a means to attenuate weight loss-associated bone loss has not yet been studied.

This Example examines daily weighted vest use during a 22 week dietary weight loss intervention in older adults with obesity, and generate preliminary treatment effect estimates on two clinically relevant indicators of bone health and subsequent fracture risk: (a) DXA-acquired regional BMD, and (b) biomarkers of bone turnover.

Methods.

Study Design. This 22 week randomized, controlled pilot trial (clinicaltrials.gov; NCT02239939) examined the effect of daily use of a weighted vest during dietary weight loss (Diet+Vest=20), as compared to a diet only control (Diet=17), in older adults with obesity. Primary aims included estimating the variability of treatment effects on regional BMD and biomarkers of bone turnover. Participants were recruited and enrolled based on the following criteria: 1) 65-79 years; 2) sedentary; 3) BMI of 30-40 kg/m2; 4) non-smoking; 5) weight stable (<5% weight change in the past 6 months); and 6) without comorbidities for which the intervention was contraindicated.

Interventions.

Dietary Weight Loss Intervention. All participants underwent a dietary weight loss intervention targeting 8-10% weight loss. Caloric deficit was achieved through a combination of meal replacements (MR), conventional foods, and weekly group nutrition/behavioral counseling sessions led by a Registered Dietitian (RD). All participants were instructed to follow the Medifast® 4 and 2 and 1 Plan®, estimated to provide 1 100-1300 cal/day. This meal plan includes a total of 4 MR products per day, with the addition of 2 lean and green meals and 1 healthy snack. The lean and green meals each consisted of 5-7 oz. lean protein, 3 servings of nonstarchy vegetables and up to 2 servings of healthy fat. The healthy snack consisted of one serving of fruit, dairy, or grain. The MR from Medifast® each contained about 90-110 kcal and 11-15 g protein. Daily food logs were collected and reviewed weekly by the RD.

Weighted Vest Intervention. Participants randomized to the weighted vest group (Diet+Vest) each received an appropriately sized weighted vest (Hyper Vest PRO®, Austin, TX) for the duration of the intervention. The vest fits comfortably under clothing, allowing for full range of motion and movement. Small slots in the vest allow the 1/8th pound weights to be evenly distributed throughout the vest. Participants in this group were asked to wear the vest on a daily basis, progressing to a goal of 10 h/day during the most active part of their day. Initially, no weight was added to the vest (vest weight alone is about 0.5 kg). The vest weight was then incrementally increased weekly according to each participant's weight loss, to a maximum amount of 15% of the participant's baseline weight. Participants also kept a daily log to record the time worn, vest weight, and any problems related to the vest use.

Measures.

Relevant covariates. Baseline demographics such as age, gender, and ethnicity were recorded based on participant self-report. Baseline and follow up weights were measured without shoes or outer garments on a Detecto scale (Detecto, Webb City, MO). Height was measured without shoes using the Heightronic 235D stadiometer (QuickMedical, Issaquah, WA). Baseline height and weight were measured at the first screening visit and were used to calculate baseline body mass index (BMI). Intervention Process Measures. Weekly weights were collected using a Tanita BWB 800 scale (Tanita, Arlington Heights, IL) in order to track the rate of weight loss. Baseline and the average of the two 22 week follow up visit weights measured on a Detecto scale (Detecto, Webb City, MO) were used to determine total amount of weight lost. Percent compliance to the dietary intervention was determined by the RD by calculating the number of calories consumed daily (based on the self-reported food logs) relative to the estimated calories prescribed (about 1200). The amount of time spent wearing the vest daily and weight in the vest were collected in self-report weekly logs completed by the Diet+Vest group. This data was used to calculate percent compliance based on 10 hours per day goal in order to determine compliance to the weighted vest protocol. Weight in the vest was recorded weekly by research staff.

Bone mineral density. Dual-energy X-ray absorptiometry (DXA) (Delphi QDR; Hologic), was used to obtain measures of areal BMD (aBMD) at the total hip, femoral neck, and lumbar spine at baseline and follow up. All scans were performed and analyzed by an ISCD certified DXA technician who evaluated each scan for proper patient positioning and analysis. Coefficients of variation (CV) from repeated measurements are 1.38% for lumbar spine aBMD, 1.21 % for total hip aBMD and 1.82% for femoral neck aBMD.

Biomarkers of bone turnover. Systemic biomarkers of interest include; bone formation markers Osteocalcin (OC), Bone Specific Alkaline Phosphatase (BALP) and Procollagen Type 1 N-Terminal Propeptide (P1 NP) and bone resorption marker C-Terminal Telopeptide of Type 1 Collagen (CTX). All blood samples were drawn under standard fasting conditions at baseline (n=37) and follow up (n=33) and stored at -80°C until later analysis.

