AU2020204029A1 - Lactobacillus paracasei AO356 strain having anti-obesity activity and composition when used for preventing, alleviating or treating obesity including the same - Google Patents
Lactobacillus paracasei AO356 strain having anti-obesity activity and composition when used for preventing, alleviating or treating obesity including the same Download PDFInfo
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/165—Paracasei
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/225—Lactobacillus
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/195—Assays involving biological materials from specific organisms or of a specific nature from bacteria
- G01N2333/335—Assays involving biological materials from specific organisms or of a specific nature from bacteria from Lactobacillus (G)
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Abstract
A novel Lactobacillus paracasei A0356 strain according to the present
disclosure, which is a strain isolated from the human body, has high stability, exhibits
the activity of inhibiting adipogenic differentiation in vitro and inducing the
differentiation of M1 and MO macrophages into M2 macrophages, and has excellent
activity of alleviating, preventing, or treating obesity, such as the activity of reducing
body weight and a reduction in blood lipid concentration through the browning of
white fat in animal experiments. Thus, the novel strain of the present disclosure has
a low possibility of causing side effects, and therefore, unlike conventional diet
functional foods or drugs, which have side effect problems, a diet effect can be
exhibited without controlling the dose thereof. Accordingly, the novel strain can be
used as a pharmaceutical composition for treating or preventing obesity or a food
composition for alleviating or preventing obesity.
7/21
38
-+- ND
36 -- HFD
-dr- L. paracasei A0356
w 34
-%.0
W 32
30 30 0
28
26
24
22
0 1 2 3 4 5 6 7 8 9 10
(weeks)
FIG. 10
Description
7/21
38 -+- ND 36 -- HFD -dr- L. paracasei A0356 w 34 -%.0 W 32
30 30
28
26
24
22 0 1 2 3 4 5 6 7 8 9 10 (weeks) FIG. 10
LACTOBACILLUS PARACASEIA0356 STRAIN HAVING ANTI-OBESITY
1. Field
The present disclosure relates to a novel Lactobacillus paracasei A0356
strain having anti-obesity activity, and a composition when used for preventing,
alleviating or treating obesity including the same.
2. Discussion of Related Art
As mankind has developed into a rich society, obesity has emerged as one of
the most serious chronic diseases. Obesity occurs due to various causes, is a
metabolic disorder caused by an imbalance between intake and consumption of
calories, and morphologically, is known to be caused by hypertrophy or hyperplasia
of adipocytes in the body.
Obesity has become a direct cause that not only psychologically disturbs
individuals, but also increases the risk of various adult diseases socially, and thus is a
major cause of an increase in national medical spending.
Specifically, obesity is directly associated with the increased prevalence of
various adult diseases such as type 2 diabetes, hypertension, hyperlipidemia, and
cardiovascular disease, and all obesity-related diseases are referred to as metabolic
syndrome or insulin resistance syndrome. These act as causes of arteriosclerosis and
cardiovascular diseases.
Obesity is not only the most common malnutrition disorder in western society,
but also in Korea, the frequency of obesity tends to be rapidly increasing due to the
improvement of diet and westernization of lifestyles, which result from economic
advances. Since the rate of obesity in Korean adults is increasing 3% each year, the
obesity problem is gradually getting worse. Therefore, there is a need to develop a
therapeutic agent or treatment method for treating and preventing obesity.
Obesity therapeutic agents, which are known to date, are broadly classified
into appetite suppressants, energy consumption promoters, and fat absorption
inhibitors, such as XenicalTM (Roche Pharmaceuticals, Switzerland), ReductiTM
(Abbott, USA), and ExoliseTM (Atopharma, France), and most obesity drugs are
appetite suppressants that suppress appetite by regulating neurotransmitters associated
with the hypothalamus. However, conventional therapeutic agents have low
persistence of efficacy, along with side effects such as heart disease, respiratory
diseases, and neurological diseases, and thus there is a need to develop more improved
obesity therapeutic agents. In addition, products being currently developed also have
little satisfactory therapeutic effect, and thus there is a need to develop a novel obesity
therapeutic agent.
On the other hand, many efforts have been made to reduce cholesterol levels
in the blood using lactic acid bacteria, which are considered safe microorganisms.
Lactobacillus, which is a metabolite that uses sugars as an energy source, produces a
large amount of lactic acid and also produces other organic acids and antibacterial
substances such as bacteriocin, but does not produce indole, skatole, phenol, amines or ammonia, or the like, which are harmful to the intestines of humans or animals.
Thus, lactobacillus is a beneficial bacterium that prevents spoilage, suppresses harmful
bacteria, and exhibits physiological activity that is beneficial to humans. Among
these, strains belonging to the genus Lactobacillus are a major member of the normal
microbial community inhabiting the intestines of the human body, and have long been
known to be important for maintaining a healthy digestive system and vaginal
environment. According to U.S. Public Health Service guidelines, all Lactobacillus
strains, which are currently deposited in the U.S. strain depository organization
(ATCC), are classified as "Bio-safety Level 1," which is recognized as having no
known potential risk of causing diseases to humans or animals.
Korean Registered Patent Publication No. 10-1471033 discloses a Weisella
sp. F22 (Accession No .: KACC 91867P) strain having excellent anti-obesity activity,
and Korean Registered Patent Publication No. 10-0264361 discloses a Lactobasillus
plantarum PM008 (KFCC-11028) strain having a cholesterol-lowering ability and
deconjugation activity against 6 types of conjugated bile acids.
However, since commercially successful technologies related to
Lactobacillus exhibiting an excellent anti-obesity effect have not yet emerged, as
having conducted research on probiotics having no side effects in the body and
exhibiting an excellent obesity treatment effect, the inventors of the present disclosure
newly discovered a Lactobacillus paracaseiA0356 strain, and confirmed that the
strain exhibited high viability and activity in the body of animals, and exhibited an
excellent effect of alleviating, preventing, or treating obesity even when the strain itself
was directly added as an active ingredient of foods and medicines, and thus completed the present disclosure.
Related Art Documents
Patent Documents
(Patent Document 0001) Patent Document 1. Korea Registered Patent
Publication No. 10-1471033
(Patent Document 0002) Patent Document 2. Korea Registered Patent
Publication No. 10-0264361
Any reference to or discussion of any document, act or item of knowledge in
this specification is included solely for the purpose of providing a context for the
present invention. It is not suggested or represented that any of these matters or any
combination thereof formed at the priority date forms part of the common general
knowledge, or was known to be relevant to an attempt to solve any problem with which
this specification is concerned.
Provided is a LactobacillusparacaseiA0356 strain (KCCM12145P) having
anti-obesity activity.
Provided are probiotics including the LactobacillusparacaseiA0356 strain
(KCCM12145P) or a culture medium thereof.
Provided is a pharmaceutical composition for preventing or treating obesity,
including the Lactobacillus paracasei A0356 strain (KCCM12145P) or a culture
medium thereof.
