WO2020096002A1 - D-アルロースを有効成分とする褐色脂肪・ベージュ脂肪細胞活性化剤 - Google Patents
D-アルロースを有効成分とする褐色脂肪・ベージュ脂肪細胞活性化剤 Download PDFInfo
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Definitions
- the present invention relates to a brown fat / beige fat cell activator. More specifically, it relates to a brown fat / beige adipocyte activator containing D-allulose.
- ⁇ Mammalian adipose tissue is classified into two groups, white adipose tissue and brown adipose tissue, according to their function and histological characteristics.
- white adipocytes existing therein accumulate excess energy in the body as fat.
- brown adipocytes have a function of burning fat and producing heat.
- the physiological role of brown adipose tissue is completely opposite to that of white adipocytes, and is a site where energy is consumed and dissipated as heat by sympathetic nerve stimulation.
- brown adipose tissue there are brown adipose cells characterized by having multilocular lipid droplets and abundant mitochondria, and UCP-1 [uncoupling protein 1 (Uncoupling Protein 1 (Uncoupling Protein 1 protein 1)] has the function of dissipating energy as heat.
- Brown adipose tissue is particularly abundant in newborns and hibernators. Its main function is for animals and newborns to generate body heat without trembling.
- white adipocytes which contain single fat droplets
- brown adipocytes contain iron, which is brown and contains numerous small droplets and a much higher number of mitochondria. Has been. Because brown adipose tissue requires more oxygen than most tissues, it has more capillaries than white adipose tissue.
- catechins contained in tea etc. and capsaicin contained in capsicum etc. have an action of activating brown adipose tissue, and a further substance having a high effect of activating brown adipocytes is desired.
- the rare sugar has an action of activating brown adipose-like cells.
- Brown adipocytes are believed to function in addition to burning energy and warming the body at low temperatures, as well as increasing energy consumption and facilitating the burning of fat. That is, if a method for activating brown adipocytes is found, it may be a new therapeutic method for controlling obesity and type 2 diabetes.
- An object of the present invention is to provide a preparation having a high activating effect on brown adipocytes.
- Brown adipocytes in addition to having the function of burning energy at low temperatures to warm the body, are believed to have the function of increasing energy consumption and making fat burn easier. Focusing on the function of cells, that is, if a method of activating brown adipocytes is found, it may be a new therapeutic method for controlling obesity and type 2 diabetes, and as a result of intensive research, brown by administration of rare sugars was found. With the knowledge of adipocyte activation and accompanying weight loss, the inventors have invented a brown adipocyte activator containing D-allulose as an active ingredient.
- activation of brown adipocytes means an action of promoting the induction of differentiation of brown adipocytes (beige adipocytes) into white adipose tissue, and / or beige adipocytes or brown adipocytes. In the above, it refers to the effect of promoting energy consumption, and can also be referred to as activation of brown fat and beige adipocytes.
- the gist of the present invention is the following brown fat / beige adipocyte activators (1) to (3). (1) A brown fat / beige adipocyte activator containing D-allulose as an active ingredient.
- the gist of the present invention is the following energy consumption promoter (4) or (5).
- the gist of the present invention is the following UCP-1 expression enhancer (6).
- UCP-1 expression enhancer (6) A UCP-1 expression enhancer containing D-allulose as an active ingredient.
- the gist of the present invention is the following compositions (7) to (11).
- (7) A composition containing the agent according to any one of (1) to (6) above.
- (8) A composition for activating brown fat / beige adipocytes, which contains D-allulose as an active ingredient.
- the composition according to (7) or (8) above for promoting the consumption of energy by heat production.
- (11) The composition according to any of (7) to (10) above, wherein the composition is a food composition.
- brown fat / beige adipocytes such as brown fat / beige adipocyte activator containing D-allulose as an active ingredient, energy consumption promoter and UCP-1 expression enhancer.
- a formulation can be provided.
- the present invention also provides a composition and a food composition containing a brown fat / beige adipocyte activator containing D-allulose as an active ingredient, an energy consumption promoter, and a UCP-1 expression enhancer. it can. Further, a composition for activating brown fat / beige adipocytes, which contains D-allulose as an active ingredient, a composition for activating brown fat / beige adipocytes by enhancing the expression of UCP-1, a food composition, etc. To provide a composition and a food composition having a UCP-1 expression promoting action and / or a brown fat / beige adipocyte differentiation promoting action which can be taken for a long time and continuously without causing side effects. You can
- FIG. 3 is a drawing showing changes in body weight and changes in blood glucose level in the experiment of Example 1 using 6-week-old mice.
- a high fat diet HFD
- HFD high fat diet
- the HFD group was given water containing 2% D-allulose
- a decrease in body weight was observed.
- the blood glucose level was measured over time in 8 weeks.
- the blood glucose level in the HFD group was higher than that in the normal group.
- the blood glucose level of the HFD + D-allulose group was lower than that of the HFD group, compared to the HFD group.
- Example 1 is a drawing showing the size and weight of brown adipocytes under the scapula and the body weight in the experiment of Example 1 using 6-week-old mice. Furthermore, it is a drawing (an image of an electron micrograph) showing the results of pathological examination of brown adipose tissue in three groups. Compared to the normal diet group, in the HFD group, fat deposition was observed in BA and white fat was observed. On the other hand, in the HFD group + 2% D-allulose group, it was found that the brown adipose tissue was morphologically comparable to that of the normal diet group, and the brown adipose tissue converted to white fat was recovered to a normal brown adipose tissue. ..
- Example 1 is a drawing showing the expression level of UCP-1 for activation of brown adipocytes in the experiment of Example 1 using 6-week-old mice.
- UCP-1 was increased in the HFD group. It was expected that UCP-1 was induced and calories were consumed as a defense reaction of the body when a large amount of fat was ingested.
- Administration of D-allulose further induced UCP-1.
- the induction of UCP-1 in the HFD group is a response to a pathological situation
- the HFD group + 2% D-allulose group the normal morphology indicates that brown adipose tissue Is assumed to be the activation of UCP-1 as a result of activation.
- FIG. 1 is a drawing showing the expression level of PPAR- ⁇ for activating brown adipocytes in the experiment of Example 1 using 6-week-old mice.
- PPAR- ⁇ is an indicator of brown adipocyte activation.
- PPAR- ⁇ was induced in the HFD group as compared with the normal group, but this seems to be a reaction of the body due to excessive lipid intake.
- HFD group + 2% D-allulose group ingestion of D-allulose more strongly induced PPAR- ⁇ , and it seems that brown adipocytes were activated.
- 1 is a drawing showing the expression level of PGC-1 ⁇ for activating brown adipocytes in the experiment of Example 1 using 6-week-old mice.
- PGC-1 ⁇ was induced in the HFD group as compared to the normal group, but this seems to be a reaction of the body due to excessive lipid intake.
- PGC-1 ⁇ was more strongly induced by ingestion of D-allulose, and PGC-1 ⁇ , which is a co-activator of PPAR- ⁇ , was induced in the downstream region of UCP-1. It is thought that this is one of the causes of the induction of erythrocyte and that brown adipocytes are activated.
- 3 is a drawing showing changes in body weight in the human clinical test of Example 2.
- Adipocytokine physiologically active substances
- Adipocytokine is known to be cells that produce and release numerous cytokines (bioactive substances) as well as energy storage sources. Cytokines produced and released from adipocytes are called adipocytokines. Adipocytokines are also deeply involved in metabolic syndrome. TNF (tumor necrosis factor) - ⁇ causes phosphorylation of IRS-1 and causes insulin resistance. Adiponectin is known to have an inhibitory effect on obesity, diabetes and arteriosclerosis, and is considered to be good. It is known that the values are decreased in obesity and diabetes.
- TNF- ⁇ is famous as a cytokine that is secreted from adipocytes and induces insulin resistance. It is also known to suppress adiponectin, which is a good adipocytokine. It is speculated that administration of D-allulose (D-psicose) in the present example lowers TNF- ⁇ , thereby improving insulin resistance and improving blood glucose control.
- mice are divided into two groups as one group. Both groups of 8 week old mice are loaded with a high fat diet (HFD). From 4 weeks after the HFD loading, the 1 group continues HFD as it is.
- HFD high fat diet
- D-allulose 0.2 mg / body weight / day
- 5 is a drawing showing changes in body weight (Body Weight) when a normal diet (Normal fod) and a high fat diet (HFD) were loaded in the mouse of Example 3.
- FIG. 5 is a drawing showing changes in body weight (BW) when D-allulose was administered to mice loaded with a high fat diet (HFD) in Example 3.
- BW body weight
- HFD high fat diet
- 7 is a drawing showing a transition of fasting blood glucose level in Example 3. In the D-allulose addition group, the fasting blood glucose level tended to decrease.
- 5 is a drawing showing changes in blood glucose level of a glucose tolerance test after 10 weeks of Example 3.
- FIG. In the glucose tolerance test the fasting blood glucose level and the blood glucose levels at 90 minutes and 120 minutes after loading were significantly low.
- 5 is a drawing showing food intake (right side diagram) and water intake (left side diagram) during the study period of Example 3.
- FIG. 5 is a drawing showing weight and area standardized by body weight of brown adipose tissue (BAT) when D-allulose was administered to mice loaded with a high fat diet (HFD) of Example 3.
- Distribution and function of brown adipose tissue (Distribution and function®n brfwn adiposese tissue) -burning energy for generating heat (Burn energy for thermal genesis) (extracted from Non-Patent Document 3).
- UCP-1 protein expression is also increased in classical brown adipose tissue.
- genes UCP-1, Prdm16 involved in heat production, and Pgcl- ⁇ gene reflecting organelle mitochondrial function involved in heat production It is a figure which shows the expression level of Tfam and the gene PPAR (gamma) related to the differentiation of fat.
- BAT-protocol, WAT-protocol for experiments with cells using a model of a cell line derived from a single clone from adult supraclavicular BAT and establishing a beige adipocyte differentiation induction study) 2 is a drawing explaining a protocol for inducing beige adipocytes.
- the WAT-protocol has a stronger effect on the induction of browning marker genes (UCP-1, Pgc-1 ⁇ , cox8b).
- D-allulose enhances Prdm16, Pgc-1 ⁇ , and PPAR ⁇ expression.