Both CTX and P1 NP were analyzed using enzyme-linked immunosorbent assay (ELISA) kits from Neo Scientific (Cambridge, MA). OC was analyzed using Quantikine ELISA kits from R&D systems (Minneapolis, MN). All samples were run in duplicate. The average of both readings was used for data analysis. BALP analyses were performed at a clinical laboratory (LabCorp, USA) following standard procedures.

Statistical analysis. Baseline demographic and clinical characteristics were summarized using descriptive measures by group and overall. Treatment effects on bone biomarkers and aBMD were estimated using general linear models both unadjusted and adjusted for baseline values of the outcome and gender. A correlation coefficient was calculated to determine the association of weight added to the vest and the amount of weight lost in the Diet+Vest group. As a pilot study, the study sample size was determined to generate estimates for future power calculations; therefore, all comparisons of treatment efficacy are considered exploratory rather than confirmatory, and a significance level of 0.05 is used throughout. All analyses were performed using SAS v9.4 (SAS Institute, Cary, NC).

Results.

Baseline characteristics. Thirty-three of the 37 randomly assigned participants (89%) completed the study. The retention of participants was not different between groups (Diet: 88%; Diet+Vest: 90%). Overall participants were aged 70.1 ± 3.0 years, 78.4% were female, 75.7% were white, and baseline BMI was 35.3 ± 2.9 kg/m2. No significant group differences were observed for baseline characteristics (Table 5). Data for baseline measures of bone health and associated reference ranges are provided in Table 5. Overall, values of DXA-acquired aBMD and biomarkers of bone turnover did not differ between groups.

Table 5. Participant Basline Characteristics.

Diet Only (n=17) Diet + Vest (n=20) Reference Ranges

Age (years) 69.9 ± 2.6 70.3 ± 3.4

Female, n (%) 14 (82.4) 15 (75.0)

White, n (%) 13 (76.5) 16 (80.0)

Weight (kg) 93.8 ± 11.5 99.4 ± 10.3

Body Mass Index (kg/m2) 35.3 ± 3.0 35.3 ± 2.8

DXA-acquired aBMD 0.85-1.25

(g/cm2)

Total Hip 0.94 ± 0.14 0.98 ± 0.13

Femoral Neck 0.74 ± 0.10 0.81 ± 0.12

Lumbar Spine 1.1 1 ± 0.19 1.16 ± 0.19

Biomarkers of Bone

Turnover

OC (ng/mL) 24.7 ± 15.3 27.3 ± 21.5 0-64

BALP (MQ/L) 15.5 ± 5.6 15.1 ± 5.2 7.4-25.4

P1 NP (ng/mL) 4.3 ± 2.4 4.8 ± 1.4 1.2-3.9

CTX (ng/mL) 6.8 ± 2.0 5.7 ± 2.6 0.8-5.3

Presented as means ± SD or n (%). Note: DXA-acquired aBMD: Duel Energy X-ray Absorptiometry acquired areal Bone Mineral Density; OC: Osteocalcin; BALP: Bone Specific Alkaline Phosphatase; P1 NP: Procollagen Type 1 N-Terminal Propeptide; CTX: C-Terminal Telopeptide of Type 1 Collagen

Intervention process measures. Both groups experienced similar and significant weight loss (Diet=-1 1.2 ± 4.4 kg; 1 1.9% and Diet+Vest= -11.0 ± 6.3 kg; 10.9%; both p<0.001 compared to baseline), with no difference between groups (p=0.91). Dietary compliance was high and similar between groups, with participants meeting daily caloric recommendations an average of 95.0 ± 9.2% of intervention days. The Diet+Vest group wore the vest for an average of 6.7 ± 2.2 h/day (range of 2.0-9.9 h/day). Overall, participants reported meeting the vest-wear goal of 10 hours/day for 67 ± 22% of the total intervention days. The weight in the vest averaged 6.3 ± 2.5 kg or 7.1 ± 3.0% of baseline body weight, which was strongly correlated to the individual amount of weight lost by participant (r=0.76).

Treatment effects on bone density and turnover. Data regarding 22 week treatment effects on regional DXA acquired aBMD, adjusted for baseline values of outcome and gender, can be viewed in Table 6 and are presented as means (95% CI). No significant differences were seen between groups in aBMD at the total hip, femoral neck or lumbar spine. However, trends toward significance were noted for changes in total hip aBMD, in that the Diet group experienced three times greater decreases as compared to the Diet +Vest group (-18.7 [-29.3, -8.1] mg/cm2 versus -6.1 [-15.7, 3.5] mg/cm2; p=0.08). The trend toward significance can also be seen in percent change in total hip aBMD, in that the Diet group saw a 1.9% decrease, while the Diet+Vest group experienced only a 0.6% decrease (p=0.08) (FIG. 1).