Provided are a food composition for preventing or alleviating obesity and a
food composition for alleviating inflammation caused by obesity, the compositions
including the Lactobacillus paracasei A0356 strain (KCCM12145P) or a culture
medium thereof.
Additional aspects will be set forth in part in the description which follows
and, in part, will be apparent from the description, or may be learned by practice of the
presented embodiments.
According to a first aspect of the present disclosure, there is provided a
LactobacillusparacaseiA0356 strain (KCCM12145P) having anti-obesity activity.
According to a second aspect of the present disclosure, there is provided a
probiotic or food composition comprising the LactobacillusparacaseiA0356 strain
(KCCM12145P) of the first aspect or a culture medium thereof.
According to a third aspect of the present disclosure, there is provided a
pharmaceutical composition comprising the Lactobacillus paracaseiA0356 strain
(KCCM12145P)of claim the firs aspect or a culture medium thereof
The Lactobacillus paracaseiA0356 strain (KCCM12145P) or the culture
medium thereof may be included in an amount of about 0.01 wt% to about 50 wt%
with respect to a total weight of the composition.
The composition may inhibit adipogenic differentiation.
The composition may induce differentiation into M2 type macrophages.
The composition may reduce body weight.
According to a fourth aspect there is provided the pharmaceutical composition of
the third aspect, when used for preventing or treating obesity.
According to a fifth aspect of the present disclosure, there is provided a food
composition for preventing or alleviating obesity, including the Lactobacillus
paracaseiA0356 strain (KCCM12145P) or a culture medium thereof.
According to a sixth aspect of the present disclosure, there is provided a food
composition for alleviating inflammation caused by obesity, including the
LactobacillusparacaseiA0356 strain (KCCM12145P) or a culture medium thereof.
According to a seventh aspect there
According to an eight aspect there is provided a method for preventing or
alleviating obesity, or alleviating inflammation caused by obesity, the method
comprising administering to a subject an effective dose of Lactobacillus paracasei
A0356 strain (KCCM12145P), the probiotic or food composition of the second aspect,
or the pharmaceutical composition of any one of the third aspect.
According to a ninth aspect there is provided use of Lactobacillusparacasei
A0356 strain (KCCM12145P) for the manufacture of a medicament for preventing or
alleviating obesity, or alleviating inflammation caused by obesity.
It is to be noted that, throughout the description and claims of this specification,
the word 'comprise' and variations of the word, such as 'comprising' and 'comprises',
is not intended to exclude other variants or additional components, integers or steps.
Modifications and improvements to the invention will be readily apparent to those
skilled in the art. Such modifications and improvements are intended to be within the
scope of this invention.
The above and other objects, features and advantages of the present disclosure
will become more apparent to those of ordinary skill in the art by describing in detail
exemplary embodiments thereof with reference to the accompanying drawings, in
which:
FIG. 1 is a view illustrating a series of analysis processes for selecting strains
having anti-obesity activity according to Experimental Example 1 of the present
disclosure;
FIG. 2 is a graph showing the lipid accumulation of each of 36 strains
measured using Oil red 0 staining according to Experimental Example 1 of the present
disclosure;
FIG. 3 is a view illustrating a series of analysis processes for selecting strains
having anti-obesity activity according to Experimental Example 2 of the present
disclosure;
FIG. 4 is a graph showing the results of measuring cytokine secretion (%) in
macrophages when treated with each of 36 dead strains according to Experimental
Example 2 of the present disclosure;
FIG. 5 is a graph showing the results of measuring a ratio of IL/10 to IL-12
in macrophages when treated with each of 36 dead strains according to Experimental
Example 2 of the present disclosure;
FIG. 6 is a graph showing the results of measuring cytokine secretion (%) in
macrophages when treated with each of 36 live strains according to Experimental
Example 2 of the present disclosure;
FIG. 7 is a graph showing the results of measuring a ratio of IL-10 to IL-12
in macrophages when treated with each of 36 live strains according to Experimental
Example 2 of the present disclosure;
FIG. 8 is a flowchart illustrating a process of setting experimental animals
and experimental groups according to Experimental Example 3 of the present
disclosure;
FIG. 9 is a graph showing the results of measuring a body weight change in
each experimental group according to Experimental Example 3 of the present
disclosure;
FIG. 10 is a graph showing the results of measuring a body weight change
according to week in each experimental group according to Experimental Example 5
of the present disclosure;
FIG. 11 is a graph showing the results of analyzing weight gain in each
experimental group according to Experimental Example 5 of the present disclosure;
FIG. 12A-E is a set of graphs showing the results of measuring fat weights of,
with respect to body weight, the liver (A), epididymal fat tissue (B), retroperitoneal fat
tissue (C), inguinal fat tissue (D), and interscapular brown adipose tissue (E), in each
experimental example according to Experimental Example 5 of the present disclosure;
FIG. 13A-F is a set of graphs showing LDL-cholesterol (A), triglycerides (TG)
(B), HDL-cholesterol (C), glucose (D), insulin (E), and HOMA-IR (F), which were
measured in serum isolated from each experimental group according to Experimental
Example 5 of the present disclosure; and
FIG. 14A-C is a set of graphs showing the results of analyzing the mRNA
expression levels of lipometabolism-related genes after extracting RNA from
epididymal white fat isolated from each experimental group and performing qPCR
analysis thereon, according to Experimental Example 5 of the present disclosure.
Exemplary embodiments of the present disclosure will be described in detail
with reference to the accompanying drawings. While the present disclosure is shown
and described in connection with exemplary embodiments thereof, it will be apparent
to those skilled in the art that various modifications can be made without departing
from the spirit and scope of the present disclosure.
Hereinafter, various aspects and various embodiments of the present
disclosure will be described in more detail.
One embodiment of the present disclosure relates to a Lactobacillus
paracaseiA0356 strain (KCCM12145P) having anti-obesity activity.
The LactobacillusparacaseiA0356 strain according to the present disclosure
is a strain isolated from the human body, and is a strain deposited in the Korean Culture
Center of Microorganisms on November 2, 2017.
The LactobacillusparacaseiA0356 strain according to the present disclosure
includes 16S rDNA having the nucleotide sequence set forth in SEQ ID NO: 1, and
the LactobacillusparacaseiA0356 strain is a Gram-positive bacterium that appears
purple in Gram staining and uses, as carbon sources, glucose, galactose, maltose, D
ribose, sucrose, lactose, trehalose raffinose, and the like.
In addition, the LactobacillusparacaseiA0356strain may further exhibit, in
addition to anti-obesity activity, an activity of inhibiting inflammation caused by
obesity. When ingested via oral administration, the LactobacillusparacaseiA0356
strain suppresses adipogenic differentiation, induces differentiation into M2
macrophages to thereby inhibit obesity, and reduces a host's intake of dietary fat, while
increasing the excretion of dietary fat, thereby reducing the body weight of a host.
In addition, the Lactobacillus paracasei A0356 strain of the present
disclosure has excellent viability against gastric acid or bile, and thus exhibits high
viability in the body of an animal, so that the strain can maintain anti-obesity activity
in the body for a long time.