- D-allulose enhances PPAR ⁇ expression, suggesting that D-allulose promotes adipogenesis.
- expression of UCP-1 and PPAR ⁇ was examined in the presence and absence of D-allulose, and the results are shown. It was shown that the presence of D-allulose increased UCP-1 and PPAR ⁇ and promoted the induction of beige adipocytes.
- WAT-Protocol has a stronger effect on the induction of UCP-1 protein expression.
- D-allulose slightly enhances UCP-1 protein expression.
- brown adipocytes include both classical brown adipocytes formed in the fetal period and brown adipocytes (also referred to as beige adipocytes or bright cells) that are induced to differentiate into white adipose tissue. Point to. That is, in the present invention, not only classical brown adipocytes in a narrow sense but also brown-like adipocytes induced in white adipose tissue are called brown adipocytes. In addition, brown-like adipocytes induced in white adipose tissue may be particularly referred to as beige adipocytes or brown adipocytes.
- White fat cells have large unicellular fat droplets and a low cytoplasm.
- brown adipocytes have small multilocular lipid droplets, and many mitochondria are present around these multilocular lipid droplets, and as a result, they have a unique brown color and are rich in sympathetic nerves and blood vessels. It has morphological and histological characteristics. Therefore, white adipocytes and brown adipocytes can be distinguished by observing the cells morphologically and histologically. There is also a difference in that white fat stores energy, but brown fat cells consume and dissipate energy as heat.
- brown adipocytes have a higher energy metabolism than white adipocytes, and release energy as heat, thereby increasing glucose uptake. Therefore, the presence of brown adipocytes can be evaluated, for example, by measuring the accumulation of glucose labeled with 18F by PET (positron emission tomography). Furthermore, in brown adipocytes, a 33 kDa protein called uncoupling protein 1 (UCP-1) is specifically expressed in the inner mitochondrial membrane of cells, so the expression of UCP-1 mRNA and UCP-1 protein were measured. By doing so, the presence of brown adipocytes can be confirmed.
- UCP-1 uncoupling protein 1
- beige fat cells Morphologically, beige adipocytes are similar to brown adipocytes, have intracellular multilocular lipid droplets, and are rich in mitochondria expressing the specific protein UCP-1. In contrast to white adipocytes, which have unicellular lipid droplets and are poor in cytoplasm. In terms of functional characteristics, unlike white adipocytes that store excess energy as neutral fat, brown adipocytes and beige adipocytes produce heat by uncoupling oxidative phosphorylation by UCP-1. .. In these respects, beige adipocytes are similar to brown adipocytes, but in the following points, they are rather close to white adipocytes.
- brown adipocytes are localized by forming cell clusters in the interscapular region and around the kidney, whereas beige adipocytes are induced and scattered in white adipose tissue such as the groin. Appear. This phenomenon is referred to as the browning of white fat.
- brown adipocytes are derived from muscle precursor cells that express ⁇ y Mothergenfactor 5 ( ⁇ yf5), which is common with skeletal muscle, whereas beige adipocytes, like white adipocytes, are ⁇ yf5-negative and plate-delivered. It is derived from a preadipocyte expressing gr? wt factor? receptor?
- Brown adipocytes and beige adipocytes have similar characteristics to those of brown adipocytes and white adipocytes, which are contrary to each other. Be done. Brown adipocytes and beige adipocytes contribute to maintaining body temperature in a cold environment as special adipocytes that generate heat in response to cold exposure. The heat-producing and energy-consuming activities possessed by these adipocytes are expected to be useful not only for regulating body temperature but also for preventing obesity and metabolic diseases. Brown adipocytes and beige adipocytes express the uncoupling protein (UCP-1) in common and have the ability to generate heat, but it has been revealed that the origin and function control mechanism of cells are different. ing. In particular, the fact that brown adipose tissue (BAT) of human adult is mainly composed of beige adipocytes is considered to be important in searching for an obesity prevention method targeting BAT.
- UCP-1 uncoupling protein
- activation of brown adipocytes means an action of promoting induction of differentiation of brown adipocytes (beige adipocytes) into white adipose tissue, and / or energy in beige adipocytes or brown adipocytes. It refers to the effect of promoting consumption.
- Activation of brown adipocytes may, among other things, increase metabolism in beige and brown adipocytes, promote energy expenditure, and convert fatty acids into heat energy. The conversion of fatty acids into heat energy is sometimes performed by UCP-1. As described above, activation of brown adipocytes may be expressed as activation of brown fat / beige adipocytes.
- the brown adipocyte activator refers to a substance having the above-described brown adipocyte activating effect.
- the presence of brown adipocytes and / or the increase in energy metabolism of brown adipocytes can be measured by measuring UCP-1 mRNA expression or UCP-1 protein, observing cells histologically, 18F It can be evaluated by measuring the accumulation of labeled glucose by PET, measuring cold-induced heat production, and the like.
- the induction of differentiation of brown adipose-like cells (beige adipocytes) into white adipose tissue is sometimes called reactivation of brown adipocytes in particular.
- the brown adipocyte activator of the present invention can promote metabolism of energy by heat production.
- Energy metabolism includes basal metabolism, exercise, daily living activities, and heat production. About 60% of daily energy consumption is due to basal metabolism, about 5% to exercise, about 24% to daily living activities, and about 10% to heat production.
- energy consumption due to heat production is for the body to respond to a sudden temperature change, and is increased by, for example, cold stimulation. It is also known to increase heat production by food intake and to generate heat to generate fever to counter infection and inflammation.
- energy consumption due to heat production means metabolic energy consumption consumed for heat production corresponding to cold stimulation, food intake, etc., which is not due to basal metabolism or muscle exercise.
- the brown adipocyte activator of the present application may increase the heat production in beige adipocytes or brown adipocytes by stimulating the sympathetic nerve, thereby promoting energy metabolism. Such heat production may occur by converting fatty acids into heat energy, and conversion of fatty acids into heat energy may be performed by UCP-1.
- the brown adipocyte activator, energy consuming agent and the like of the present invention, and compositions containing them may enhance energy metabolism not in the liver or muscle but in brown adipose tissue, thereby enhancing the expression of UCP-1. There is also.
- the content of D-allulose in the brown adipocyte activator or UCP-1 expression enhancer of the present invention is not particularly limited, but is preferably 0.3 to 50 g per day in terms of weight and blended in an amount to be ingested. If necessary, it may be blended in an amount of 0.3 to 5 g, 0.5 to 3 g, 1.5 to 4.5 g, 0.5 to 5 g, 0.5 to 50 g, or 0.5 to 20 g. There is also.
- other brown adipocyte activators, hypothermia inhibitors, energy consumption promoters, UCP-1 expression promoters, metabolism promoters and the like may be used in combination.
- the intake of D-allulose is not particularly limited, but in a human body weighing 60 kg, the daily intake is 0.3 to 50 g by weight conversion, and the intake amount is 0.3 to 5 g or 0.5 to 0.5 g. In some cases it may be preferable to ingest an amount such as -3 g, 1.5-4.5 g, 0.5-5 g, 0.5-50 g, or 0.5-20 g.
- the method for producing a brown adipocyte activator of the present invention may include a step of producing D-allulose.
- the form of D-allulose used in the present invention is arbitrary as long as it does not impair the effects of the present invention as in the above.
- a method for obtaining a rare sugar D-allulose, at present, a production method obtained by treating fructose with an enzyme (epimerase) is generally used. Further, it can be obtained by a method (Patent Document 1) in which a rare sugar syrup or isomerized sugar is used as a raw material and treated with a system in which one or more selected from the group consisting of a basic ion exchange resin, an alkali, and a calcium salt is present.
- the rare sugar syrup (trade name: rare sugar sweet) produced in this way is mainly composed of glucose and fructose, and D-psicose 5.4 g / 100 g, sorbose 5.3 g / 100 g, tagatose 2.0 g / 100 g, and allose 1. It contains 4 g / 100 g and mannose 4.3 (Non-Patent Document 1).
- rare sugars such as D-psicose can be produced by using an enzymatic method, an alkaline method, etc., but it has been revealed that they are also contained in plants such as leaves of Zuina.
- the present invention also provides a composition containing the above-described brown adipocyte activator (brown fat / beige adipocyte activator), a hypothermia inhibitor, an energy consumption promoter, or a UCP-1 expression enhancer. ..
- the composition of the present invention can be in various forms such as powder, liquid, solid, granule, tablet, paste, gel, emulsion, cream, sheet, spray and foam.
- the food composition of the present invention may be a powder, beverage or tablet. Further, the food composition of the present invention, dry powder, beverages such as tea and soft drinks, tablets and capsules such as supplements, processed foods such as retort foods, luxury items such as desserts, seasonings, dairy products, fats and oils. It may be a processed product or the like, and may have various forms such as powder, liquid, solid, granules, granules, paste and gel. Furthermore, the food composition of the present invention includes not only food for humans and the like, but also feed for other animals such as livestock.
- the content of the brown adipocyte activator (brown fat / beige adipocyte activator) in the composition of the present invention is not particularly limited, but the dose is D-allulose (D-).
- the daily dose of psicose is preferably 0.3 to 50 g, but may be increased or decreased depending on the age and symptoms.
- the above-mentioned daily amount of the brown adipocyte activator, energy consumption promoter, or UCP-1 expression enhancer of the present invention is divided into once a day, or divided into 2 or 3 times a day at appropriate intervals. It is preferable to administer before, after, or with a meal.
- D-allulose (D-psicose) is contained so that the composition contains 0.1 to 50% by weight. It is preferably 0.5 to 30% by weight, more preferably 1 to 10% by weight.
- D-allulose (D-psicose) is less than 0.1% by weight in the composition, the brown adipocyte activating effect is insufficient. Further, if D-allulose (D-psicose) exceeds 50% by weight in the composition, it is not preferable from an economical point of view.
- composition of the present invention in order to further enhance the body temperature lowering inhibitory action and energy consumption promoting action, brown adipocyte activation action, body temperature lowering inhibitory action and energy consumption promoting action, etc. Certain other substances may be added.
- additives can be arbitrarily selected and used in combination as necessary. Excipients and the like can be included as additives.