Data for 22 week treatment effects on biomarkers of bone turnover adjusted for baseline values of outcome and gender can be viewed in Table 6 and are presented as means (95% CI). No significant differences between groups were noted for changes in OC, BALP, P1 NP and CTX. Trends towards significance were noted for bone formation marker BALP, in that the Diet+Vest group experienced increases, while the Diet group decreased (0.59 [-0.33, 1.50] μg/L versus -0.70 [-1.70, 0.31] μg/L; p=0.07). Additionally, while not significant, biomarkers of formation OC and P1 NP appeared to increase or be attenuated in the Diet+Vest group compared to the Diet group (OC: 0.63 [-3.77, 5.03] ng/mL versus -0.07 [-4.89, 4.76] ng/mL; p=0.83, P1 NP:-0.06 [-0.47, 0.35] ng/L versus -0.24 [-0.71 , 0.24] ng/L; p=0.57).

The trend toward significance for biomarker BALP is more clearly depicted when expressed as percent change, in that the Diet+Vest group experienced a 3.8% increase, while the Diet group saw a 4.6% decrease (p=0.07) (FIG. 2). Stratification of aBMD and biomarker treatment effects by gender were also examined, with overall results largely aligning with the female subset due to the disproportionate about of women (78%) in the study sample.

Table 6. 22 week treatment effects on DXA-acquired regional BMD and biomarkers of bone turnover (Adjusted for Baseline Values of the Outcome and Gender)

Diet only Diet+Vest p-value

Mean (95% CI) Mean (95% CI)

Δ DXA-acquired

aBMD (mg/cm2)

Total Hip -18.7 (-29.3, -8.1) -6.1 (-15.7, 3.5) 0.08

Femoral Neck -9.8 (-23.3, 3.7) -11.9 (-24.1 , 0.3) 0.82

Lumbar Spine 22.9 (7.7, 38.0) 13.7 (-0.2, 27.5) 0.37

Δ Biomarkers of Bone

Turnover

OC (ng/mL) -0.07 (-4.89, 4.76) 0.63 (-3.77, 5.03) 0.83

BALP (MQ/L) -0.70 (-1.70, 0.31) 0.59 (-0.33, 1.50) 0.07

P1 NP (ng/mL) -0.24 (-0.71 , 0.24) -0.06 (-0.47, 0.35) 0.57

CTX (ng/mL) -0.1 1 (-0.45, 0.23) -0.03 (-0.33, 0.27) 0.73

BMD: areal Bone Mineral Density; OC: Osteocalcin; BALP: Bone Specific Alkaline

Phosphatase; P1 NP: Procollagen Type 1 N-Terminal Propeptide; CTX: C-Terminal Telopeptide of Type 1 Collagen

Discussion.

The use of a weighted vest to mimic gravitational loading for at least 1/4th of a day over a 22 week period, coupled with a dietary intervention protocol inducing an average weight loss among both groups of 11.3%, resulted in marginally attenuated losses in total hip aBMD in the Diet+Vest group (-6.1 mg/cm2 vs. -18.7 mg/cm2; p=0.08) and increased BALP (0.59 μg/L vs. -0.70 μg/L or +3.8% vs. -4.6%; p=0.07) compared to diet only. These provocative findings warrant replication from a larger, adequately powered trial.

To date, no study has examined the combination of weighted vest use during dietary weight loss on bone health, although several studies have examined components individually. Behavioral-based weight loss interventions (yielding 7-10% weight loss), for example, consistently result in a loss of hip aBMD to the order of 0.010 to 0.015 g/cm2 (2). This treatment effect is on par with what we observed in the Diet group (e.g., 0.019 g/cm2) and although smaller than what is considered clinically meaningful for fracture risk prediction (19), it is larger than what might be expected annually from advanced age alone (0.002-0.006 g/cm2/year) (20). Weighted vest use in weight stable adults has been shown to attenuate age-related loss in hip aBMD by around 0.025 g/cm2, when compared to active controls (21). Thus, original findings presented here showing modestly attenuated loss in hip aBMD by 0.013 g/cm2 when weighted vest use is coupled with weight loss, confirm and extend prior literature demonstrating the osteogenic potential of weighted vest use and may signal long term clinical significance.

