Note: Descriptions are shown in the official language in which they were submitted.
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A COMPOSITION COMPRISING MANNOHEPTULOSE FOR USE IN THE TREATMENT OR
PREVENTION OF OVERWEIGHT AND OBESITY
FIELD OF THE INVENTION
The present invention is directed to a method of treating or preventing
overweight and
obesity in a mammal comprising administering to the mammal a composition
comprising an
effective amount of a mannoheptulose (mHep). Further, the present invention
encompasses a
composition comprising a mHep and a process of making the composition.
BACKGROUND OF THE INVENTION
Overweight and obesity are significant problems in mammals, particularly in
humans and
domesticated animals such as, for example, pets (e.g., dogs, cats). According
to the United States
Centre for Disease Control (CDC), about 1/3 (33.3%) of all adult humans in the
U.S. are
overweight (i.e., BMI = 25 kg/m2 to 29.9 kg/m2), and more than 1/3 (35.7%) are
obese (i.e., BMI
> 30 kg/m2). Unfortunately, the pets are not any healthier than their owners.
According to the
2011 statistical data from the Association for Pet Obesity Prevention's
(APOP), in the United
States 53% of adult dogs and 55% of adult cats are either overweight or obese
(based on similar
scoring system and the Body Condition Chart (BCS) for Assessing Obesity in
Cats and Dogs,
developed by Greg Sunvold from IAMS (1998)).
It is important to note that whether humans and domesticated animals are
considered
overweight or obese does not depend on body weight, but instead on the
percentage of body fat.
Overweight and obesity is the accumulation of excess adipose tissue (i.e.,
body fat) due to, for
example, overconsumption of calories and/or lack of exercise. Excessive
accumulation of body
fat occurs when the synthesis and deposition of fat (e.g., triglycerides) into
adipocytes exceed
their breakdown. Over time, this excessive accumulation of body fat leads to
overweight then
obesity, if left untreated.
Being overweight or obese will clearly increase morbidity and mortality. It
may also
exacerbate many health problems, both independently and in conjunction with
other diseases.
For example, if overweight or obese dogs are left untreated, especially as
adult dogs (i.e., about 6
to 8 years old) or senior dogs (i.e., about 9 years old and above), then their
quality of life may
decrease due to the increased risks of developing chronic diseases such as,
for example, diabetes
mellitus, cancer, hypertension, pulmonary cardiovascular, or degenerative
joint disease. Thus,
the benefits of not being overweight or obese include not only a longer life,
but also provide a
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higher quality of life. Senior dogs are further disadvantaged due to the fact
that they are
susceptible to "age-related increase in body fat" that may contribute to
becoming overweight or
obese. Accordingly, the need still exists for new or improved methods of
treating or preventing
overweight and obesity in mammals, particularly where the mammal is a senior
pet.
In addition to adipose tissue's role as a repository of surplus energy (i.e.,
fat) for the body,
it has been recognized as an endocrine organ that produces hormones such as,
for example, the
sex hormone estrogen. Estrogen is present in both male and female animals. It
plays an
important role in regulating the function and development of adipocytes that
form the adipose
tissue and maintenance of normal body fat composition (Cooke, P.S. et al.,
Exp. Biol. Med.,
229:1127-35, 2004). In fact, diminished estrogen levels, for example, after
menopause in
humans and the spaying/neutering of pets for population control reasons, have
been correlated
with increased accumulation of adipose tissue (body fat) (Pergola, G.D., Int.
J. Obesity, 24:S59-
S63, 2000; Cooke, P.S. et al., (2004), supra.; and Mohamed, M.K., et al., Eur.
J. Endocrinol.
142:307-14, 2000).
Estrogen may mediate its effects on adipose tissue in different ways. For
example,
estrogen may affect the number and size of adipocytes; modulate the rate of
lipogenesis and
lipolysis; and increase appetite or decrease energy expenditure (Pergola,
G.D., (2000), supra;
Cooke, P.S. et al., (2004), supra; and Naaz, A., et al., Endocrinology
144:3315-20, 2003).
Hormone replacement therapy and dietary supplementation with estrogen are
common
approaches that attempt to reverse these effects (Sayegh, R.A., et al.,
Meopause 6:312-5, 2002).
However, both therapies may be expensive and require strict patient compliance
with the
regimens in order for them to be effective.