- the excipient may be any as long as it is usually used in a desired form, for example, wheat starch, rice starch, corn starch, potato starch, dextrin, starches such as cyclodextrin, crystalline celluloses, Examples thereof include sugars such as lactose, glucose, sugar, reduced maltose, starch syrup, fructooligosaccharides and emulsified oligosaccharides, and sugar alcohols such as sorbitol, erythritol, xylitol, lactitol and mannitol. These excipients can be used alone or in combination of two or more.
- composition of the present invention may optionally contain other components such as a colorant, a preservative, a thickener, a binder, a disintegrant, a dispersant, a stabilizer, a gelling agent, and an antioxidant.
- a colorant such as a colorant, a preservative, a thickener, a binder, a disintegrant, a dispersant, a stabilizer, a gelling agent, and an antioxidant.
- surfactants, preservatives, pH adjusters, oils, powders, coloring materials, water, alcohols, thickeners, chelating agents, silicones, antioxidants, UV absorbers, humectants, fragrances various medicinal ingredients
- Well-known substances such as antiseptics, pH adjusters and neutralizers can be appropriately selected and used.
- the brown adipocyte activator (brown fat / beige adipocyte activator) of the present invention induces differentiation of brown adipocytes (beige adipocytes) into white adipose tissue, and / or beige adipocytes or brown adipocytes.
- Obesity can be prevented and / or suppressed by promoting metabolism by an approach of activating adipocytes, particularly promoting systemic energy consumption due to heat production. Therefore, it is also effective for treatment and / or prevention of diseases caused by obesity.
- by activating brown adipocytes and increasing cold-induced heat production it is possible to prevent the body from cooling, and by increasing food-induced heat production, it is possible to enhance energy metabolism by diet.
- D-allulose which is the active ingredient of the present invention
- D-psicose which is the active ingredient of the present invention
- various foods we eat cola, castella, maple syrup, etc.
- D-psicose the rare sugar D-allulose
- brown adipocytes The presence of brown adipocytes can be confirmed by a known method. Examples include staining with a fluorescent dye capable of detecting lipid droplets in cells, and detection of a gene product (mRNA or protein) expressed in brown adipocytes. Examples of fluorescent dyes that can detect lipid droplets in cells include Oil Red O and BODIPY. Examples of the gene product expressed in brown adipocytes include UCP-1, CIDEA, PGC-1 ⁇ , PPAR- ⁇ and the like.
- UCP-1 is a gene that is specifically expressed in brown adipocytes, encodes a mitochondrial inner membrane protein that uncouples oxidative phosphorylation, and is considered to be responsible for the function of brown adipocytes. This is one of the particularly preferable indicators for brown adipocytes.
- the activation of brown adipocytes was performed by evaluating the expression levels of UCP-1, PPAR- ⁇ , and PGC-1 ⁇ .
- Brown adipose tissue (BAT) or brown adipocytes is one of the two types of fat or adipose tissue found in mammals. The other type is white adipose tissue. Brown adipose tissue is particularly abundant in newborns and hibernators. Its main function is for animals and newborns to generate body heat without trembling.
- brown adipocytes In contrast to white adipocytes, which contain single fat droplets, brown adipocytes contain iron, which is brown and contains numerous small droplets and a much higher number of mitochondria. Has been. Brown adipose tissue also collects more capillaries than white adipose tissue because brown adipose tissue requires more oxygen than most tissues.
- UCP-1 uncoupling protein
- UCP-1 The uncoupling protein is often abbreviated as UCP, which is an acronym for Uncoupling protein.
- Uncoupling proteins are proteins in the inner membrane of mitochondria that can dissipate a transmembrane proton gradient before generating energy for oxidative phosphorylation.
- Five types of UCP-1 to UCP-5 are known in mammals. Instead of producing ATP, energy is used to generate heat, so uncoupling proteins perform normal physiological functions such as non-exercise-free heat production during hibernation.
- UCP-1 is present only in brown adipocytes
- UCP-2 is found in white adipocytes, immune system cells, nerve cells and the like
- UCP-3 is mainly present in skeletal muscle, heart and other muscle tissues. Since the synthesis of UCP-3 protein is remarkably reduced in skeletal muscle of diabetic patients, it is considered to be related to heat production or fat metabolism.
- UCP-1 When noradrenaline binds to the ⁇ 3 receptor on brown adipocytes, UCP-1 is produced, uncoupling in mitochondria and producing heat. In many yellow people, including Japanese, genetic mutations in the ⁇ 3 receptor gene often occur and produce less heat, but they save calories and are hard to consume. Sometimes called a gene. Mitochondrial uncoupling protein (UCP) has the function of uncoupling the oxidative phosphorylation reaction in the inner mitochondrial membrane and dissipating energy as heat. Regarding UCP (UCP-1), which is the most representative of brown adipose tissue, (1) UCP-1 function is decreased in obese animals, and (2) UCP-1 is increased in animals that do not become obese after polyphagia is doing.
- UCP-1 which is the most representative of brown adipose tissue
- mice in which the expression of UCP-1 is artificially reduced are obese and those in which they are highly expressed lose weight. Therefore, if UCP-1 is activated, an antiseptic effect can be expected. Therefore, drugs and foods for that purpose are being searched for, and a representative example thereof is an adrenoreceptor agonist specific to adipocytes.
- ⁇ -agonists stimulate lipolysis in white adipocytes and at the same time activate UCP-1 to convert free fatty acids into heat and ultimately reduce body fat.
- brown adipose tissue is present in a very small amount in adults. However, if the administration of the ⁇ agonist is continued, normal adipocytes become brown and UCP-1 increases.
- PGC-1 ⁇ is also present in skeletal muscle, and its amount increases when exercise is performed. Therefore, it is considered that an increase in PGC-1 ⁇ amount due to exercise leads to changes in the properties of skeletal muscle.
- PGC-1 ⁇ is a coactivator of PPAR- ⁇ , PPAR- ⁇ , and other transcriptional regulators. It is expressed not only in muscle but also in the liver and brown adipose tissue. In the liver, expression is increased during fasting to promote gluconeogenesis, and in brown adipose tissue, the transcriptional program for thermogenic adaptation is regulated. When PGC-1 ⁇ is introduced into white adipocytes, brown adipocyte-like changes such as enhanced mitochondrial biosynthesis and increased UCP-1 expression occur.
- Full-length PGC-1 ⁇ is 113 kDa and is induced in brown adipocyte tissue by cold exposure, in liver and kidney by fasting, and in skeletal muscle by exercise.
- PPAR- ⁇ is a member of the nuclear receptor superfamily. To date, three subtypes of ⁇ , ⁇ , and ⁇ ( ⁇ ) have been reported. The ⁇ subtype (PPAR- ⁇ ), which was first discovered, was named because it was activated by a fibrate, which is a peroxisome proliferating agent. It is considered to be a group of transcription factors closely related to intracellular metabolism of hydrocarbons, lipids, proteins, etc. and cell differentiation. Both subtypes form a heterodimer with the retinoid X receptor (RXR) and bind to the PPAR response element (PPRE).
- RXR retinoid X receptor
- PPRE PPAR response element
- PPAR- ⁇ is strongly expressed in the liver, brown adipose tissue, heart, and kidney, and is activated with free fatty acids as physiological ligands, leading to a decrease in blood triglyceride concentration.
- Exogenous ligands include so-called fibrate drugs such as bezafibrate and clofibrate.
- fibrate drugs such as bezafibrate and clofibrate.
- Most of the target genes are genes related to lipid metabolism, and they are major targets of drugs for improving hypertriglyceridemia.
- Prdm16 is a transcription factor that plays an important role as a switch for inducing differentiation into brown adipocytes and beige adipocytes.
- Prdm16 forms a complex with C / EBP ⁇ and has a methyl group transfer activity, and thus induces the differentiation of Myf5-positive cells into brown adipocytes.
- the lysine methyltransferase EHMT1 was identified as the only histone methyltransferase responsible for the transmethylation activity of the Prdm16 transcription complex.
- the Prdm16 / EHMT complex plays a role in suppressing skeletal muscle-related gene expression in mouse BAT and activating a gene program for differentiation from precursor brown adipocytes to brown adipocytes.
- Prdm16 suppresses the expression of white fat-related genes such as resistin and induces beige fat-related gene programs, and thus plays a very important role as a differentiation switch from preadipocyte to beige adipocyte.
- Mitochondrial transcription factor A Mitochondrial transcription factor A (Mit Fresh chondral tran- Cripton® A: TFAM) was purified and cloned as a transcription factor of mitochondrial DNA by Clayton et al.
- TFAM is a protein belonging to the high mobility group (HMG) family proteins, and as with most HMG family proteins, can bind DNA nonspecifically to a DNA sequence.
- TFAM mitochondrial DNA
- Mitochondria are responsible for most ATP production through oxidative phosphorylation and are the center of energy metabolism in the body.
- Adipocytokine It is a generic term for physiologically active substances secreted from fat cells.
- [Leptin] A hormone secreted by fat cells. It has the function of suppressing appetite and activating energy metabolism.
- HbA1c Glucose is bound to hemoglobin (Hb) existing in red blood cells. The lifespan of red blood cells is about 4 months, during which red blood cells travel around the body and glucose binds to hemoglobin.
- HbA1c hemoglobin avancy
- HbA1c value reflects the state of glycemic control in the past 1-2 months.
- Glycoalbumin is a glycated protein that reflects the state of blood sugar. It is used as an index for blood glucose control in the past 1-2 weeks.
- Adiponectin It is a secretory protein secreted from fat cells. Blood levels are orders of magnitude higher than general hormones, reaching the ⁇ g / ml order.
- Actions include stimulating glucose uptake without insulin receptor, burning of fatty acid, action of decreasing intracellular fatty acid to increase sensitivity of insulin receptor, and enhancement of insulin sensitivity by activating AMP kinase in liver.
- [TNF- ⁇ ] Adipose tissue secretes inflammatory cytokines, and TNF- ⁇ inhibits glucose uptake into cells and reduces sensitivity to insulin. Further, it has been reported that TNF- ⁇ promotes the production of fatty acids in adipocytes and hepatocytes and causes antiglycerinemia mainly through TNFR1.
- adipocytokines physiologically active substances
- MCP-1 vascular endothelial cells, adipocytes
- LDL (low-density lipoprotein) receptor family is a multifunctional protein that controls intracellular uptake of various ligands including LDL or signal transduction.