Similarly, the effect of diet induced weight loss has been shown to affect biomarkers of bone turnover, in particular, those of bone resorption. Key findings from a recent meta-analysis show significant increases in both CTX and NTX of 4.72 nmol/L (95% CI, 2.12 to 7.30 nmol/L) and 3.70 nmol/L (95% CI, 0.90 to 6.50 nmol/L) for weight loss studies lasting 2 or 3 months in duration. This can indicate an early effect of diet induced weight loss to promote bone resorption that may have been missed in the present study due to biomarker measurement occurring only at baseline and 22 week follow up. Weighted vest use in weight stable adults has been shown to affect biomarkers of bone formation. A six week RCT conducted by Roghani et al. (17) saw increases in BALP of 7.3% (p=0.05) in the exercise and weighted vest group and 10.3% (p=0.03) in the exercise only group; compared to their sedentary control group who experienced a 1.9% decrease. In this Example, Diet+Vest group experienced a 3.8% increase in BALP, while the Diet group saw a 4.6% decrease (p=0.07).

Although not specifically designed to examine the effect of weighted vest use during intentional weight loss, it is worth discussing the present findings in light of the lone RCT of weighted vest use where weight loss was achieved through exercise alone (18). Jessup et al. (18) randomized healthy, Caucasian women to participate in a 32 week exercise program while wearing a weighted vest (up to 10% of baseline body weight) or to a sedentary control group. Women wearing the weighted vest lost 5% of their body weight, yet increased femoral neck aBMD by 1.7%, while sedentary controls decreased by 0.4% (p=0.02). Although participants in the Diet+Vest group of the present study did not experience increases in aBMD, total hip aBMD loss was attenuated in comparison to the Diet group (-0.6% versus- 1.9%, p=0.08), which supports an osteogenic role of weighted vest use. This minor discordance may be due to absolute weight loss differences (5% loss (18) versus 1 1 % loss in the present study) and fundamental differences between exercise-induced and diet-induced weight loss (22).

This Example measured aBMD at various sites and four biomarkers of bone turnover in order to provide a comprehensive assessment of the state of bone remodeling in response to treatment. Changes to bone biomarker CTX differed from that experienced in previous studies.

This Example can demonstrate the efficacy of weighted vest use during intentional weight loss to modestly attenuate loss in total hip aBMD while increasing bone formation.

References for Example 2.

1. Chaston TB, Dixon JB, O'Brien PE. Changes in fat-free mass during significant weight loss: A systematic review. Int J Obes (Lond) 2007;31 :743-750.

2. Zibellini J, Seimon RV, Lee CM, Gibson AA, Hsu MS, et al. Does diet-induced weight loss lead to bone loss in overweight or obese adults? A systematic review and meta-analysis of clinical trials. J Bone Miner Res. 2015;30:2168-2178. 3. Schwartz AV, Johnson KC, Kahn SE, Shepherd JA, Nevitt MC, et al. Effect of 1 year of an intentional weight loss intervention on bone mineral density in type 2 diabetes: Results from the Look AHEAD randomized trial. J Bone Miner Res. 2012;27:619-627.

4. Villareal DT, Fontana L, Das SK, Redman L, Smith SR, et al. Effect of two year caloric restriction on bone metabolism and bone mineral density in non-obese younger adults: A randomized clinical trial. J Bone Miner Res. 2016;31 :40-51.

5. Ensrud KE, Ewing SK, Stone KL, Cauley JA, Bowman PJ, et al. Intentional and unintentional weight loss increase bone loss and hip fracture risk in older women. J Am Geriatr Soc. 2003;51 :1740-1747.

6. Ensrud KE, Fullman RL, Barrett-Connor E, Cauley JA, Stefanick ML, et al. Voluntary weight reduction in older men increases hip bone loss: the osteoporotic fractures in men study. J Clin Endocrinol Metab. 2005;90:1998-2004.

7. Mussolino ME, Looker AC, Madans JH, Langlois JA, Orwoll ES. Risk factors for hip fracture in white men: The NHANES I epidemiologic follow-up study. J Bone Miner Res. 1998; 13:918- 924.

8. Langlois JA, Mussolino ME, Visser M, Looker AC, Harris T, et al. Weight loss from maximum body weight among middle-aged and older white women and the risk of hip fracture: The NHANES I epidemiologic follow-up study. Osteoporos Int. 2001 ; 12:763-768.

9. Bolam KA, van Uffelen JG, Taaffe DR. The effect of physical exercise on bone density in middle-aged and older men: A systematic review. Osteoporos Int. 2013;24:2749-2762.

10. Kohrt WM, Bloomfield SA, Little KD, Nelson ME, Yingling VR, et al. American college of sports medicine position stand: Physical activity and bone health. Med Sci Sports Exerc. 2004;36:1985-1996.

11. Beavers DP, Beavers KM, Loeser RF, Walton NR, Lyles MF, et al. The independent and combined effects of intensive weight loss and exercise training on bone mineral density in overweight and obese older adults with osteoarthritis. Osteoarthritis Cartilage. 2014;22:726- 733.

12. Shah K, Armamento-Villareal R, Parimi N, Chode S, Sinacore DR, et al. Exercise training in obese older adults prevents increase in bone turnover and attenuates decrease in hip bone mineral density induced by weight loss despite decline in bone-active hormones. J Bone Miner Res. 2011 ;26:2851-2859.