Also, another embodiment of the present disclosure relates to probiotics
including the Lactobacillus paracasei A0356 strain (KCCM12145P) or a culture
medium thereof.
The LactobacillusparacaseiA0356 strain according to the present disclosure
may be used as it is in a cultured state, or may be used in the form of dry powder.
In the present disclosure, the culture medium refers to the entire medium
including: a cultured strain obtained by culturing, for a certain period of time, the
Lactobacillus paracaseiA0356 strain in a known liquid medium or solid medium
capable of supplying nutrients so that the LactobacillusparacaseiA0356 strain can
grow and survive in vitro; a metabolite thereof; extra nutrients; or the like, and the
culture medium also includes a culture medium from which the strain is removed after
being cultured.
The culture medium may be centrifuged or filtered, or concentrated, and these processes may be performed according to the needs of one of ordinary skill in the art.
In the present disclosure, probiotics refer to intestinal flora that are beneficial
to health, i.e., living microorganisms, i.e., living bacteria, which provide benefits to
the health of a host. In general, probiotics are consumed as part of fermented foods
such as yogurt or as dietary supplements.
The LactobacillusparacaseiA0356 strain of the present disclosure, which is
a strain of the genus Lactobacillus known as probiotics, has excellent viability against
gastric acid and bile, and has anti-obesity activity, and thus may be used as a probiotic.
The Lactobacillus paracaseiA0356 strain (KCCM12145P) or the culture
medium thereof may be included in an amount of about 0.01 wt% to about 50 wt%
with respect to a total weight of the composition.
The composition may be administered such that the number of live bacteria
of the Lactobacillus paracasei A0356 strain included in the composition is a
concentration of less than 5x107 CFU, but this has to be selected depending on a patient
and a situation, and the number of live bacteria in the composition is not intended to
limit the scope of the present disclosure.
Another embodiment of the present disclosure relates to a pharmaceutical
composition for preventing or treating obesity and a food composition for preventing
or alleviating obesity, the compositions including the LactobacillusparacaseiA0356
strain (KCCM12145P) or a culture medium thereof.
The LactobacillusparacaseiA0356 strain according to the present disclosure
may be used as it is in a cultured state or may be used in the form of dried powder.
In the present disclosure, the culture medium refers to the entire medium including: a cultured strain obtained by culturing, for a certain period of time, the
Lactobacillus paracaseiA0356 strain in a known liquid medium or solid medium
capable of supplying nutrients so that the LactobacillusparacaseiA0356 strain can
grow and survive in vitro; a metabolite thereof; extra nutrients; or the like, and the
culture medium also includes a culture medium from which the strain is removed after
being cultured. The culture medium from which the strain has been removed may be
a sterilized culture medium including dead bacteria, or may be a filtrate or centrifuged
supernatant from which the strain is removed by filtration or centrifugation.
The culture medium may be centrifuged or filtered, or concentrated, and these
processes may be performed according to the needs of one of ordinary skill in the art.
The Lactobacillus paracaseiA0356 strain (KCCM12145P) or the culture
medium thereof is included in an amount of about 0.01 wt% to about 50 wt% with
respect to the total weight of the composition, and may be directly used, may be used
after concentration, or may be diluted after concentration or drying and used.
The effect of alleviating, treating or preventing obesity according to the
present disclosure is expected to be obtained by the Lactobacillus paracaseiA0356
strain that, while proliferating, inhibits the differentiation of mast cells, induces
differentiation into M2 type macrophages, and reduces a host's intake of dietary fat,
while increasing the excretion of dietary fat, thereby reducing the body weight of the
host, and the composition may be used as it is in a liquid state, or may also be dried
and powdered.
The expression "including as an active ingredient" means including the
Lactobacillus paracaseiA0356 strain or the culture medium thereof in an amount sufficient to achieve obesity-alleviating, -treating, or -preventing efficacy or activity.
The term "prevention" means all actions that inhibit or delay the onset, spread,
and recurrence of obesity via administration of the composition, and the term
"treatment" means all actions that improve or beneficially change the symptoms of
obesity via administration of the composition.
The food composition may be prepared by formulating the composition in the
form of capsules, tablets, powder, granules, liquids, pills, flakes, pastes, syrups, gels,
jellies, or bars, or may be prepared into a general food form by adding the composition
to food substances such as beverages, teas, spices, gum, or confectionaries, and means
a food composition that has specific health effects when ingested, but has an advantage
that, unlike general drugs, the food composition uses food as raw materials, and thus
has no side effects that may occur when drugs are administered for a long time.
The food composition is very useful because it may be ingested daily. The
amount of the LactobacillusparacaseiA0356 strain or the culture medium thereof
added in such a food composition varies depending on the type of target food, and thus
cannot be equally defined, but the strain may be added within a range that does not
impair the original taste of food, and the amount of the strain generally ranges from
about 0.01 wt% to about 50 wt%, preferably about 0.1 wt% to about 20 wt%, with
respect to the target food. In addition, in the case of a food composition in the form
of capsules, tablets, powders, granules, liquids, pills, flakes, pastes, syrups, gels, jellies,
or bars, the strain is generally added in the range of about 0.1 wt% to about 100 wt%,
preferably about 0.5 wt% to 80 wt%.
The food composition may include, in addition to the Lactobacillusparacasei
A0356 strain or the culture medium thereof as an active ingredient, ingredients that
are commonly added in food preparation, and examples of the ingredients include
proteins, carbohydrates, fat, nutrients, a seasoning agent, and a flavoring agent.
Examples of the above-described carbohydrates include general sugars such as
monosaccharides, e.g., glucose and fructose; disaccharides, e.g., maltose, sucrose, and
oligosaccharides; and polysaccharides, e.g., dextrin and cyclodextrin, and sugar
alcohols such as xylitol, sorbitol, and erythritol.
As the flavoring agent, a natural flavoring agent (thaumatin and stevia
extracts (e.g., rebaudioside A and glycyrrhizin) and a synthetic flavoring agent
(saccharin, aspartame, and the like) may be used.
For example, when the food composition of the present disclosure is prepared
as drinks and beverages, the food composition may further include, in addition to the
LactobacillusparacaseiA0356 strain or a culture medium thereof, citric acid, liquid
fructose, sugar, glucose, acetic acid, malic acid, fruit juice, various plant extracts, and
the like.
In addition, the pharmaceutical composition for preventing or treating obesity
including, as an active ingredient, the Lactobacillus paracasei A0356 strain or a
culture medium thereof may be administered such that the number of live bacteria of
the Lactobacillus paracaseiA0356 strain is included at a concentration of less than
5x107, preferably 5x103 CFU to 5x107 CFU, but this has to be selected depending on
a patient and a situation, and the number of live bacteria in the composition is not
intended to limit the scope of the present disclosure.