- LDL low-density lipoprotein
- LDL is oxidized by free radicals and other oxidants to become oxidized LDL, it is not recognized by normal LDL receptors, but is recognized by macrophage scavenger receptors and is taken up indefinitely, resulting in macrophage foaming. Became clear.
- Example 1 The effect of administration of D-allulose, which is one of rare sugars, on brown adipocytes (abbreviation of BAT of brown adipose tissue brown adipose tissue) was examined. In the experiment, 6-week-old mice were used, divided into 3 groups, 5 mice each, and treated for 8 weeks as described below. 1. Protocol: (1) Ordinary food and water drinking group (Normal Food) (2) High fat diet and drinking water group (HFD) (3) High-fat diet and a group that drinks water containing 2% D-allulose (HFD + 2% D-allulose)
- Evaluation item (1) Transition of body weight (Body Weight), Blood glucose transition (2) Size and weight of brown adipocytes under the scapula (3) Pathological evaluation of morphological changes of brown adipocytes (4) UCP activation of brown adipocytes Of P-1, PPAR- ⁇ and PGC-1 ⁇ expression levels
- the high fat diet increased the body weight after 8 weeks of observation.
- the HFD group was given water containing 2% D-allulose, a decrease in body weight was observed.
- the blood glucose level was measured over time in 8 weeks.
- the blood glucose level in the HFD group was higher than that in the normal group.
- the blood glucose level of the HFD + D-allulose group was lower than that of the HFD group, compared to the HFD group.
- PPAR- ⁇ is an index of the activation of brown adipocytes
- PPAR- ⁇ was higher in the HFD group than in the normal group.
- was induced which seems to be a reaction of the body due to excessive lipid intake.
- ingestion of D-allulose more strongly induced PPAR- ⁇ , and it seems that brown adipocytes were activated.
- FIG. 6 which shows the activation level of brown adipocytes by the expression level of PGC-1 ⁇ , PGC-1 ⁇ was induced in the HFD group as compared with the normal group, which was caused by excessive lipid intake.
- Example 2 The effect of rare sugar D-psicose (D-allulose) on type 2 diabetic patients was examined.
- [Method] ⁇ Selection criteria> Type 2 diabetic patients (HbA1c: 6.5% or more) who cannot obtain sufficient effects by any of the following treatments (borderline diabetes) 1) Diet and exercise therapy only 2) In addition to diet and exercise therapy, drug therapy ⁇ Exclusion criteria> 1) Patients who are contraindicated for D-allulose (D-psicose) administration 2) Patients who are participating in other clinical trials 3) Pregnant women, pregnant women, lactating women or women who may be pregnant 4) HbA1c is 8% or more 5) Patients with poor glycemic control 5) Patients with severe renal dysfunction (serum creatinine value of 1.5 mg / dl or more) 6) Patients with other serious complications ⁇ Method of conducting experiment> D-allulose (D-psicose) powder: Stick shape 5g / pack (manufactured by Rare Suite
- D-allulose D-psicose
- adipocytokines various adipose tissue-derived physiologically active substances, (adipocytokines) and their actions
- leptin and adiponectin did not show any particularly significant changes during 3 months of D-psicose administration.
- TNF- ⁇ is famous as a cytokine secreted from adipocytes and causing insulin resistance. It is also known to suppress adiponectin, which is a good adipocytokine.
- D-psicose lowers TNF- ⁇ , thereby improving insulin resistance and improving glycemic control.
- MCP-1 is secreted from the inflammatory layer (vascular endothelial cells, adipocytes), induces monocyte migration, differentiation into macrophages, expression of oxidized LDL receptor, and is an important cytokine that forms arteriosclerosis.
- D-allulose D-psicose
- 12 type 2 diabetic patients 4 males and 8 females
- a dose of 5 g once a day, 3 times a day. Compared blood tests.
- TNF- ⁇ and MCP-1 were significantly decreased before and after administration. In particular, TNF- ⁇ was significantly decreased 2 months after administration.
- the body weight decreased by an average of 1 kg three months after administration.
- D-allulose (D-psicose) may be useful for administration in patients with type 2 diabetes.
- Example 3 Similar to Example 1, the effects of D-allulose administration on brown adipocytes (abbreviated as BAT of brown adipose tissue Brown adipose tissue) were decreased, resulting in weight loss and body fat reduction due to beige adipocyte differentiation induction. We examined the effect of. (Purpose) To confirm the effect of administration of D-allulos on brown adipose tissue in mice. In addition, the differentiation of beige adipocytes will be examined using changes in the expression of UCP-1 and the like as markers. 1. Protocol: Five mice are divided into two groups as one group. Both groups of 8 week old mice are loaded with a high fat diet (HFD).
- HFD high fat diet
- FIG. 13 shows the results of changes in blood glucose level in the glucose tolerance test after 10 weeks. Glucose was administered intraperitoneally, and blood glucose levels were measured 0, 15, 30, 60, 90, and 120 minutes later. In the D-allulose administration group, the blood glucose level after 90 and 120 minutes was significantly lower than that in the control group. 5) As shown in Fig. 14, there was no significant change in food intake (right side) and water intake (left side) in both groups during the study period. 6) FIG. 15 shows the results of the study on the weight and area of brown adipocytes (BAT) when D-allulos was administered to mice loaded with a high fat diet (HFD).
- BAT brown adipocytes
- Non-Patent Document 3 the present way of thinking of adipose tissue (Non-Patent Document 3) will be described with reference to FIG.
- white adipocytes that accumulate fat and brown adipocytes that have a function of burning fat to generate heat.
- Many proteins called uncoupling protein (UCP-1) are expressed in brown adipocytes, and UCP-1 generates heat, burns fat, and converts it into energy.
- Beige adipocytes like white adipocytes, have extremely low UCP-1 expression, but UCP-1 is highly expressed by stimulation such as cold. At this time, the adipocytes become heat-producing like brown adipocytes, and the white adipocytes have a brownish trait. Brown adipocytes and beige adipocytes contribute to maintaining body temperature in a cold environment as special adipocytes that generate heat in response to cold exposure. The heat-producing and energy-consuming activities possessed by these adipocytes are expected to be useful not only for regulating body temperature but also for preventing obesity and metabolic diseases.
- brown adipocytes and beige adipocytes express UCP-1 in common and have a thermogenic ability, it has been known that the origin and function control mechanism of cells are different.
- Classic brown adipocytes have been developed in small rodents, especially hibernators, and are present as brown adipocyte masses between the scapula, axilla, and around the kidney.
- the differentiation and tissue formation of brown adipocytes are completed in the fetal period, whereas the differentiation of beige adipocytes is induced in response to stimuli such as exposure to cold environment, and disappears when the stimuli disappear.
- BAT brown adipocytes
- FIG. 7 The results of the examination of the expression of UCP-1 mRNA in beige adipocytes and brown adipocytes in the mice administered with D-allulose to the mice loaded with high fat diet (HFD) are shown in FIG.
- the figure on the left side shows that the expression of UCP-1 is predominantly increased by administration of D-allulose in beige adipocytes. That is, it indicates that beige adipocytes are induced to differentiate by D-allulose.
- the right panel shows that UCP-1 expression is also increased in classical brown adipose tissue. Administration of D-allulos may contribute to weight loss via beige adipocyte induction and brown adipocyte activation.
- FIG. 8 The results of the examination of the expression of UCP-1 mRNA in beige adipocytes and brown adipocytes in the mice administered with D-allulose to the mice loaded with high fat diet (HFD) are shown in FIG.
- the figure on the left side shows that the expression of UCP
- FIG. 18 shows the results of the study on the expression of UCP-1 protein in beige adipocytes and brown adipocytes in the mice to which D-allulose was administered to the mice loaded with high fat diet (HFD).
- HFD high fat diet
- the figure on the left side shows that the expression of UCP-1 protein is predominantly increased by administration of D-allulose in beige adipocytes. That is, it indicates that beige adipocytes are induced to differentiate by D-allulose.
- the right panel shows that the expression of UCP-1 protein is also increased in classical brown adipose tissue. Administration of D-allulos may contribute to weight loss via beige adipocyte induction and brown adipocyte activation.
- FIG. 20 shows BAT for experiments using cells (establishing a cell line derived from a single clone from BAT of the adult supraclavicular fossa and using a model for studying induction of differentiation into beige adipocytes).
- -Protocol and WAT-Protocol are drawings for explaining the protocol for inducing beige adipocytes.
- FIG. 21 is a diagram illustrating a protocol in which D-allulose is added to a protocol for inducing beige adipocytes in two of the BAT-protocol and the WAT-protocol in an experiment using cells.
- FIG. 22 shows by fat staining that addition of D-allulose to the differentiation induction protocol promotes induction into beige adipocytes.
- FIG. 23 examines the expression of various markers as an evaluation of beige adipocytes induced by the differentiation induction protocol.
- the WAT-protocol has a stronger effect on the induction of browning marker genes (UCP-1, Pgc-1 ⁇ , cox8b).
- UCP-1, Pgc-1 ⁇ , cox8b browning marker genes
- D-allulose enhances Prdm16, Pgc-1 ⁇ , and PPAR ⁇ expression.
- D-allulose enhances PPAR ⁇ expression, suggesting that D-allulose promotes adipogenesis.
- the brown adipocyte activator of the present invention By ingesting the brown adipocyte activator of the present invention containing D-allulose, the brown adipocytes and beige adipocytes are activated, and by promoting the energy consumption of the whole body, the amount of fat is reduced and eventually obesity is reduced. Expected to be resolved.
- D-allulose (15 g daily intake in humans resulted in significant weight loss after 3 months. In humans, it also contributed to the growth of brown adipose tissue and the acquisition of a "slim body". In general, aging reduces metabolism and makes the body feel chills, but intake of D-allulose increases energy metabolism (heat production) to prevent / improve chills in the body.
- the brown adipocyte-activating action of D-allulose induces differentiation of brown-like adipocytes (beige adipocytes) into white adipose tissue.