13. Villareal DT, Shah K, Banks MR, Sinacore DR, Klein S. Effect of weight loss and exercise therapy on bone metabolism and mass in obese older adults: A one year randomized controlled trial. J Clin Endocrinol Metab. 2008;93:2181-2187. 14. Center for Disease Control and Prevention. Facts about physical activity. 2016.

15. Courteix D, Valente-dos-Santos J, Ferry B, Lac G, Lesourd B, et al. Multilevel approach of a

1 year program of dietary and exercise interventions on bone mineral content and density in metabolic syndrome-The RESOLVE randomized controlled trial. PLoS ONE. 2015; 10:e0136491.

16. Frost HM. Bone "mass" and the "mechanostat": A proposal. Anat Rec. 1987;219: 1-9.

17. Roghani T, Torkaman G, Movasseghe S, Hedayati M, Goosheh B, et al. Effects of short- term aerobic exercise with and without external loading on bone metabolism and balance in post-menopausal women with osteoporosis. Rheumatol Int. 2013;33:291-298.

18. Jessup JV, Home C, Vishen RK, Wheeler D. Effects of exercise on bone density, balance and self-efficacy in older women. Biol Res Nurs. 2003;4: 171-180.

19. Cefalu CA. Is bone mineral density predictive of fracture risk reduction? Curr Med Res Opin. 2004;20:341-349.

20. Warming L, Hassager C, Christiansen C. Changes in bone mineral density with age in men and women: a longitudinal study. Osteoporos Int. 2002; 13: 105-1 12.

21. Snow CM, Shaw JM, Wnters KM, Wtzke KA. Long-term exercise using weighted vests prevents hip bone loss in postmenopausal women. J Gerontol A Biol Sci Med Sci. 2000;55:M489-491.

22. Villareal DT, Fontana L, Weiss EP, Racette SB, Steger-May K, et al. Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: A randomized controlled trial. Arch Intern Med. 2006; 166:2502-2510.

Example 3.

About two years following completion of the intitial period of caloric restriction for weight loss as described in Examples 1 and 2, some of the subjects from each of the groups (Vest plus Diet and Diet only groups) were reevaluated. There was an equal distribution of returnees between Vest plus Diet and Diet only groups (n=9, each group). Two thirds of the Vest plus Diet group were female (n=6). All of the Diet only group that returned for reevaluation were female (n=9). The average follow-up time was 25.1 ± 3.6 months for the Vest plus Diet group. The average follow-up time was 25.8 ± 2.4 months for the Diet only group. The range for follow-up time was 19-31 months.

Table 7 shows some of the results observed in the subjects that returned approximately

2 years post initial trial. The amount of weight regained during the follow-up in the subjects was about 2-fold more in the Diet only group as compared to the Vest plus Diet group. The Diet only group regained on average about 1 1.2 kg/per subject and the Vest plus Diet group regained on average about 6.4 kg/per subject. No difference across gender could be detected. The final weight change (after the approximate 25 month follow-up period) was positive (+1.4 kg) for the Diet only group and negative (-5.2 kg) for the Vest plus Diet group. Again, no gender

differences were observed. The RMR returned to baseline with weight regain in the Diet only group. However, there was no change in RMR from where RMR was at the end of the 22 week trial period (as described in Examples 1 and 2) in the group that had worn the vest while dieting. The amount of weight regained was observed to correlate with changes in RMR with weight loss (WL) (FIGS. 5A-5B, R = -0.39, p = 0.11 ,; without outlier of 600 kcal /day decrease in RMR: R = -0.43; p = 0.09).

Table 7. Post-Trial Weight Gain

No Vest/Diet only (n=9; female=9)

Baseline Post AWL Recall AWG Total WL

Body

93.6±14.1 83.8±12.0 -9.8±4.9 95.0±18.7 11.2±7.6 +1.4±6.7

Weight (kg)

RMR

1366±305 1136±272 -230±161 1364±252 228±234 -1±296 (kcal/d)

%fat 48.5±2.6 45.7±2.2 49.5±3.0

Vest + Diet (n=9; females=6)

Body

100.0±8.8 88.4±7.9 -11.6±5.7 94.8±7.3 6.4±5.3 -5.2±5.6

Weight (kg)

RMR

1430±168 1406±154 -24±83 1419±298 13±238 -11 ±245 (kcal/d)

%fat 45.4±7.5 42.1 ±7.8 45.1 ±7.1

The present disclosure will be better understood upon review of the following features, which should not be confused with the claims.