In addition, the culture medium is included in the composition at a dose of
0.001 mg/kg or more, preferably 0.1 mg/kg or more, more preferably 10 mg/kg or
more, even more preferably 100 mg/kg or more, still more preferably 250 mg/kg or
more, and most preferably 0.1 g/kg or more. The LactobacillusparacaseiA0356
strain, which is a strain isolated from the human body, does not have side effects on
the human body even when administered an excess dose of live bacteria, and thus, the
quantitative upper limit of the LactobacillusparacaseiA0356 strain included in the
composition of the present disclosure may be selected by one of ordinary skill in the
art within an appropriate range.
The pharmaceutical composition may be prepared using a pharmaceutically
acceptable and physiologically acceptable adjuvant in addition to the active ingredient,
and the adjuvant includes excipients, disintegrants, sweeteners, binders, coating agents,
expanding agents, lubricants, flavoring agents, or the like.
The pharmaceutical composition may be formulated by further including one
or more pharmaceutically acceptable carriers, in addition to the active ingredient
described above for administration.
Formulations of the pharmaceutical composition may be granules, powders,
tablets, coated tablets, capsules, suppositories, liquids, syrups, juices, suspensions,
emulsions, drops, injectable liquids, or the like. For example, for formulation in the
form of tablets or capsules, the active ingredient may be combined with an oral, non
toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. In
addition, if desired or necessary, suitable binders, lubricants, disintegrants, and
colorants may also be included as a mixture. Suitable binders include, but are not
limited to, natural sugars such as starch, gelatin, glucose, or beta-lactose, sweeteners of com, natural and synthetic gum such as acacia, tragacanth, or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.
Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite,
and xanthan gum.
Pharmaceutically acceptable carriers in compositions formulated as liquid
solution are sterile and biocompatible, and as the carrier, saline, sterile water, Ringer's
solution, buffered saline, an albumin injection solution, a dextrose solution, a
maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these
components may be used. As necessary, other general additives such as antioxidants,
buffers, and bacteriostatic agents may be added. In addition, diluents, dispersants,
surfactants, binders, and lubricants may be additionally added to formulate into
injectable formulations such as aqueous solutions, suspensions, and emulsions, pills,
capsules, granules, or tablets.
Furthermore, the compositions of the present disclosure may be formulated
according to each disease or ingredient using methods disclosed in Remington's
Pharmaceutical Science, Mack Publishing Company, Easton PA by appropriate
methods in the art.
The pharmaceutical composition may be administered orally or parenterally,
and in the case of parenteral administration, the pharmaceutical composition may be
administered via intravenous injection, subcutaneous injection, intramuscular injection,
intraperitoneal injection, transdermal administration, or the like, and oral
administration is preferably used.
A suitable dose of the pharmaceutical composition may vary depending on factors, such as formulation method, administration method, the age, body weight, and gender of a patient, pathologic conditions, diet, administration time, administration route, excretion speed, and reaction sensitivity, and ordinarily skilled doctors can easily determine and prescribe an effective dose for targeted treatment or prevention.
According to an exemplary embodiment, a daily dose of the pharmaceutical
composition ranges from about 0.001 g/kg to about 10 g/kg.
The pharmaceutical composition may be formulated using a pharmaceutically
acceptable carrier and/or an excipient by a method, which may be easily carried out by
one of ordinary skill in the art to which the present disclosure pertains, to be prepared
in a unit dose form or to be contained in a multi-dose container. In this regard, the
formulation may be a solution in oil or an aqueous medium, a suspension, an emulsion,
an extract, powder, granules, tablets, or capsules, and may further include a dispersing
agent or a stabilizing agent.
Hereinafter, the present disclosure will be described in further detail with
reference to the following examples and the like. However, these examples and the
like should not be construed as limiting the scope and content of the present disclosure.
In addition, based on the disclosure of the present disclosure including the following
examples, it is obvious that those of ordinary skill in the art can easily carry out the
present disclosure in which experimental results are not specifically presented, and it
is also obvious that these changes and modifications fall within the appended claims.
In addition, the experimental results presented below are only representative
experimental results of the examples and comparative examples, and the effects of various embodiments of the present disclosure, which are not explicitly presented below, are described in detail in the corresponding parts.
Example 1. 36 Strains
To select a candidate group of probiotics having anti-obesity activity, 36
strains (see Table 1) derived from the human body were collected, and each strain was
isolated and identified, and shown in Table 1. Each strain was cultured in MRS
medium (Difco, 288110) at 37 C for 18 hours to 24 hours.
Table 1
No. Strain name 1 Lactobacillus sakei subsp. Sakei 2 Streptococcus infantariussubsp. Coli 3 Bacillus licheniformis 4 Bacillus siamensis 5 Lactobacillus sakei subsp. Carnosus 6 Enterococcusfaecalis 7 Enterococcus hirae 8 CarnobacteriummaltaromaticumBA 9 Lactobacillus reuteri 10 Enterococcusfaecium 11 Enterococcusfaecium 12 Enterococcusfaecium 13 Lactobacillusfermentum 14 Lactobacillus mucosae 15 LactobacillusparacaseiA0365 16 Lactobacillus acidilactici 17 Lactobacillus zeae 18 Enterococcusfaecium 19 Lactobacillus reuteri 20 Lactobacillusjohnsonii 21 Lactobacilluspentosus 22 Lactobacillus gasseri 23 Lactobacillus ruminis 24 Lactobacillus mesenteroides subsp. Mesenteroides 25 Obesumbacteriumproteus 26 D29 27 101-7
28 102-4 29 M40a 30 Lactobacillus acidophilus 31 Lactobacillus rhamnosus 32 Pediococcuspentosaceus 33 Bifidobacterium lactis 34 Bifidobacterium breve 35 Lactobacillus acidophilus 36 Lactobacillus intestinalis
Experimental Example 1. Selection of Strains Having Adipogenesis
Inhibitory Activity
To evaluate the anti-obesity efficacy of the upper tier candidate strains, the
ability to inhibit the differentiation of pre-adipocytes (3T3-L1 cells) into adipocytes
(Example 1) and the ability to regulate macrophages (splenic macrophages isolated
from mice) (Example 2) were analyzed and compared.
(1) Experimental Method
The accumulation of lipids in adipocytes is the most representative
characteristic of obesity. Adipocytes are formed by the differentiation of pre
adipocytes derived from stem cells, and while 3T3-L1 cells (pre-adipocytes)
differentiate into adipocytes, intracellular fat globules are formed through
morphological and biochemical changes, and as the differentiation progresses, the size
of fat globules increases. Since most fat globules consist of proteins such as
triglycerides and perilipin A, the degree of fat differentiation may be confirmed by
measuring the intracellular content of triglycerides.
Thus, 3T3-L1 cells, which are representative pre-adipocytes, were treated
with each of the upper tier candidate strains, differentiation was induced, and the intracellular content of triglycerides (TG) was measured to evaluate the activity of inhibiting adipogenesis.
For the above-described TG content measurement experiment, culturing of
cells was maintained for at least 8 days or longer. In addition, to exclude the impact
of the upper tier candidate strains on the growth of 3T3-L1 cells, the upper tier
candidate strains were treated in a dead form.