Accordingly, the need still exists for new or improved methods of treating or
preventing
overweight or obesity in a mammal, which may result from weight gain due to,
for example,
menopause in humans or spaying/neutering of animals, particularly wherein the
methods require
minimal additional cost and are easy for the patient/animal to comply. For
example, the mHep
is already incorporated in the pet food composition, then the animal only
needs to eat to be
treated.
Consumers believe healthy longevity of their pet can be achieved through a
combination
of proper nutrition from a high-quality diet, spaying and neutering,
maintenance of an active
lifestyle, and routine visits to veterinary. The pet food industry has
explored the use of caloric
restriction mimetic as a strategy for delivering against this demand of proper
nutrition in pet
food. It is believed that caloric restriction leads to an increase in median
lifespan (i.e., age at
50% population survival) and maximal lifespan (i.e., age of longest lived
individual). Recent
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studies show that the amount of time the lifespan of an animal is extended
will progressively
increase as caloric in-take is reduced and the duration of the caloric
restricted diet increases. In
one study, the lifespan of a monkey was increased by more than 30% because the
animal had
started on caloric restriction shortly after birth (Mattson, M.P. et al., J.
Nutr. Biol. 16, 3:129-137,
2005). It has also been shown that 10% to 40% reductions in caloric in-take
are effective to
improve the quality of life by delaying and/or preventing age-related
diseases.
An example of a caloric restriction mimetic is mannoheptulose (mHep), which is
a seven-
carbon sugar found in a variety of natural sources such as, for example,
avocados, figs, and
primrose. It is believed that mHep is effective for extending lifespan and
life quality in both
lower and higher organisms. As a caloric-restriction mimetic, mHep competes
with glucose for
binding to hexokinase-1, an enzyme in the glycolysis reaction, due to the
similarity between their
structures. The result is that glucose metabolism is inhibited and fatty acid
synthesis is
prevented. This leads to decrease levels of fat deposition in adipocytes that
may eventually lead
to weight loss. In a related role, mHep may function as a glucose anti-
metabolite to block the
normal metabolism of carbohydrate. The resulting physiological changes may
include: lower
tissue glucose levels, decrease plasma insulin levels and reduction of body
weight (see PCT
Publication No. W02012/61446A1). Both effects result from mHep's inhibition of
carbohydrate
metabolism. To date, mHep has not been shown to impact adipocyte expression or
activity, and
particularly not linked to overweight and obesity.
Given the magnitude of the growing problem with excessive weight gain in
today's
human and pet populations, there is still a need for new or improved methods
of treating and
preventing overweight and obesity in mammals. In an embodiment, the mammals
are preferably
chosen from sub-groups that have elevated risk of adiposity brought on by, for
example, changes
in hormonal homeostasis (i.e., menopausal humans and spayed/neutered pets) or
arose from
normal age-related weight gains (i.e., senior humans or senior pets),
particular if the animal is
otherwise healthy.
It is desirable that the new or improved methods would also benefit growing
pets,
preferably if the growing pets are overweight or obese or have been
spayed/neutered before
reaching sexual maturity. Alternatively, by administering mHep early-on to the
growing pet, the
animal is exposed to caloric restriction mimetic for a longer duration thereby
increasing the
chance of extending the lifespan in those animals.
SUMMARY OF THE INVENTION
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In a first aspect, the present invention is directed to a new use of mHep
based on the
discovery of different molecular processes and mechanisms by which mHep
provides new
benefits to the mammal. The inventor discovered that mHep inhibits fat stem
cells from
differentiation into adipocytes, and thereby lessens the body's fat storage
capacity due to reduced
levels of adipocytes. It has also been discovered that mHep inhibits
adipocytes from exhibiting
adipogenic or lipogenic effect that may result in the excessive build-up of
fatty tissue
contributing to body weight increase. By this discovery, the inventor have
identified new
methods of using mHep for treating or preventing overweight and obesity in
mammals, wherein
the method comprises administering to the mammal a composition comprising an
effective
amount of a mHep.
In one embodiment, the method relates to a mammal that is a pet, more
particularly,
wherein the pet is selected from: (a) a growing pet (e.g., puppy, kitten) that
may be overweight or
obese, reproductively-intact, or spayed/neutered; (b) an adult pet that may be
overweight or
obese, reproductively-intact, or spayed/neutered; or (c) a senior pet that may
be overweight or
obese, reproductively-intact, or spayed/neutered.