Feature 1. A method of attenuating a decrease of resting metabolic rate in a subject undergoing caloric restriction, the method comprising: (a) measuring a reference/initial body weight of the subject; (b) Administering an amount of external weight to the subject for an amount of time per day for at least one week during the period of caloric restriction, wherein the amount of external weight is added by coupling an external or internal apparatus to the subject;

(c) re-measuring the body weight of the subject after at least one week of caloric restriction; and

(d) increasing the amount of external weight administered to the subject such that a sum of the body weight of the subject and the external weight is within about ± 20 percent of the reference body weight obtained in step (a).

Feature 2. The method of Feature 1 , wherein steps (b)-(d) are repeated one or more times.

Feature 3. The method of any one of Features 1-2, wherein steps (b)-(d) are repeated daily.

Feature 4. The method of any one of Features 1-3, wherein steps (b)-(d) are repeated 1-365 times.

Feature 5. The method of any one of Features 1-4, wherein steps (b)-(d) are repeated weekly.

Feature 6. The method of any one of Features 1-5, wherein steps (b)-(d) are repeated 1-52 times.

Feature 7. The method of any one of Features 1-6, wherein steps (b)-(d) are repeated until a desired amount of weight loss in the subject is achieved.

Feature 8. The method of any one of Features 1-7, wherein the subject is 65 years of age or older.

Feature 9. The method of any one of Features 1-8, wherein the subject has a body mass index greater than about 25 kg/m2 prior to performing step (a) for the first time.

Feature 10. The method of any one of Features 1-9, wherein the subject has a body mass index ranging from about 25 kg/m2 to about 40 kg/m2 prior to performing step (a) for the first time.

Feature 11. The method of any one of Features 1-10, wherein the caloric restriction comprises the subject consuming about 800 kcal/day to about 2000 kcal/day or about 1 100 kcal/day to about 1300 kcal/day.

Feature 12. The method of any one of Features 1-11 , wherein the apparatus comprises a vest, a belt, a strap, a cuff, a pair of pants or shorts, an undergarment, a shirt, a jacket, a sock or pair of socks, or a shoe or pair of shoes, or any combination thereof.

Feature 13. The method of any one of Features 1-12, wherein the apparatus is configured to receive one or more weights.

Feature 14. The method of c any one of Features 1-13, wherein the apparatus weighs about 0.1 kg to about 2.0 kg.

Feature 15. The method of any one of Features 1-14, wherein the apparatus weighs about 0.5 kg. Feature 16. The method of any one of Features 1-15, wherein a bone mineral density loss in the subject is less than a reference bone mineral density loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.

Feature 17. The method of any one of Features 1-16, wherein a bone formation in the subject is increased.

Feature 18. The method of any one of Features 1-17, wherein a bone formation in the subject is increased.

Feature 19. The method of any one of Features 1-18, wherein a loss of muscle strength loss in the subject is less than a reference muscle strength loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.

Feature 20. A method of attenuating a decrease in a resting metabolic rate attributed to weight loss or caloric restriction in a subject undergoing caloric restriction, the method comprising: adding an amount of external weight to the subject for a period of time per day for a number of days, wherein a sum of the bodyweight of the subject and the amount of external weight does not exceed 20 percent of a starting bodyweight of the subject, and wherein the amount of external weight, the period of time per day, and the number of days is effective to attenuate the decrease in the resting metabolic rate in the subject.

Feature 21. The method of Feature 20, wherein the number of days ranges from 1- 365 days.

Feature 22. The method of any one of Features 20-21 , wherein the number of days is

7 days.

Feature 23. The method of any one of Features 20-22, wherein the amount of external weight ranges from about 0.1 kg to about 20 kg.

Feature 24. The method of any one of Features 20-23, wherein the amount of external weight ranges from about 1 percent to about 15 percent of the subject's starting bodyweight prior adding any amount of external weight to the subject.

Feature 25. The method of any one of Features 20-24, wherein the period of time per day ranges from about 6 hours to about 10 hours.

Feature 26. The method of any one of Features 20-25, wherein the period of time per day is about 4 to about 8 hours. Feature 27. The method of any one of Features 20-26, wherein the period of time per day is about 6 hours.

Feature 28. The method of any one of Features 20-27, further comprising the step of increasing the amount of external weight added to the subject after the number of days, wherein the total amount of external weight added does not exceed 15 % of the subject's starting bodyweight.

Feature 29. The method of any one of Features 20-28, wherein the number of days is 1-365 days.

Feature 30. The method of any one of Features 20-29, wherein the number of days is

7 days.

Feature 31. The method of any one of Features 20-30, wherein the amount of external weight is increased by 0.1 to 5.0 kg.

Feature 32. The method of any one of Features 20-31 , wherein the amount of external weight is increased by an amount that is about 1-20 % of the subject's starting bodyweight.