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Abstract
Description
つまり褐色脂肪細胞を活性化する方法が見つかれば、肥満や2型糖尿病をコントロールする新たな治療法となる可能性がある。 本発明は、褐色脂肪細胞に対し高い活性化効果を有する製剤を提供することを目的とする。
本発明において、「褐色脂肪細胞の活性化」とは、白色脂肪組織中に褐色脂肪様細胞(ベージュ脂肪細胞)が分化誘導されることを促進する作用、及び/又はベージュ脂肪細胞や褐色脂肪細胞におけるエネルギー消費を促進する作用のことを言い、褐色脂肪・べージュ脂肪細胞の活性化ともいうことができる。
本発明は、以下の(1)ないし(3)の褐色脂肪・ベージュ脂肪細胞活性化剤を要旨とする。
(1)D-アルロースを有効成分として含有する褐色脂肪・ベージュ脂肪細胞活性化剤。
(2)少なくともD-アルロースを含有し、かつ、UCP-1発現促進作用を有する褐色脂肪・ベージュ脂肪細胞活性化剤。
(3)UCP-1の発現を亢進させることにより褐色脂肪・ベージュ脂肪細胞を活性化する、上記(1)または(2)に記載の褐色脂肪細胞活性化剤。
(4)D-アルロースを有効成分として含有するエネルギー消費促進剤。
(5)褐色脂肪・ベージュ脂肪を活性化することによりエネルギーの消費を促進する、上記(4)に記載のエネルギー消費促進剤。
(6)D-アルロースを有効成分として含有するUCP-1発現亢進剤。
(7)上記(1)ないし(6)のいずれかに記載の剤を含む組成物。
(8)D-アルロースを有効成分として含有する褐色脂肪・ベージュ脂肪細胞活性化用組成物。
(9)熱産生によるエネルギーの消費を促進するための、上記(7)または(8)に記載の組成物。
(10)UCP-1の発現を亢進させることにより褐色脂肪・ベージュ脂肪肪細胞を活性化する、上記(7)ないし(9)のいずれかに記載の組成物。
(11)前記組成物が食品組成物である、上記(7)ないし(10)のいずれかに記載の組成物。
本発明において褐色脂肪細胞とは、胎児期に形成される古典的褐色脂肪細胞および白色脂肪組織中に分化誘導される褐色脂肪様細胞(ベージュ脂肪細胞又はブライト細胞と呼ぶこともある)の両方を指す。つまり、本発明では、狭義の古典的褐色脂肪細胞のみならず、白色脂肪組織中に誘導された褐色様の脂肪細胞も褐色脂肪細胞と呼ぶ。また、白色脂肪組織中に誘導される褐色様の脂肪細胞を特にベージュ脂肪細胞または褐色脂肪様細胞と呼ぶこともある。
白色脂肪細胞は、単房性の大型な脂肪滴を有し細胞質が少ない。一方、褐色脂肪細胞は、小型の多房性脂肪滴を有し、この多房性脂肪滴の周りに多数のミトコンドリアが存在して、そのため特有の褐色を帯び、交感神経や血管が豊富であるという形態学的・組織学的な特徴を持つ。従って、白色脂肪細胞と褐色脂肪細胞は、形態学的・組織学的に細胞を観察することにより区別できる。また、白色脂肪はエネルギーを貯蔵するが褐色脂肪細胞はエネルギーを熱として消費・散逸するという違いがある。また、褐色脂肪細胞は白色脂肪細胞よりもエネルギーの代謝が高く、エネルギーを熱として放出するためにグルコースの取込みが増加する。したがって、褐色脂肪細胞の存在は、例えば、18Fで標識したグルコースの集積をPET(陽電子放射断層撮影)で測定することにより評価できる。さらに、褐色脂肪細胞では、脱共役蛋白質1(UCP‐1)と呼ばれる33kDaの蛋白質が細胞中のミトコンドリア内膜に特異的に発現しているので、UCP‐1mRNAの発現やUCP‐1タンパク質を測定することにより褐色脂肪細胞の存在を確認できる。
形態学的特徴としては、ベージュ脂肪細胞は褐色脂肪細胞に類似しており、細胞内に多房性脂肪滴を持ち、特異的タンパク質UCP‐1を発現したミトコンドリアに富んでいる。単房性脂肪滴を持ち細胞質に乏しい白色脂肪細胞とは対照的である。機能的特徴をみると、余剰エネルギーを中性脂肪として貯蔵する白色脂肪細胞とは異なり、褐色脂肪細胞とベージュ脂肪細胞はUCP‐1が酸化的リン酸化を脱共役させることにより、熱産生を行う。これらの点では、ベージュ脂肪細胞は褐色脂肪細胞と似ているといえるが、以下の点ではむしろ白色脂肪細胞に近い。まず存在部位として,マウスでは褐色脂肪細胞は肩甲間や腎周囲に細胞塊を形成して局在するのに対し、ベージュ脂肪細胞は鼠径部などの白色脂肪組織中に誘導的かつ散在的に出現する。この現象は、白色脂肪の褐色化(brоwning оf white fat)と呼ばれる。次に発生起源として、褐色脂肪細胞は骨格筋と共通するМyоgenic factоr 5(Мyf5)を発現する筋前駆細胞に由来するのに対し、ベージュ脂肪細胞は白色脂肪細胞同様、Мyf5陰性で、plate‐derived grоwth factоr receptоr α(PDGFRα)やsmооth muscle actin(SMA)を発現する前駆脂肪細胞に由来する。このように、ベージュ脂肪細胞は褐色脂肪細胞や白色脂肪細胞と類似の特徴と相反する特徴を併せ持っているため、単に白色脂肪細胞が性質を変化させたものではなく、第三の脂肪細胞と考えられる。
褐色脂肪細胞やベージュ脂肪細胞は、寒冷曝露に応じて熱を産生する特殊な脂肪細胞として、寒冷環境での体温維持に寄与している。これらの脂肪細胞が持つ熱産生・エネルギー消費活性は、体温調節能のみならず、肥満や代謝性疾患の予防にも役立つことが期待されている。褐色脂肪細胞とベージュ脂肪細胞は、脱共役タンパク質(Uncoupling rotein :UCP‐1)を発現し、熱産生能を有する点は共通しているが、細胞の起源や機能制御機構は異なることがわかってきている。特に、ヒト成人の褐色脂肪組織(Brown adipose tissue:BAT)が主にベージュ脂肪細胞により構成されている事実は、BATを標的とした肥満予防法を探索する上で重要と考えられる。
本発明の褐色脂肪細胞活性化剤、エネルギー消費剤等、及びそれらを含む組成物は肝臓や筋肉内ではなく、褐色脂肪組織におけるエネルギー代謝を高めることもあり、UCP-1の発現を亢進させることもある。
また、本発明の組成物は、褐色脂肪細胞活性化作用、体温低下抑制作用やエネルギー消費促進作用等を一層高めるために、褐色脂肪細胞活性化作用、体温低下抑制作用やエネルギー消費促進作用等がある他の物質を添加してもよい。
[BAT]
褐色脂肪組織(Brown adipose tissue、BAT)または褐色脂肪細胞は哺乳類で見つかった2つのタイプの脂肪または脂肪組織の1つである。もう1つのタイプは白色脂肪組織である。褐色脂肪組織は、新生児や冬眠動物では特に豊富である。その主な機能は、動物や新生児が体を震わせないで体の熱を生成することである。単一の脂肪滴が含まれている白色脂肪細胞とは対照的に、褐色脂肪細胞は、鉄を含んでおり、それが茶色を呈し、多数の小さな液滴とはるかに多い数のミトコンドリアが含まれている。褐色脂肪組織はほとんどの組織よりも多くの酸素を必要とするため、褐色脂肪組織はまた、白色脂肪組織よりも多くの毛細血管が集まっている。
ノルアドレナリンが褐色脂肪細胞上のβ3受容体に結合すると、UCP-1(脱共役タンパク質)が生成され、ミトコンドリアで脱共役が起こり熱が産生される。動物の冬眠時に良く見られる運動に伴わない熱産生の手段である。
褐色脂肪細胞は、赤ちゃんに最も多くある。その理由は、体温を維持するため。命を守るためなのである。成人は、厳しい寒さの中に置かれると、ぶるぶる震えます。そうして筋肉を動かして熱を作っているのであるが、赤ちゃんは筋肉が少なく、自分で体温を調節できない。赤ちゃんは生命維持のため褐色脂肪細胞が多くあるが、その後必要がなくなり、次第に減っていく。加齢とともに増加していくBMI。それとは逆に褐色脂肪細胞は減少していき、肥満が引き起こされる。“脂肪を燃やす脂肪”とも言える褐色脂肪細胞がなくなると、太りやすくなるということである。褐色脂肪組織の数や働きを高めることが2型糖尿病や肥満症の新しい治療法につながると期待されている。
[UCP‐1]
脱共役タンパク質は、Uncoupling proteinの頭文字を取ってUCPと略されることが多い。脱共役タンパク質(UCP)は、酸化的リン酸化のエネルギーを生成する前に、膜間のプロトン勾配を浪費することができるミトコンドリアの内膜のタンパク質である。哺乳動物ではUCP-1~UCP-5の5つのタイプが知られている。ATPを生産する替わりに、エネルギーが熱を生成するために使用されるため、脱共役タンパク質は冬眠時の運動を伴わない熱産生のような正常な生理機能を果たしている。UCP-1は褐色脂肪細胞にのみ存在し、UCP‐2は白色脂肪細胞、免疫系細胞、神経細胞などに認められ、UCP‐3は主に骨格筋、心臓などの筋組織において多く存在する。糖尿病患者の骨格筋においてUCP‐3タンパクの合成が著明に低下していることから、熱産生あるいは脂肪代謝に関連していると考えられている。ノルアドレナリンが褐色脂肪細胞上のβ3受容体に結合すると、UCP‐1が生成され、ミトコンドリアで脱共役が起こり熱が産生される。日本人を含めた黄色人種ではβ3受容体の遺伝子に遺伝変異が起こっていることが多く、熱を産生することが少ない反面、カロリーを節約し消費しにくいことから、この変異した遺伝子を節約遺伝子と呼ぶことがある。
ミトコンドリア脱共役蛋白質(UCP)はミトコンドリア内膜での酸化的リン酸化反応を脱共役させ、エネルギーを熱として散逸する機能を持っている。最も代表的な褐色脂肪組織のUCP(UCP‐1)については、(1)肥満動物ではUCP-1の機能が低下している、(2)多食しても肥満しない動物はUCP-1が増加している。人為的にUCP-1の発現を低下させたマウスは肥満し、高発現マウスはやせるなどの事実が知られている。したがって、UCP-1を活性化すれば、抗満効果が期待できるので、そのための薬物や食品が探索されているが、その代表例が脂肪細胞特異的なアドレナリン受容体のアゴニストである。事実、βアゴニストは白色脂肪細胞での脂肪分解を促すと同時にUCP-1を活性化して遊離した脂肪酸を熱に変え、最終的に体脂肪を減少させる。マウス等と異なり成人では、褐色脂肪組織はごく少量しか存在しない。しかしβアゴニストの投与を続けると、通常の脂肪細胞が褐色化しUCP-1が増加する。さらにUCP-1と相同な蛋白質UCP-2,UCP-3がヒトの骨格筋や白色脂肪組織などに広く存在しているので、これらを含めてUCPは抗肥満のターゲット分子の一つと考えられている。