In another embodiment, the method comprises administering to the mammal a
composition comprising an effective amount of an mHep to inhibit or reduce the
differentiation
process of fat stem cells into adipocytes in the mammal such that the mammal's
body fat storage
capacity decreases by about at least 5%, about at least 10%, or about at least
20%, relative to an
untreated mammal.
In yet another embodiment, the method wherein the administration comprises
feeding to
the mammal a composition comprising a daily dosage amount of from about 1
mg/kg to about 50
mg/kg of a mHep, and wherein the composition is selected from the group
consisting of a pet
food, a supplement, and a liquid, wherein the supplement or the liquid can be
taken separately or
added to the pet food. The composition can be selected from the group
consisting of wet
composition (i.e., having a total moisture content of greater than 50%, by
weight of the product),
moist composition (i.e., having a total moisture content of from about 16% to
about 50%, by
weight of the product), semi-moist composition, dry composition and
combinations thereof. The
composition can be nutrionally balanced pet food composition.
In another aspect, the present invention is directed to a method of increasing
the lifespan
of a mammal, preferably a growing pet such as, for example, a puppy or a
kitten, by
administering to the mammal a composition comprising an effective amount of a
mHep to reduce
the caloric in-take of the young pet, wherein the administration starts within
a window of about
one month to 3 years of the birth of the animal. The reduction in caloric in-
take is preferably
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anywhere within a range of about 10% to about 50% of the caloric in-take prior
to the
administration.
In yet another aspect, the present invention is directed to a pet food
composition
comprising an effective amount of an mHep for promoting or maintaining a
healthy body fat of
5 growing pets, and wherein the mHep is present in the composition at from
about 0.0001% to
about 10% by weight of the composition. The pet food composition is preferably
a high fat food
composition with a fat content present in the composition from at least about
15% to at least
about 45% by weight of the composition. The higher fat content provides more
palatability to the
pet food composition, while the mHep minimizes and/or counters any negative
effects on body
weight gain.
These and other features of the present invention will become apparent to one
skilled in
the art upon review of the following detailed description when taken in
conjunction with the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
While the specification concludes with claims particularly pointing out and
distinctly
claiming the invention, it is believed that the invention will be better
understood from the
following description of the accompanying figures wherein:
FIG. 1A shows the body condition chart for assessing obesity in dogs.
FIG. 1B shows the body condition chart for assessing obesity in cats.
FIG. 2 shows the oil staining showing mHep inhibiting MSC differentiation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, articles such as "a" and "an" when used in a claim, are
understood to
mean one or more of what is claimed or described.
Within the context of this specification the term "about" is interpreted to
mean optionally
plus or minus 20%, preferably optionally plus or minus 10%, more preferably
optionally plus or
minus 5%, even more preferably optionally plus or minus 2%, and most
preferably optionally
plus or minus 1 %.
As used herein, the terms "include", "includes" and "including" are meant to
be non-
limiting.
"Obesity", as used herein refers to an increase in body weight beyond the
limitation of
skeletal and physical requirement, as a result of excessive body fat
accumulation. A human
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subject is "obese" if he has a Body Mass Index (BMI) above 30 kg/m2 according
to the United
States CDC guidelines. A pet such as, for example, a cat or dog, is identified
as being "obese" if
the animal possess the physical attributes using the guidelines set out in the
Body Condition
Chart (BCS) for Assessing Obesity in Cats and Dogs, developed by Greg Sunvold
from JAMS
(1998), and reproduced in FIGS. 1A (dogs) and 1B (cats). For all other types
of mammals,
similar Body Condition Charts and scoring systems, such as a Body Condition
Score, are
available to provide guidance for determining whether the subject is "obese".
"Overweight" as used herein means weighing more than is normal or necessary,
especially having more body weight than is considered normal or healthy for
one's age or build.
A human subject is "overweight" if he has a Body Mass Index (BMI) between 25.0
kg/m2 to 29.9
kg/m2 according to the United States CDC guidelines. A pet such as, for
example, a cat or dog,
is identified as being "overweight" if the animal possess the physical
attributes using the
guidelines set out in the Body Condition Chart (BCS) for Assessing Obesity in
Cats and Dogs,
developed by Greg Sunvold from JAMS (1998), and reproduced in FIGS. 1A
(dogs) and 1B
(cats). For all other types of mammals, similar Body Condition Charts and
scoring systems are
available to provide guidance for determining whether the subject is "obese".