Feature 33. The method of any one of Features 20-32, further comprising the step of weighing the subject after the number of days and increasing the amount of external weight added to the subject such that a sum of the bodyweight of the subject and the amount of external weight does not exceed 15 percent of the starting bodyweight of the subject.

Feature 34. The method of any one of Features 20-33, wherein the steps of weighing the subject after the number of days and increasing the amount of external weight added to the subject are repeated a number of times.

Feature 35. The method of any one of Features 20-34, wherein the number of days is 1-28 days.

Feature 36. The method of any one of Features 20-35, wherein the number of days is

7 days.

Feature 37. The method of any one of Features 20-36, wherein the number of times the steps are repeated is 1-50.

Feature 38. The method of any one of Features 20-37, wherein the subject has a body mass index of about 30 kg/m2 or greater prior to adding the amount of external weight to the subject.

Feature 39. The method of any one of Features 20-38, wherein the subject has a body mass index of about 25 kg/m2 to about 40 kg/m2 prior to adding the amount of external weight to the subject. Feature 40. The method of any one of Features 20-39, wherein the subject is about 65 years of age or older.

Feature 41. The method of any one of Features 20-40, wherein a bone mineral density loss in the subject is less than a reference bone mineral density loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.

Feature 42. The method of any one of Features 20-41 , wherein a bone formation in the subject is increased.

Feature 43. Use of an apparatus configured to provide a gravitational load or apply an external weight to a subject for a period of time per day for the attenuation of a decrease in resting metabolic rate attributed to weight loss or caloric restriction in the subject.

Feature 44. The method of any one of any one of Features 1-43, wherein a weight loss in the subject is within about 10% of a reference weight loss of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.

Feature 45. The method of any one of Features 1-44, wherein the attenuating the decrease in the resting metabolic rate of the subject comprises a change in the resting metabolic rate of not more than 15%, 10%, or 5%.

Feature 46. The method of any one of Features 1-45, wherein a decrease in the resting metabolic rate of the subject is about 50% less than a reference decrease in resting metabolic rate of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.

Feature 47. The method of any one of Features 1-46, wherein a weight loss in the subject is within about 10% of a reference weight loss of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.