Prior to the TG experiment, as a result of confirming cytotoxicity through
water soluble tetrazolium (WST) analysis for the upper tier candidate strains,
cytotoxicity was not shown at a concentration of 1x107 CFU to 1x106 CFU, and thus
in order to measure adipogenesis inhibitory activity, the concentration of dead bacteria
of the treated upper tier candidate strains was fixed at 1x107 CFU/well to 1x106
CFU/well.
Specifically, to investigate the effect of each candidate strain on the degree of
lipid accumulation in a fat differentiation process, Oil Red 0 staining was performed
according to the methods of Negrel and Dani. 100% confluent 3T3-L1 cells were
treated with 1x107 CFU/mL of each of the 36 upper tier candidate strains, and cultured
in MDI medium (DMEM + FBS + PS + Insulin + Dexamethasone + IBMX + Insulin).
After 10 days of differentiation, the culture medium was removed, followed by
washing with PBS and then fixing with 10% formaldehyde for 10 minutes. The10%
formaldehyde was removed and saturated formaldehyde was added again to fix the
cells for 1 hour or more. Thereafter, 60% isopropanol was added and immediately
removed, followed by washing with distilled water, and fat globules were stained with a solution for Oil red 0 staining for 30 minutes, and then washed with distilled water.
The intracellular lipid accumulation of the stained fat globules was observed using a
microscope and photographed to visually observe the effect of 36 strains on lipid
accumulation during fat differentiation. To confirm the accumulated fat, the Oil red
0 dye was eluted by adding isopropanol in a dry state, and then absorbance at 490 nm
was measured using a multi-plate reader. At this time, isopropanol was used as a
blank.
(2) Conclusion
FIG. 1 is a view illustrating a series of analysis processes for selecting strains
having anti-obesity activity according to Experimental Example 1 of the present
disclosure. FIG. 2 is a graph showing the lipid accumulation of each of 36 strains
measured using Oil red 0 staining according to Experimental Example 1 of the present
disclosure.
As illustrated in FIG. 2, as a result of comparing the intracellular contents of
triglycerides (TG) of the 36 strains, a 10% or more decrease in TG content was
confirmed in strain Nos. 2, 3, 5, 6, 7, 8, 12, 13, 15, 16, 21, 24, 28, and 29, and it was
confirmed that, among these, strain Nos. 15 and 21 exhibited the greatest adipogenesis
inhibitory activity.
Experimental Example 2. Evaluation of Regulatory Ability of
Macrophages (Splenic Macrophages Isolated from Mice)
In adipose tissue, there are macrophages that regulate inflammatory responses,
in addition to adipocytes. Thus, when obesity occurs, chronic inflammation or diabetes is accompanied by macrophages present in adipose tissue.
Under normal conditions, M2 type macrophages are present in adipose tissue,
and these are anti-inflammatory macrophages that alleviate inflammation and have
maintenance and protective activity so as not to exhibit insulin resistance. In contrast,
in the case of obesity, macrophages infiltrate into adipose tissue, and M2 type
macrophages are switched into M1 type macrophages. M1 type macrophages are
inflammatory macrophages and are known to produce chemicals called pro
inflammatory cytokines and chemokines. For example, M1 type macrophages
induce the production of cytokines such as IL-Ibeta, TNF-alpha, IL-6, and IL-12,
causing inflammation and promoting insulin resistance.
Thus, to prevent diseases accompanied by obesity, such as inflammation and
diabetes, the degree of conversion from M1 type into M2 type macrophages and
whether to induce differentiation from MO type macrophages into M2 type
macrophages were analyzed to evaluate the ability of each strain to regulate
macrophages.
(1) Experimental Method
To select strains capable of regulating macrophages, spleens were isolated
from mice, and then splenocytes were isolated, and since various immune cells such
as T cells and B cells are present in splenocytes, only CD11b and macrophages were
isolated using an MACS system to conduct an experiment. The isolated
macrophages were dispensed into a 96 well plate at a density of1 x 106cells/well, and
then cultured for 2 hours or longer, and when the macrophages were stably adhered to
the bottom of each well, 100 ng/ml of LPS and each of 3 x 107 CFU/well of 36 strains
(dead or live form) were added. After 48 hours, the supernatant was recovered and
the secretion amounts of produced IL-12 and IL-10 were measured by ELISA. At
this time, IL-12 is an identification factor for M1 type macrophages, and IL-10 is an
identification factor for M2 type macrophages.
FIG. 3 is a view illustrating a series of analysis processes for selecting strains
having anti-obesity activity according to Experimental Example 2 of the present
disclosure. FIG. 4 is a graph showing the results of measuring cytokine secretion (%)
in macrophages when treated with each of 36 dead strains according to Experimental
Example 2 of the present disclosure. FIG. 5 is a graph showing the results of
measuring aratio of IL/10to IL-12 in macrophages when treated with each of 36 dead
strains according to Experimental Example 2 of the present disclosure. FIG. 6 is a
graph showing the results of measuring cytokine secretion (%) in macrophages when
treated with each of 36 live strains according to Experimental Example 2 of the present
disclosure. FIG. 7 is a graph showing the results of measuring a ratio of IL-10 to IL
12 in macrophages when treated with each of 36 live strains according to Experimental
Example 2 of the present disclosure.
Referring to FIGS. 4 and 5, it was confirmed that, upon treatment with dead
bacteria, 12 strains (strain Nos.: 1, 3, 6, 8, 10, 16, 20, 21, 22, 30, 31, and 33) exhibited
a 2-fold or more increase in the IL-10/IL-12 ratio.
As illustrated in FIGS. 6 and 7, it was confirmed that, upon treatment with
live bacteria, a total of 11 strains (strains Nos.: 1, 3, 5, 6, 7, 8, 13, 14, 15 16, and 23)
exhibited a three-fold or more increase in the IL-10/IL-12 ratio.
From among the strains identified based on the above-described results, strains exhibiting both fat differentiation inhibitory activity and the ability to regulate macrophages although one or the other was not excellent were preferentially selected, and as a result, a total of 4 strains were selected. Specifically, strains 3 and 6 were selected because it was confirmed that they had adipogenesis inhibitory activity in vitro and exhibited the highest IL-1O/IL-12 ratio, and strain 13 was selected because it was confirmed that it exhibited both adipogenesis inhibitory activity and macrophage regulatory activity in vitro.
In addition, strain 15, which is LactobacillusparacaseiA0356, was selected
because it was confirmed that the strain exhibited the strongest fat differentiation
inhibitory activity and had a relatively high IL10/IL12 ratio.
(3) Conclusion
Taken together the results of Experimental Examples 1 and 2, 4 strains (strain
Nos.: 3, 6, 13, and 15) exhibiting excellent adipogenesis inhibitory activity and
excellent regulatory activity against macrophages were selected, and to secondarily
select, from among the selected 4 strains, strains exhibiting excellent anti-obesity
activity even in vivo, in vivo anti-obesity activities were compared through an in-vivo
experiment, which will be described below.