[PGC-1α]
運動による糖代謝促進へのPGC-1αの関与:運動をある程度継続して行った骨格筋では、ミトコンドリアと呼ばれる細胞内の小器官の数が増加して脂肪の燃焼が盛んになり、血液中のブドウ糖(血糖)を骨格筋に取り込む糖輸送体GLUT4が増加することにより糖の代謝が活発になる。PGC-1αという遺伝子の転写を制御する物質は、ミトコンドリアの合成を促進する働きを有し、骨格筋培養細胞での実験ではGLUT4を増加させる。PGC-1αは骨格筋にも存在し、運動を行うとその量が増えることから、運動によってPGC-1α量が増加することが骨格筋の性質の変化に結びつくものと考えられる。PGC-1αはPPAR-α、PPAR-γ、および他の転写調節因子の活性化補助因子である。筋肉をはじめ肝臓や褐色脂肪組織で発現しており、肝臓では絶食時に発現増加して糖新生を促進し、褐色脂肪組織では熱発生適応に関する転写プログラムを調節している。白色脂肪細胞にPGC-1αを導入 するとミトコンドリア生合成の増強やUCP-1の発現増加などの褐色脂肪細胞様変化が生じる。完全長のPGC-1αは113kDaで、寒冷暴露により褐色脂肪細胞組織に、絶食により肝臓と腎臓に、運動により骨格筋に誘発される。
PPAR-αは核内レセプタースーパーファミリーのメンバーである。現在までにα,γ,δ(β)の三つのサブタイプが報告されている。最初に発見されたαサブタイプ(PPAR-α)がペルオキシソーム増殖剤であるフィブラート系薬剤により活性化されたことからその名が付いた。炭化水素,脂質,タンパク質等の細胞内代謝と細胞の分化に密接に関与している転写因子群であるとされている。いずれのサブタイプもレチノイドX受容体(RXR)とヘテロ2量体を形成してPPAR応答配列(PPRE)に結合する。
PPAR-αは肝臓や褐色脂肪組織、心臓、腎臓で強く発現しており、遊離脂肪酸などを生理的なリガンドとして活性化され、血中トリグリセリド濃度の低下などを導く。外因性リガンドとしてはベザフィブラート、クロフィブラートなどのいわゆるフィブラート系の薬物がある。標的遺伝子のほとんどは脂質代謝関連の遺伝子であり、高トリグリセリド血症改善薬の主要な標的となっている。
[Prdm16]
Prdm16は、褐色脂肪細胞およびベージュ脂肪細胞への分化誘導スイッチとして重要な役割を担う転写因子である。Prdm16はC/EBPβと複合体を形成し、メチル基転移活性を持つことにより,Myf5陽性細胞から褐色脂肪細胞への分化を誘導する。Prdm16転写複合体のメチル基転移活性を担う唯一のヒストンメチル化酵素として、リシンメチルトランスフェラーゼEHMT1を同定された。Prdm16・EHMT複合体は、マウスのBATにおいて骨格筋関連遺伝子発現を抑制し、前駆褐色脂肪細胞から褐色脂肪細胞に分化するための遺伝子プログラムを起動する役割を担っている。さらに、Prdm16はresitinなどの白色脂肪関連遺伝子の発現を抑制し、ベージュ脂肪関連遺伝子プログラムを誘導する働きも持っており、前駆脂肪細胞からベージュ脂肪細胞の分化スイッチとしても非常に重要な役割を担っている。
[Tfam]
ミトコンドリア転写因子A(Mitоchоndrial tran-
scriptiоn factоr A:TFAM)はミトコンドリアDNAの転写因子としてClaytоnらによって精製、クローニングされた。TFAMは、hight mоbility grоup(HMG)ファミリータンパク質に属するタンパク質で、HMGファミリータンパク質の多くがそうであるように、DNA配列に非特異的にDNAに結合できる。TFAMの変化量とミトコンドリアDNAの量には相関性があり、ミトコンドリアDNAの複製は転写に依存しているため、TFAMの発現量はミトコンドリアの機能評価として代用されている。ミトコンドリアは酸化的リン酸化を通じて大半のATP産生を担い、生体におけるエネルギー代謝の中心である。
[アディポサイトカイン]
脂肪細胞から分泌される生理活性物質の総称である。
[レプチン]
脂肪細胞から分泌されるホルモン。食欲を抑制し、エネルギー代謝を活性化させる機能をもつ。
[HbA1c]
赤血球に存在するヘモグロビン(Hb)に、ブドウ糖が結合したものである。赤血球の寿命は約4か月であり、この間に赤血球が体内をめぐり、ヘモグロビンにブドウ糖が結合する。血液中のブドウ糖が多いほどHbA1cの値(ヘモグロビンエーワンシー)は高くなり、HbA1c値は過去1~2か月の血糖コントロールの状態を反映する。
[GA]
グリコアルブミンは血糖の状態を反映する糖化蛋白質である。過去1~2週間の血糖コントロールの指標として用いられている。
[アディポネクチン]
脂肪細胞から分泌される分泌蛋白である。血中濃度は一般的なホルモンに比べて桁違いに多く、μg/mlオーダーに達する。作用としては、インスリン受容体を介さない糖取り込み促進作用、脂肪酸の燃焼、細胞内の脂肪酸を減少してインスリン受容体の感受性を上げる作用、肝臓のAMPキナーゼを活性化させることによるインスリン感受性の亢進、動脈硬化抑制、抗炎症、心筋肥大抑制など、多彩である。善玉アディポサイトカインである。
[TNF-α]
脂肪組織は炎症性サイトカインを分泌しており、TNF-αにより細胞内へのグルコースの取り込み阻害やインスリンに対する感受性低下が生じる。また、TNF-αは脂肪細胞や肝細胞における脂肪酸の産生を促進し、主にTNFR1を介して抗グリセリン血症を引き起こすことが報告されている。脂肪細胞から分泌されるアディポサイトカイン(生理活性物質)の1つで、筋肉、脂肪組織や肝臓での糖の働きを抑制する作用がある。肥満時には増加し、糖尿病や動脈硬化などのリスクを高める。脂肪細胞から分泌され、インスリン抵抗性を惹起するサイトカインとして有名である。
[MCP-1]
炎症層(血管内皮細胞、脂肪細胞)から分泌され、単球の游走、マクロファージへの分化、酸化LDL受容体の発現を誘導し、動脈硬化を形成する重要な因子である。D-プシコースを3ヶ月間投与することで、MCP-1濃度が有意に低下しており、D-プシコースに抗動脈硬化作用があることが示唆される。
[酸化LDL受容体] LDL(低比重リポタンパク質)受容体ファミリーはLDLをはじめとする種々のリガンドの細胞内取り込み、あるいはシグナル伝達を司る多機能タンパク質である。フリーラジカルなどの酸化物質によりLDLが酸化を受け酸化LDLとなると、通常のLDL受容体で認識されず、マクロファージのスカベンジャー受容体で認識されて、際限なく取り込まれることでマクロファージの泡沫化を招くことが明らかとなった。
希少糖の一種であるD-アルロース(D-allulose)投与による褐色脂肪細胞(褐色脂肪組織Brown adipose tissueの略 BAT)への影響について検討した。実験は6週齢のマウスを使用し、3群、各5匹に分け、下記のように処理を8週間おこなった。
1.プロトコール:
(1)普通食及び水の飲水をおこなう群(Normal Food)
(2)高脂肪食及び水の飲水をおこなう群(HFD)
(3)高脂肪食及びD-アルロース(D-allulose)を2%含有した水を飲水する群(HFD+2%D-allulose)
(1)体重(Body Weight)の推移、
血糖値(Blood Glucose)の推移
(2)肩甲骨下の褐色脂肪細胞またはのサイズ及び重量
(3)褐色脂肪細胞の形態的な変化を病理的に評価
(4)褐色脂肪細胞の活性化をUCP-1、PPAR-α、PGC-1αの発現量の評価
1)体重の推移、血糖値の推移の結果を図1に示す。
高脂肪食を負荷した群では体重が増加した。高脂肪食及びD-アルロース群(HFD+2%D-allulose)では、高脂肪食群と比較して体重の減少が認められた。また血糖値の推移も、高脂肪食群では、血糖値が高値を示したが、高脂肪食及びD-アルロース群では、血糖値の低下を認めた。
2)肩甲骨下の褐色脂肪細胞のサイズ及び重量、および体重の結果を図2に示す。
高脂肪食を負荷した群では褐色脂肪細胞が減少した。高脂肪食及びD-アルロース群では、高脂肪食群と比較して褐色脂肪細胞の増加が認められた。
組織染色でも、高脂肪食群では脂肪化を認めたが、高脂肪食及びD-アルロース群(HFD+2%D-allulose)では正常を変わらない状態に改善していた。
4)褐色脂肪細胞の活性化をUCP-1、PPAR-α、PGC-1αの発現量の評価の結果をそれぞれ図4、図5、図6に示す。
高脂肪食及びD-アルロース群(HFD+2%D-allulose)では、高脂肪食群と比較して褐色脂肪細胞のマーカー遺伝子発現増強が認められた。
図1に示すように、D-アルロースのマウス体重に及ぼす影響について、高脂肪食(HFD)は8週間の観察で体重を増加させた。HFD群に2%D-アルロース含有水を飲水させると、体重の減少が認められた。また8週間において血糖値を経時的に測定した。HFD群においては、血糖値が通常群に比較して高値を示した。HFD+D-アルロース群はHFDに比較して血糖値は、HFD群に比較して低下した。
6週齢のマウスを使用する本実施例の実験における肩甲骨下の褐色脂肪細胞のサイズ及び重量、および体重を示す図2、さらに3群における褐色脂肪組織の病理的に検討の結果を示す図3が示すように、通常食群に比較してHFD群では、BATに脂肪沈着を認め、白色脂肪化していた。一方、HFD群+2%D-アルロース群では、通常食群に比較して形態的に褐色脂肪組織は遜色がなく、白色脂肪化した褐色脂肪組織が通常の褐色脂肪組織へ回復したことが判明した。
褐色脂肪細胞の活性化をUCP-1の発現量で示す図4が示すように、HFD群でUCP-1が増加していた。多量の脂肪摂取にともない生体の防御反応としてUCP-1を誘導し、カロリー消費していることが予想された。D-アルロースの投与は、さらにUCP-1を誘導していた。病理組織と合わせて考えると、HFD群でのUCP-1の誘導は、病的な状況への対応であり、HFD群+2%D-アルロース群では、正常な形態であることより、褐色脂肪組織が分化増殖した結果のUCP-1の活性化であると推定している。