Claims

We Claim:
1. A method of attenuating a decrease of resting metabolic rate in a subject undergoing caloric restriction, the method comprising:
(a) measuring a reference/initial body weight of the subject;
(b) Administering an amount of external weight to the subject for an amount of time per day for at least one week during the period of caloric restriction, wherein the amount of external weight is added by coupling an external or internal apparatus to the subject;
(c) re-measuring the body weight of the subject after at least one week of caloric restriction; and
(d) increasing the amount of external weight administered to the subject such that a sum of the body weight of the subject and the external weight is within about ± 20 percent of the reference body weight obtained in step (a).
2. The method of claim 1 , wherein steps (b)-(d) are repeated one or more times.
3. The method of claim 1 , wherein steps (b)-(d) are repeated daily.
4. The method of claim 3, wherein steps (b)-(d) are repeated 1-365 times.
5. The method of claim 1 , wherein steps (b)-(d) are repeated weekly.
6. The method of claim 5, wherein steps (b)-(d) are repeated 1-52 times.
7. The method of claim 1 , wherein steps (b)-(d) are repeated until a desired amount of weight loss in the subject is achieved.
8. The method of any one of claims 1-7, wherein the subject is 65 years of age or older.
9. The method of any one of claims 1-7, wherein the subject has a body mass index greater than about 25 kg/m2 prior to performing step (a) for the first time.
10. The method of any one of claims 1-7, wherein the subject has a body mass index ranging from about 25 kg/m2 to about 40 kg/m2 prior to performing step (a) for the first time.
11. The method of any one of claims 1-7, wherein the caloric restriction comprises the subject consuming about 800 kcal/day to about 2000 kcal/day or about 1 100 kcal/day to about 1300 kcal/day.
12. The method of any one of claims 1-7, wherein the apparatus comprises a vest, a belt, a strap, a cuff, a pair of pants or shorts, an undergarment, a shirt, a jacket, a sock or pair of socks, or a shoe or pair of shoes, or any combination thereof.
13. The method of claim 12, wherein the apparatus is configured to receive one or more weights.
14. The method of claim 12, wherein the apparatus weighs about 0.1 kg to about 2.0 kg.
15. The method of claim 12, wherein the apparatus weighs about 0.5 kg.
16. The method of any one of claims 1-7, wherein a bone mineral density loss in the subject is less than a reference bone mineral density loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.
17. The method of claim 16, wherein a bone formation in the subject is increased.
18. The method of any one of claims 1-7, wherein a bone formation in the subject is increased.
19. The method of any one claims 1-7, wherein a loss of muscle strength loss in the subject is less than a reference muscle strength loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.
20. A method of attenuating a decrease in a resting metabolic rate attributed to weight loss or caloric restriction in a subject undergoing caloric restriction, the method comprising:
adding an amount of external weight to the subject for a period of time per day for a number of days, wherein a sum of the bodyweight of the subject and the amount of external weight does not exceed 20 percent of a starting bodyweight of the subject, and wherein the amount of external weight, the period of time per day, and the number of days is effective to attenuate the decrease in the resting metabolic rate in the subject.
21. The method of claim 20, wherein the number of days ranges from 1-365 days.
22. The method of claim 20, wherein the number of days is 7 days.
23. The method of claim 20, wherein the amount of external weight ranges from about 0.1 kg to about 20 kg.
24. The method of claim 20, wherein the amount of external weight ranges from about 1 percent to about 15 percent of the subject's starting bodyweight prior adding any amount of external weight to the subject.
25. The method of any one of claims 20-24, wherein the period of time per day ranges from about 6 hours to about 10 hours.
26. The method of claim 25, wherein the period of time per day is about 4 to about 8 hours.
27. The method of claim 26, wherein the period of time per day is about 6 hours.
28. The method of claim 21 , further comprising the step of increasing the amount of external weight added to the subject after the number of days, wherein the total amount of external weight added does not exceed 15 % of the subject's starting bodyweight.
29. The method of claim 28, wherein the number of days is 1-365 days.
30. The method of claim 28, wherein the number of days is 7 days.
31. The method of any one of claims 28-30, wherein the amount of external weight is increased by 0.1 to 5.0 kg.
32. The method of any one of claims 28-30, wherein the amount of external weight is increased by an amount that is about 1-20 % of the subject's starting bodyweight.
33. The method of claim 21 , further comprising the step of weighing the subject after the number of days and increasing the amount of external weight added to the subject such that a sum of the bodyweight of the subject and the amount of external weight does not exceed 15 percent of the starting bodyweight of the subject.
34. The method of claim 33, wherein the steps of weighing the subject after the number of days and increasing the amount of external weight added to the subject are repeated a number of times.
35. The method of any one of claims 33-34, wherein the number of days is 1-28 days.
36. The method of any one of claims 33-34, wherein the number of days is 7 days.
37. The method of claim 36, wherein the number of times the steps are repeated is
1-50.
38. The method of claim 21 , wherein the subject has a body mass index of about 30 kg/m2 or greater prior to adding the amount of external weight to the subject.
39. The method of claim 21 , wherein the subject has a body mass index of about 25 kg/m2 to about 40 kg/m2 prior to adding the amount of external weight to the subject.
40. The method of claim 21 , wherein the subject is about 65 years of age or older.
41. The method of claim 21 , wherein a bone mineral density loss in the subject is less than a reference bone mineral density loss for the otherwise same subject undergoing the otherwise same caloric restriction except without the administered external weight.
42. The method of claim 21 , wherein a bone formation in the subject is increased.
43. Use of an apparatus configured to provide a gravitational load or apply an external weight to a subject for a period of time per day for the attenuation of a decrease in resting metabolic rate attributed to weight loss or caloric restriction in the subject.
44. The method of any one of claims 1-7 and 20-24, wherein a weight loss in the subject is within about 10% of a reference weight loss of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.
45. The method of any one of claims 1-7 and 20-24, wherein the attenuating the decrease in the resting metabolic rate of the subject comprises a change in the resting metabolic rate of not more than 15%, 10%, or 5%.
46. The method of any one of claims 1-7 and 20-24, wherein a decrease in the resting metabolic rate of the subject is about 50% less than a reference decrease in resting metabolic rate of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.
47. The method of claim 46, wherein a weight loss in the subject is within about 10% of a reference weight loss of the otherwise same subject undergoing the same caloric restriction for the same period of time except without the external weight.
PCT/US2018/043063 2017-07-20 2018-07-20 Methods of attenuating undesirable metabolic adaptations to weight loss induced by caloric restriction WO2019018752A1 (en)

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Arthritis Pilot for Preserving Muscle While Losing Weight (APPLE", WAKE FOREST UNIVERSITY HEALTH SCIENCES, 15 September 2014 (2014-09-15) *
GUPTA, S, MD: "Balance Is Restored by Weighting the Body", EVERYDAYHEALTH.COM, 4 June 2013 (2013-06-04), pages 3 - 9, XP055563700, Retrieved from the Internet <URL:https://www.everydayhealth.com/hs/sanjay-gupta/balance-is-restored-by-weighting-the-body/> *
NORMANDIN, E ET AL.: "Effect of Resistance Training and Caloric Restriction on the Metabolic Syndrome", MED SCI SPORTS EXERC, vol. 49, no. 3, March 2017 (2017-03-01), pages 413 - 419 *

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