Experimental Example 3. Confirmation of Effect of Anti-Obesity
Activity of Selected 4 Strains through Animal Experiment
A. Experimental Animals and Experimental Groups
6-week-old male C57BL/6 mice were purchased from Central Lab Animal
Inc. and used as experimental animals, and were raised under 12 hour light/dark conditions at a temperature of 20+2 °C and a humidity of 555%. After purchase, the experimental animals were acclimatized for 2 weeks, and then grouped into 5 mice per group and set as experimental groups as shown in Table 2.
Table 2
Classification Experimental groups (N -5) Normal diet Normal control fed normal feed (ND, 10% fat), orally administered 100 pl/head of PBS 5 times a week for 8 weeks High fat diet Negative control (HFD, 45% fat) fed high fat feed for induction of obesity, orally administered 100 pl/head of PBS 5 times a week for 8 weeks A After high fat feed for inducing obesity was ingested, 108 CFU/head of strain No. 3 (Bacilluslichenformis) was orally administered five times a week for 0-4 weeks, and then 5 x 10 CFU/head thereof was orally administered five times a week for 5-8 weeks B After high fat feed for inducing obesity was ingested, 108 CFU/head of strain No. 6 (Enterococcusfaecalis)was orally administered five times a week for 0-4 weeks, and then 5 x 10 CFU/head thereof was orally administered five times a week for 5-8 weeks C After high fat feed for inducing obesity was ingested, 108 CFU/head of strain No. 13 (Lactobacillusfermentum)was orally administered five times a week for 0-4 weeks, and then 5 x 10 CFU/head thereof was orally administered five times a week for 5-8 weeks D After high fat feed for inducing obesity was ingested, 108 CFU/head of strain No. 15 (Lactobacillusparacasei AO356) was orally administered five times a week for 0-4 weeks, and then 5 x 10 CFU/head thereof was orally administered five times a week for 5-8 weeks
For all experimental groups, except for Normal diet and High fat diet, feed
was mixed with each strain, and then the mixture of the feed and the strain was orally
administered. FIG. 8 illustrates a process of setting experimental animals and
experimental groups according to Experimental Example 3 of the present disclosure.
B. Body Weight, Feed Intake, and Drinking Water Volume
For all experimental groups, the body weight change (g), feed intake (g), and
drinking water volume (ml) of experimental animals were measured from the time of feeding feed until the experimental animals were sacrificed. Feed intake and water intake were measured three times a week, cages were changed twice a week, and body weight was measured once a week for comparison.
FIG. 9 is a graph showing the results of measuring a body weight change in
each experimental group. As illustrated in this drawing, a decrease in weight gain
was clearly confirmed in strain 15, i.e., LactobacillusparacaseiA0356.
Experimental Example 4. Identification of Selected Strain
16S rDNA Analysis
The finally selected strain was subjected to genetic analysis of 16S rDNA,
which is a bacterial base conservation sequence, using universal bacterial primers
(518F,800R)forPCR(SEQIDNO:1). The results were analyzed using NCBI Blast
(http://www.ncbi.nlm.nih.gov/).
The inventors named Lactobacillus paracasei A0356 "Lactobacillus
paracaseiA0356 (KCCM12145P :)" and deposited the strain in the Korean Culture
Center of Microorganisms on November 2, 2017.
Depository Name: Korean Culture Center of Microorganisms (overseas)
Accession No.: KCCM12145P
Date of Deposit: 20171102
Experimental Example 5. Confirmation of Effect of Anti-Obesity
Activity of Finally Selected A0356 Strain in Animal Experiment
A. Strain Culture
To produce the Lactobacillus paracaseiA0356 strain, which was finally
selected, the LactobacillusparacaseiA0356 strain was streaked and inoculated onto
a solid medium (Lactobacilli MRS Agar; BD Difco Co, USA) and cultured at 37 C
for 24 hours. During the culture process, it was thoroughly checked whether
contamination occurred in the bacteria and a single colony was formed, and then the
next experiment was conducted. After the culture was completed, colonies were
collected from each solid medium, which was then inoculated into 5 mL of a liquid
medium (Lactobacilli MRS broth; BD Difco Co, USA) and cultured at 37 C and 140
rpm for 24 hours, and then the colonies were inoculated at 1%(v/v) into 200 mL of
other prepared liquid media (Lactobacilli MRS broth; BD Difco Co, USA), thereby
increasing bacteria stepwise. The activated Lactobacillus paracaseiA0356 strain
was subjected to 2.4 L-5 L main culture, incubated at 37 °C and 140 rpm for 24 hours,
and then centrifuged (Avanti J-E, Beckman Coulter, USA) at 6,000 rpm and 4 C for
15 minutes to recover the colonies. The recovered colonies were washed twice with
sterile 0.85% physiological saline, and then lyophilized (FDCF-12003, OPERON,
Korea), and powdered and stored at -80 C until use.
B. Experimental Animals and Experimental Groups
6-week-old male C57BL/6 mice were purchased from Central Lab Animal
Inc. and used as experimental animals, and were raised under 12 hour light/dark cycles
at a temperature of 20+2 °C and a humidity of 555%. After purchase, the
experimental animals were acclimatized for 2 weeks, and then grouped into 10 mice per group according to randomized complete block design and set as experimental groups as shown in Table 3.
During the acclimatization period, for the uniformity of intestinal microbial
flora in the animal model, litter was mixed at 2-3 day intervals. Subsequently, the
animals were grouped into 10 mice per experimental group, and a normal diet (ND)
group was fed a normal diet and the remaining groups were fed a high fat diet (Rodent
diet with 45%kcal Fat, Research Diets, USA). The LactobacillusparacaseiA0356
strain was weighed in accordance with a concentration of 5x107 CFU/head, and then
suspended in sterile PBS, and orally administered 5 times a week for 10 weeks at a
certain time.
At the end of the experimental period, the experimental animals were fasted
for 12 hours or longer, and then blood was collected through retro-orbital blood
collection and left at room temperature for 30 minutes or longer, followed by
centrifugation at 1,690 x g for 10 minutes to separate serum, and the serum was used
in an experiment. The liver tissue, epididymal fat tissue, retroperitoneal fat tissue,
inguinal fat tissue, and interscapular brown adipose tissue were extracted and washed
with saline to remove moisture, and white fat attached to the interscapular brown fat
tissue was removed, and then the weight of each fat was measured.
Table 3
Classification Experimental groups (N = 10) ND Normal control fed normal diet (ND, 10% fat), orally administered 100 pl/head of PBS 5 times a week for 10 weeks HFD Negative control fed high fat feed for inducing obesity (Rodent diet with 45%kcal Fat, Research Diets, USA), orally administered 100 pl/head of PBS 5 times a week for 10 weeks L. paracasei After high fat feed for inducing obesity was ingested, 5x107 CFU/head of
AO356 finally selected Lactobacillus paracasei AO356 strain was orally administered 5 times a week for 10 weeks
C. Body Weight, Feed Intake, and Drinking Water Volume
For all experimental groups, the body weight change (g), feed intake (g), and
drinking water volume (ml) of experimental animals were measured from the time of
feeding feed until the experimental animals were sacrificed. Feed intake and water
intake were measured every day, cages were changed twice a week, and body weight
was measured once a week for comparison.