褐色脂肪細胞の活性化をPPAR-αの発現量を示す図5が示すように、PPAR-αは褐色脂肪細胞の活性化の指標であるところ、HFD群で通常群に比較してPPAR-αが誘導されていたが、これは過剰な脂質の摂取による生体の反応と思われる。HFD群+2%D-アルロース群では、D-アルロースの摂取により、より強くPPAR-αが誘導されており、褐色脂肪細胞が活性化されていると思われる。
褐色脂肪細胞の活性化をPGC-1αの発現量で示す図6が示すように、HFD群で通常群に比較して、PGC-1αが誘導されていたが、これは過剰な脂質の摂取による生体の反応と思われる。HFD+2%D-アルロース群では、D-アルロースの摂取により、より強くPGC-1αが誘導されており、PPAR-αの活性化補助因子であるPGC-1αの誘導は、下流域にあるUCP- 1の誘導をきたした一因と思われ、褐色脂肪細胞が活性化されていると思われる。
D-アルロースの投与により褐色脂肪細胞の活性化が刺激され、熱産生亢進、脂肪燃焼、代謝亢進を増強することにより、体重減少に寄与したと考えられる。今後の展望として、D-アルロースを摂取することで、『やせやすい』体質を獲得できる可能性を示している。
2型糖尿病患者に対する希少糖D-プシコース(D-アルロース)の効果について検討した。
[方法]
〈選択基準〉
下記のいずれかの治療で十分な効果が得られない2型糖尿病患者
(HbA1c:6.5%以上)(境界型糖尿病)
1)食事療法・運動療法のみ
2)食事療法・運動療法に加えて薬物療法
〈除外基準〉
1)D-アルロース(D-プシコース)投与禁忌に該当する患者
2)他の臨床治験に参加中の患者
3)妊婦、産婦、授乳婦または妊娠の可能性がある女性
4)HbA1cが8%以上の血糖コントロール不良である患者
5)重度の腎機能障害(血清クレアチニン値1.5mg/dl以上)を認める患者
6)他の重篤な合併症を有する患者
〈実験実施方法〉
D-アルロース(D-プシコース)散剤:スティック形状1本5g/包(レアースイート社製造)
1回5gを1日3回経口投与した。
3ヶ月間観察が可能であった2型糖尿病患者12名(男4例、女8例)を対象に、投与前と投与後12週後の一般所見、血液検査を比較した。(ウィルコクソン符号付順位和検定)
実施に当たってはヘルシンキ宣言、臨床研究に関する倫理指針に準拠している香川大学医学部倫理委員会承認
今回の試験においてD-アルロース(D-プシコース)を3ヶ月間投与することにより、3ヶ月後には有意に体重の減少を認めている。
種々の脂肪組織由来生理活性物質、(アディポサイトカイン)とその作用について、レプチン、アディポネクチンは、D-プシコース投与中3ヶ月間は特に有意な変化を認めなかった。
よく知られているようにTNF-αは、脂肪細胞から分泌され、インスリン抵抗性を惹起するサイトカインとして有名である。また善玉アディポサイトカインであるアディポネクチンを抑制することも知られている。本実施例のD-プシコースの投与により、TNF-αが低下することはインスリン抵抗性を改善し、血糖コントロールを改善することが推測される。
またMCP-1は炎症層(血管内皮細胞、脂肪細胞)から分泌され、単球の游走、マクロファージへの分化、酸化LDL受容体の発現を誘導し、動脈硬化を形成する重要なサイトカインである。D-アルロース(D-プシコース)スを3ヶ月間投与することで、MCP-1濃度が有意に低下しており、D-アルロース(D-プシコース)に抗動脈硬化作用があることが示唆される。
(1)2型糖尿病患者12名(男4例,女8例)を対象に,D-アルロース(D-プシコース)を1回5gを1日3回経口投与し、投与前後12週の一般所見、血液検査を比較した。
(2)HbA1c、GA、レプチン、アディポネクチンに有意差は認められなかった。
(3)TNF-α、MCP-1は投与前後で有意に低下していた。特にTNF-αは投与後 二ヶ月で有意に低下していた。
(4)体重は投与後三ヶ月で平均1kg低下していた。
(5)D-アルロース(D-プシコース)は2型糖尿病患者投与で有用な可能性がある。
実施例1と同様に、D-アルロース(D-allulose)投与による褐色脂肪細胞(褐色脂肪組織Brown adipose tissueの略 BAT)への影響について、ベージュ脂肪細胞の分化誘導による体重減少、体脂肪減少への効果について検討した。
(目的)マウスにおいてD-allulosを投与することが褐色脂肪組織へ及ぼす影響を確認する。またベージュ脂肪細胞の分化について、UCP-1などの発現の変化などをマーカーにして検討を行う。
1.プロトコール:
マウス5匹を1群として2群に分ける。両群8週齢マウスに高脂肪食(HFD)を負荷する。HFD負荷後4週後より、1群はそのままHFDを継続する。別の1群はHfdに加えてD-allulos(0.2mg/体重g/日)をゾンデにて胃へ投与する。10週目まで体重、摂食量、飲水量、血糖値をモニターする。
2.結果
1)高脂肪食(HFD)負荷時の体重増加について、結果を図10に示す。
マウス各5匹における普通食と高脂肪食(HFD)時の体重増加について観察している。高脂肪食(HFD)負荷時には、普通食に比較して明らかな体重増加を認められる。
2)図11に高脂肪食(HFD)負荷したマウスにD-アルロースを投与した時の体重の変化を示している。
D-アルロース投与前の高脂肪食(HFD)負荷4週間では両群に体重増加に差を認めない。
D-アルロース投与開始後2週間目(高脂肪食開始後6週目)より両群の体重に優位な差を認めた。
D-アルロース投与群においては、投与開始2週間目より優位に体重の増加が減少した。
3)空腹時血糖値の推移について、結果を図12に示す。
高脂肪食(HFD)負荷したマウスにD-allulosを投与した時の体重の変化を示している。D-allulos投与開始後3週間目(高脂肪食開始後6週目)より空腹時の血糖値の低下を認めた。
4)10週経過後のブドウ糖負荷試験の血糖値の推移について、結果を図13に示す。
腹腔内にブドウ糖を投与し、0、15、30、60、90、120分後の血糖値を測定した。D-アルロース投与群では、90、120分後の血糖値が対象群に比較して優位に低下していた。
5)図14に示すとおり、研究期間中の摂食量(右側図)、飲水量(左側図)には両群に優位な変化はなかった。
6)高脂肪食(HFD)負荷したマウスにD-allulosを投与した時の褐色脂肪細胞(BAT)の重量および面積に関する検討について、結果を図15に示す。
D-アルロース投与群においては、褐色脂肪細胞(BAT)の重量および面積の拡大が認められ、実施例1と同様の結果を得た。
褐色脂肪細胞(BAT)の形態学的な検討において、実施例1の図3と同様に、普通食を摂取した時に褐色脂肪細胞(BAT)の組織像に比べて、高脂肪食(HFD)を負荷したマウスの褐色脂肪細胞(BAT)の組織像は全体的に脂肪が沈着し、脂肪化が進んでおり、一方、高脂肪食(HFD)を負荷に2%のD-allulosを飲水させた群の褐色脂肪細胞(BAT)の組織像は、普通食摂取群とほぼ同様な形態であり、高脂肪食(HFD)負荷群に認められた脂肪の沈着は認められなかった。
ここで、現在の脂肪組織の考えかた(非特許文献3)を図16で説明する。
ベージュ脂肪細胞、あるいはベージュ脂肪細胞は、2012年、第3の脂肪細胞としてハーバード大学医学部ダナ・ファーバー癌研究所のブルース・スピーゲルマン博士の研究チームによって単離された。
脂肪細胞には、脂肪を蓄積する白色脂肪細胞と、脂肪を燃焼し熱を産生する働きを持つ褐色脂肪細胞が存在している。褐色脂肪細胞には脱共役タンパク質(uncоupling prоtein 1:UCP-1)というタンパク質が多く発現しており、UCP-1が熱を生み出し、脂肪を燃やし、エネルギーに変える働きをする。ベージュ脂肪細胞は白色脂肪細胞のようにUCP-1の発現が非常に低い細胞が、寒さなどの刺激によりUCP-1が高発現する。その際にこの脂肪細胞は褐色脂肪細胞のように熱産生を行うようになり、白色脂肪細胞が褐色様の形質を持つようになる。褐色脂肪細胞やベージュ脂肪細胞は、寒冷曝露に応じて熱を産生する特殊な脂肪細胞として、寒冷環境での体温維持に寄与している。これらの脂肪細胞が持つ熱産生・エネルギー消費活性は、体温調節能のみならず、肥満や代謝性疾患の予防にも役立つことが期待されている。褐色脂肪細胞とベージュ脂肪細胞は、UCP-1を発現し、熱産生能を有する点は共通しているが、細胞の起源や機能制御機構は異なることがわかってきている。古典的な褐色脂肪細胞は、小型げっ歯類、特に冬眠動物で発達しており、肩甲骨間や腋窩、腎周囲に褐色脂肪細胞塊として存在している。褐色脂肪細胞の分化と組織形成は胎仔期に完成するのに対し、ベージュ脂肪細胞の分化は寒冷環境への曝露などの刺激に応じて誘導され、刺激がなくなると消失していく。この誘導性・可塑性は、発生時より存在し続ける“既存型”の褐色脂肪細胞や白色脂肪細胞と比して最大の特徴といえる。
機能的特徴をみると、余剰エネルギーを中性脂肪として貯蔵する白色脂肪細胞とは異なり、褐色脂肪細胞とベージュ脂肪細胞はUCP-1が酸化的リン酸化を脱共役させることにより、熱産生を行う。これらの点では、ベージュ脂肪細胞は褐色脂肪細胞と似ているといえる。
近年,陽電子画像診断法(fluоrоdeоxyglucоse‐
pоsitrоn missiоn tоmоgraphy:FDG‐PET)を用いた研究により、ヒトでも一定量、褐色脂肪細胞(BAT)が存在することは明らかになった。ヒトにおけるBATの存在部位は、肩甲骨間、腎周囲、鎖骨上窩部、腋下部,傍脊椎部などである。近年の研究より成人が持つBATは主にベージュ脂肪細胞により構成されていることが示唆された。このことは,成人のBAT活性が夏に最小になり、冬に最大になる、すなわち誘導性および可塑性を持つという事実によっても支持される。BAT活性変化量と体脂肪変化量の間には負の相関が認められる。この結果により、ヒトBAT(ベージュ脂肪細胞)が肥満を軽減するための有効な刺激標的になることが明らかになった。