FIG. 10 is a graph showing the results of measuring a body weight change
according to week in each experimental group. FIG. 11 is a graph showing the results
of analyzing weight gain in each experimental group. The feed intake (g/day), the
drinking water intake (g/day), and calorie consumption (kcal/day) are shown in Table
4.
Table 4
ND HFD L. paracasei P value A0356 Average daily food 3.56±0.05 2.64±0.04 2.55±0.05 <0.001 intake (g/day) Average daily water 3.81±0.08 2.96±0.09 2.99±0.20 0.003 intake (g/day) Average daily calorie 12.83±0.17 13.36±0.21 12.88±0.23 N.S. intake_(kcal/day) ________________________ _____
According to FIGS. 10 and 11 and Table 4, it can be seen that, as a result of
administering the LactobacillusparacaseiA0356 strain to mice fed high fat feed for
10 weeks, an effect of significantly inhibiting weight gain is shown, compared to the
HFD group fed only high fat feed.
That is, since it was confirmed that a body weight that is 10.63% lower than
that in the HFD group fed high fat feed was obtained, it was confirmed that, although
high fat feed was ingested, the LactobacillusparacaseiA0356 strain inhibited weight
gain by 31.33% compared to the HFD group, from which it can be seen that the
LactobacillusparacaseiA0356 strain has an effect of inhibiting weight gain.
The amount of calories consumed was calculated from feed intake. The
average daily feed intake and water intake showed significant differences between the
ND and HFD groups. This is expected to be due to the difference in the composition
and properties of the feed, and it was confirmed that, while the ND group ingested
more feed than the HFD group, the water intake also increased.
It is confirmed that the HFD group and L. paracaseiA0356 group showed
no difference in feed intake, water intake, and calorie consumption, from which it can
be seen that, the activity of inhibiting weight gain of the Lactobacillus paracasei
A0356 strain, which was demonstrated through the previous experiments, was not due
to a decrease in feed intake or calorie consumption.
D. Analysis of Liver, Epididymal Fat, Retroperitoneal Fat, Inguinal Fat,
and Interscapular Fat
At the end of the experimental period, the experimental animals were fasted
for 12 hours or longer, and then liver tissue, epididymal fat tissue, retroperitoneal fat
tissue, inguinal fat tissue, and interscapular brown adipose tissue were extracted and
washed with saline to remove moisture, and white fat attached to the interscapular
brown adipose tissue was removed. Then, weight in contrast to body weight was measured, and the results thereof are shown in Table 5 below and FIGS. 12A to 12E.
In Table 5 and FIGS. 12A to 12E, Liver denotes liver fat, EFT denotes epididymal fat
tissue, RFT denotes retroperitoneal fat tissue, IFT denotes inguinal fat tissue, and
iBAT denotes interscapular brown adipose tissue.
Table 5
Tissue weight ND HFD HFD + P value (mg) L. paracaseiA0356 Liver 834.6±15.48 916.16±28.37 838.88±17.99 N.S. EFT 270.49±9.51a 1741.68±188.37c 1149.36±104.3 1 b <0.001 RFT 82.00±22.96a 642.58±57.26c 4 14 .01±50.2 5b <0.001 IFT 159.19±14.20a 873.74±84.50c 5 6 7 . 8 9 ± 5 4 .8ob <0.001 iBAT 54.27±2.59a 88.10±5.91c 64.05±5.43b 0.001 Serum leptin 0.296±0.034a 7.200±1.482c 3 .4 3 5 ±0.7 5 6b <0.001 (pg/mi)
According to FIG. 12 and Table 5, it was confirmed that the HFD group fed
a high fat diet exhibited a slight increase in the weight of liver tissue compared with
the ND group and the LactobacillusparacaseiA0356-administered group.
It can also be confirmed that the HFD group fed a high fat diet exhibited great
increases in the weights of epididymal fat tissue (EFT), retroperitoneal fat tissue (RFT),
inguinal fat tissue (IFT), and interscapular brown adipose tissue (iBAT), whereas,
when Lactobacillus paracasei A0356 was administered, each tissue exhibited a
significant decrease in fat weight.
On the other hand, serum leptin, which is a cytokine secreted from adipose
tissue, is known to increase in proportion to an increase in adipose tissue, and is one
of the representative indicators of obesity. As a result of examining a change in fat
weight, it can be seen that the HFD group fed a high fat diet exhibited an increase in fat weight, whereas, when Lactobacillus paracasei A0356 was administered, a significant decrease in fat weight was shown.
E. Serum biochemical analysis
When the experiment was completed, the animal model was fasted for 12
hours or longer, and then blood was collected through retro-orbital blood collection
and left at room temperature for 30 minutes or longer, followed by centrifugation at
1,690 x g for 10 minutes to separate serum, and the serum was used.
By using the serum, the concentrations of insulin and leptin in the serum were
measured using an ELISA-based assay kit. Homeostasis model assessment for
insulin resistance (HOMA-IR) was calculated using Equation 1 below by using the
measured serum glucose and serum insulin concentrations. Serum triglycerides,
HDL-cholesterol and LDL-cholesterol concentrations were measured using
colorimetry, and serum glucose concentrations were measured using UV
spectrophotometry.
[Equation 1]
HOMA-IR = fasting glucose (mg/dL) X fasting insulin (ptU/mL)/2430
FIG. 13 is a set of graphs showing LDL-cholesterol (a), triglycerides (TG)
(b), HDL-cholesterol (c), glucose (d), insulin (e), and HOMA-IR (f), which were
measured in serum isolated from each experimental group according to Experimental
Example 5 of the present disclosure.
As illustrated in FIG. 13, when a high fat diet is repeatedly ingested (HFD
group), blood glucose and insulin concentrations are increased, and hyperglycemia and hyperinsulinemia are induced, promoting insulin resistance. This was also confirmed through the experimental examples of the present disclosure.
Specifically, it was confirmed that the HFD group exhibited a significant
increase in blood glucose and insulin concentrations compared with the ND group.
Furthermore, it was confirmed that, when a LactobacillusparacaseiA0356 strain was
administered (L. paracasei A0356 group), overall decreases in LDL cholesterol,
triglycerides (TG), HDL-cholesterol, glucose, and insulin were shown.
It was also confirmed that HOMA-IR, which is calculated using fasting blood
glucose and insulin concentrations and is used as an indicator of insulin resistance, was
also increased in the HFD group, whereas a significant decrease in HOMA-IR was
shown in an L. paracasei A0356 group fed the same diet, but administered the
LactobacillusparacaseiA0356 strain.
Insulin inhibits lipolysis in adipocytes and transports blood fatty acids and
glucose into cells to accumulate in the form of triglycerides. As in the HFD group,
the action of insulin does not work properly in an insulin-resistant state, resulting in
promoted dissociation of fatty acids and decreased activity of lipoprotein lipase (LPL),
and consequently, dyslipidemia, in which LDL cholesterol or triglycerides in the blood
increase, may occur. That is, it was confirmed that, in the HFD group, dyslipidemia,
in which serum triglyceride and LDD cholesterol concentrations increase, occurred,
but such a phenomenon could be significantly reduced in the L. paracaseiA0356
group fed the same high fat diet, but administered the LactobacillusparacaseiA0356
strain.
F. RNA Precipitation and qPCR Analysis
The epididymal white fat tissue of each experimental group was partially cut
and total RNA was extracted using an RNeasy lipid tissue kit, and cDNA was
synthesized using oligo-dT primers. qPCR was performed using a SYBR green
qPCR (Qiagen) kit.
FIG. 14 is a set of graphs showing the results of analyzing the mRNA
expression levels of lipometabolism-related genes after extracting RNA from
epididymal white fat tissue isolated from each experimental group and performing
qPCR analysis thereon, according to Experimental Example 5 of the present disclosure.
In general, it is known that brown fat among adipose tissues in the body is
responsible for energy consumption through heat generation, and white fat is
responsible for storing energy in the form of fat. Therefore, in the present disclosure,
it was examined whether the LactobacillusparacaseiA0356 strain, which was finally
selected, coverts white fat into brown fat to thereby have the effect of treating diseases
such as obesity.
An increase in the expression rate of UCP1 in white fat promotes the heat
generating ability of mitochondria of white fat, the browning/beige fat of white fat is
promoted by the increase in the expression rate of the UCP1 gene through a p3
adrenergic agonist, cold exposure, or exercise, and anti-obesity effects through a
reduction in body fat, and the like have been reported.
UCP1 plays an important role in the browning of white visceral fat.
Referring to FIG. 14, it can be confirmed that the expression rate of the UCP1 gene,
which had been decreased in the HFD group, was restored in the L. paracaseiA0356 group.
In addition, PGCIa is a gene that plays an important role in the browning of
white fat by promoting the expression rate of the FNDC5 protein that secretes irisin,
which is a hormone that promotes the expression of UCP1, and it can be seen that the
expression rate of PGCla was reduced in the HFD group, whereas the expression rate
of PGCla was significantly restored in the L. paracaseiA0356 group.
In addition, it can be seen that the expression levels of the PRDM16, Cidea,
and PPARy genes were increased via administration of the Lactobacillus paracasei
A0356 strain, wherein these genes are transcriptional factors that regulate gene
programming for browning of white adipose tissue.
Meanwhile, it was confirmed in FIG. 14C that CD36, which had been reduced
in the HFD group, was significantly increased by administration of the Lactobacillus
paracaseiA0356 strain, which is necessary for the normal function of brown fat, and
particularly, fatty acids play a role in moving polyunsaturated fatty acids into cells,
and such polyunsaturated fatty acids act as ligands with the highest affinity, activating
PPARy.
Taken together, it was confirmed that, when the Lactobacillus paracasei
A0356 strain was administered to an animal model with high fat diet-induced obesity,
the strain not only had anti-obesity activity such as a reduction in body fat and
inhibition of weight gain by a high fat diet, but also had an effect of increasing the
expression of genes related to the browning of white fat.
As is apparent from the foregoing description, a Lactobacillus paracasei
A0356 strain according to the present disclosure, which is a strain isolated from the human body, has high stability, exhibits the ability to inhibit adipogenic differentiation in vitro and the activity of inducing the differentiation of M1 and MO macrophages into M2 macrophages, and has excellent activity of alleviating, preventing, or treating obesity, such as the activity of reducing body weight and a reduction in blood lipid concentration through the browning of white fat in animal experiments. Thus, the novel strain of the present disclosure has a low possibility of causing side effects, and therefore, unlike conventional diet functional foods or drugs, which have side effect problems, a diet effect can be exhibited without controlling the dose thereof.
Accordingly, the novel strain can be used as a pharmaceutical composition for treating
or preventing obesity or a food composition for alleviating or preventing obesity.
Therefore, the novel strain according to the present disclosure can be used as
a novel medical substance that is effective in preventing, alleviating, and treating
obesity.
It should be understood that embodiments described herein should be
considered in a descriptive sense only and not for purposes of limitation.
Descriptions of features or aspects within each embodiment should typically be
considered as available for other similar features or aspects in other embodiments.
While one or more embodiments have been described with reference to the figures, it
will be understood by those of ordinary skill in the art that various changes in form
and details may be made therein without departing from the spirit and scope as defined
by the following claims.
Claims (11)
1. A LactobacillusparacaseiA03 56 strain (KCCM12145P)having anti
obesity activity.
2. A probiotic or food composition comprising the Lactobacillus
paracaseiA0356 strain (KCCM12145P)of claim 1 or a culture medium thereof.
3. A pharmaceutical composition comprising the Lactobacillus
paracaseiA0356 strain (KCCM12145P)of claim 1 or a culture medium thereof.
4. The pharmaceutical composition of claim 3, wherein the Lactobacillus
paracaseiA0356 strain (KCCM12145P)or the culture medium thereof is included in
an amount of about 0.01 wt% to about 50 wt% with respect to a total weight of the
composition.
5. The pharmaceutical composition of claim 3 or 4, wherein the
composition inhibits adipogenic differentiation.
6. The pharmaceutical composition of any one of claims 3 to 5, wherein
the composition induces differentiation into M2 type macrophages.
7. The pharmaceutical composition of any one of claims 3 to 6, wherein
the composition reduces body weight.
8. The pharmaceutical composition of any one of claims 3 to 7, when
used for preventing or treating obesity..
9. A food composition when used for preventing or alleviating obesity,
the food composition comprising the Lactobacillus paracasei A0356 strain
(KCCM12145P)of claim 1 or a culture medium thereof.
10. A food composition when used for alleviating inflammation
caused by obesity, the food composition comprising the Lactobacillus paracasei
A0356 strain (KCCM12145P)of claim 1 or a culture medium thereof.
10. A method for preventing or alleviating obesity, or alleviating
inflammation caused by obesity, the method comprising administering to a subject an
effective dose of LactobacillusparacaseiA0356 strain (KCCM12145P), the probiotic
or food composition of claim 2, or a pharmaceutical composition of any one of claims
3 to 7.
11. Use of LactobacillusparacaseiA0356 strain (KCCM12145P) for the
manufacture of a medicament for preventing or alleviating obesity, or alleviating
inflammation caused by obesity.
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AU2023255046A AU2023255046B2 (en) | 2020-06-17 | 2023-10-27 | Lactobacillus paracasei AO356 strain having anti-obesity activity and composition when used for preventing, alleviating or treating obesity including the same |
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