左側図面は、ベージュ脂肪細胞においてはD-アルロースを投与することにより優位にUCP-1の発現が増加している。つまりD-アルロースによりベージュ脂肪細胞が分化誘導されていることを示している。
右側図面は、古典的な褐色脂肪組織においてもUCP‐1の発現が増加している。
D-allulosの投与は、ベージュ脂肪細胞の誘導および褐色脂肪細胞の活性化を介して体重減少に寄与している可能性がある。
8)高脂肪食(HFD)負荷したマウスにD-アルロースを投与したマウスにけるベージュ脂肪細胞、褐色脂肪細胞のUCP-1タンパクの発現の検討について、結果を図18に示す。
左側図面は、ベージュ脂肪細胞においてはD-アルロースを投与することにより優位にUCP-1タンパクの発現が増加している。つまりD-アルロースによりベージュ脂肪細胞が分化誘導されていることを示している。
右側図面は、古典的な褐色脂肪組織においてもUCP-1タンパクの発現が増加している。
D-allulosの投与は、ベージュ脂肪細胞の誘導および褐色脂肪細胞の活性化を介して体重減少に寄与している可能性がある。
9)D-allulos投与によるベージュ脂肪細胞の誘導および褐色脂肪細胞の活性化の詳細について、熱の産生に関与する遺伝子UCP-1, Prdm16, 熱産生に関与するオルガネラのミトコンドリアの機能を反映する遺伝子、Pgcl-α、Tfam、 脂肪の分化に関係する遺伝子PPARγの発現について検討し結果を図19に示す。
左側図面は、ベージュ脂肪細胞での検討では、UCP-1、Prdm16、Pgcl-α、Tfam、PPARγともの発現が増加しており、ベージュ脂肪細胞が強く誘導されていることを示している。
右側図面は、褐色脂肪細胞では、UCP-1、Prdm16、Tfamの発現が増加していた。これらが褐色脂肪細胞の活性化に関与していることが推定される。
図21は、細胞を使った実験において、BAT-プロトコール、WAT-プロトコールの二つがベージュ脂肪細胞を誘導するプロトコールにD-アルロースを追加するプロトコールついて説明する図面である。
図22は、D-アルロースを分化誘導プロトコールに追加することにより、ベージュ脂肪細胞への誘導が促進されることを脂肪染色で示している。
D-アルロースの追加(右)によりоil-red-O(脂肪染色)が促進されている。
図23は、分化誘導プロトコールによって誘導されたベージュ脂肪細胞の評価として様々なマーカーの発現を検討している。WAT-プロトコールは、褐変マーカー遺伝子(UCP-1、Pgc-1α、cоx8b)の誘導により強い影響を及ぼす。WAT-プロトコールを使用すると、D-アルロースはPrdm16、Pgc-1α、およびPPARγの発現を強化する。
両方の分化プロトコールで、D-アルロースはPPARγの発現を増強し、D-アルロースが脂肪生成を促進することを示唆している。
すなわち、D-アルロース投与群においては、全てのマーカーが優位に増加し、ベージュ脂肪細胞誘導のプロセスを優位に促進していた。
図24において、プロトコールによって誘導されたベージュ脂肪細胞の評価として様々なマーカーの発現を検討している。UCP-1とPPARγをD-アルロース存在、非存在かで検討している。D-アルロースの存在でUCP‐1とPPARγが増加し、ベージュ脂肪細胞の誘導が促進されていることが示された。
BAT-プロトコーと比較して、WAT-プロトコールはUCP-1タンパク質発現の誘導により強い影響を及ぼす。WAT-プロトコールを使用すると、D-アルロースはUCP-1タンパク質の発現をわずかに高める。
3.結論的考察
D-アルロースの投与により体重減少が認められる。この体重減少効果は、ベージュ脂肪細胞が分化誘導されたこと、褐色脂肪細胞が活性化されたことによると考えられる。
Claims (11)
- D-アルロースを有効成分として含有する褐色脂肪・ベージュ脂肪細胞活性化剤。
- 少なくともD-アルロースを含有し、かつ、UCP‐1発現促進作用を有する褐色脂肪・ベージュ脂肪細胞活性化剤。
- UCP-1の発現を亢進させることにより褐色脂肪・ベージュ脂肪細胞を活性化する、請求項1または2に記載の褐色脂肪・ベージュ脂肪活性化剤。
- D-アルロースを有効成分として含有するエネルギー消費促進剤。
- 褐色脂肪・ベージュ脂肪細胞を活性化することによりエネルギーの消費を促進する、請求項4に記載のエネルギー消費促進剤。
- D-アルロースを有効成分として含有するUCP‐1発現亢進剤。
- 請求項1ないし6のいずれか1項に記載の剤を含む組成物。
- D-アルロースを有効成分として含有する褐色脂肪・ベージュ脂肪細胞活性化用組成物。
- 熱産生によるエネルギーの消費を促進するための、請求項7または8に記載の組成物。
- UCP‐1の発現を亢進させることにより褐色脂肪・ベージュ脂肪細胞を活性化する、請求項7ないし9のいずれか1項に記載の組成物。
- 前記組成物が食品組成物である、請求項7ないし10のいずれか1項に記載の組成物。
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EP19881272.9A EP3878457A4 (en) | 2018-11-08 | 2019-11-07 | BROWN/BEIGE ADIPOCYTE ACTIVATING AGENT WITH D-ALLULOSE AS AN ACTIVE INGREDIENT |
JP2020555590A JPWO2020096002A1 (ja) | 2018-11-08 | 2019-11-07 | D−アルロースを有効成分とする褐色脂肪・ベージュ脂肪細胞活性化剤 |
CN201980073333.8A CN113015533A (zh) | 2018-11-08 | 2019-11-07 | 以d-阿洛酮糖为有效成分的褐色脂肪·米色脂肪细胞活化剂 |
MX2021005451A MX2021005451A (es) | 2018-11-08 | 2019-11-07 | Agente activador de adipocitos pardos y beige que contiene d-alulosa como ingrediente activo. |
US17/292,166 US20210386767A1 (en) | 2018-11-08 | 2019-11-07 | Brown and beige adipocyte activating agent containing d-allulose as active ingredient |
KR1020217017195A KR20210091211A (ko) | 2018-11-08 | 2019-11-07 | D-알룰로오스를 유효 성분으로 하는 갈색 지방·베이지 지방 세포 활성화제 |
JP2024007170A JP2024032817A (ja) | 2018-11-08 | 2024-01-22 | D‐アルロースを有効成分とする褐色脂肪・ベージュ脂肪細胞活性化剤 |
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WO2010113785A1 (ja) | 2009-03-30 | 2010-10-07 | 松谷化学工業株式会社 | 目的とするヘキソースを所定量含む原料糖とは異なる糖組成の糖組成物の製造方法および製造された糖組成物の用途 |
WO2014175119A1 (ja) * | 2013-04-26 | 2014-10-30 | 松谷化学工業株式会社 | エネルギー消費の促進および/またはエネルギー消費機能低下の治療および/または予防剤、または方法 |
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EP2843044A1 (en) * | 2013-09-03 | 2015-03-04 | Roquette Frères | Improved variant of D-psicose 3-epimerase and uses thereof |
WO2016004093A2 (en) * | 2014-07-01 | 2016-01-07 | Stealth Biotherapeutics Corp | Therapeutic compositions including galectin-3 inhibitors and uses thereof |
KR101692033B1 (ko) * | 2015-09-01 | 2017-01-03 | 경북대학교 산학협력단 | D-싸이코스를 유효성분으로 함유하는 지질 관련 대사성 질환의 예방 또는 치료용 조성물 |
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WO2010113785A1 (ja) | 2009-03-30 | 2010-10-07 | 松谷化学工業株式会社 | 目的とするヘキソースを所定量含む原料糖とは異なる糖組成の糖組成物の製造方法および製造された糖組成物の用途 |
WO2014175119A1 (ja) * | 2013-04-26 | 2014-10-30 | 松谷化学工業株式会社 | エネルギー消費の促進および/またはエネルギー消費機能低下の治療および/または予防剤、または方法 |
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CN113015533A (zh) | 2021-06-22 |
KR20210091211A (ko) | 2021-07-21 |
JP2024032817A (ja) | 2024-03-12 |
EP3878457A1 (en) | 2021-09-15 |
US20210386767A1 (en) | 2021-12-16 |
EP3878457A4 (en) | 2022-07-27 |
MX2021005451A (es) | 2021-06-18 |
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