"Mammal" as used herein means a primate, such as a human, ape or monkey, or
domesticated animal such as, for example, a pet.
"Pet" as used herein means a domesticated animal including, domesticated dogs
(canines),
cats (felines), horses, cows, ferrets, rabbits, pigs, rats, mice, gerbils,
hamsters, horses, and the
like. Pet is also referred to as "companion animals" herein.
"Growing pet" as used herein refers to a subset of "pet" and includes young
animals that
are still undergoing development and are not yet sexually mature.
"Kitten" as used herein refers to a type of "growing pet" and includes
domesticated cats
which are 3 years old or less, or about 2 years old or less, or about 1 year
old or less.
"Puppy" as used herein refers to a type of "growing pet" and includes
domesticated dogs
which are 3 years old or less, or about 2 years old or less, or about 1 year
old or less.
"Adult pet" as used herein refers to a subset of "pet" and includes, for
example,
domesticated dogs (canines) and cats (felines) that are between about 3 years
old and about 8
years old.
"Senior pet" as used herein refers to a subset of "pet" and includes, for
example,
domesticated dogs (canines) and cats (felines) that are about 9 years old and
above.
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"Reproductively-intact" as used herein means that the animal can still
reproduce as they
have not undergone any procedures to remove or disable the sexual organs
(e.g., ovaries,
testicles).
"Menopause" as used herein means the period of permanent cessation of
menstruation in
a female human, and typically occurs between the ages of about 45 and about
55. Menopause is
marked by dramatic variations in hormone levels such as, for example,
decreases in estrogen
levels due to the ovaries no longer producing eggs.
"Spaying" or "neutering" as used herein means surgical procedures performed on
animals
for population control. "Neutering" is the removal of the testicles from a
male animal, and
"spaying" is the removal of ovaries from a female animal. "Spaying" or
"neutering" can also
cover pets that have been altered with respect to their sex organs, for
example, through natural
causes such as an anatomical defect, biochemical or genetic abnormality, or
disease, for example,
post-andropausal having reduced circulating estradiol levels relative to a
healthy non-obese
control animal.
"Treating" or "treatment" as used herein means the treatment of the conditions
of
overweight and obesity in a mammal and includes:
(i) inhibiting the conditions of overweight and obesity, i.e., arresting
its development;
(ii) relieving the conditions of overweight and obesity, i.e., causing
regression of the
conditions of overweight or obesity; or
(iii) relieving
the symptoms resulting from the conditions of overweight or obesity,
i.e., relieving the conditions of overweight or obesity without addressing the
underlying disease or condition.
"Preventing" as used herein means to stop the conditions of overweight and
obesity from
occurring.
"Ameliorating" as used herein means to make the conditions of overweight and
obesity
become bearable.
"Healthy body weight" as used herein means body weight range that is deemed to
be
healthy. It can be determined by Body Mass Index (BMI) based on height and
weight.
According to the U.S. CDC guidance, the range of BMI for a normal body weight
is 18.5 kg/m2
to 24.9 kg/m2.
"Healthy body fat" as used herein means age-adjusted percentage of body fat
that is
considered healthy for a mammal. Healthy body fat comprises: (i) essential
body fat, and (ii)
storage body fat. Essential body fat is required for maintaining life's
necessary functions and
reproduction. Storage body fat consists of fat accumulation in adipose tissue.
The present
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invention intends to limit the percentage of the storage body fat to minimize
the adverse weight
gain.
"Fat stem cells" or "adipose stem cells" as used herein means multipotent
cells that can
differentiate into tissue cells, such as, adipocytes (i.e., fat cells). They
are ubiquitously available
and are found in adipose tissue. Fat stem cells are also known as "adipose-
derived adult stem
(ADAS) cells", "adipose-derived stromal cells (ADSC)", "adipose stromal cells
(ASC)", "adipose
mesenchymal stem cells (AdMSC)", "preadipocytes", "processed lipoaspirate
(PLA) cells", and
"adipose-derived stromal/stem cells (ASCs)".
"Adipocytes" as used herein means the cells that specialize in storing energy
as fat for the
body and are the primary cells that compose adipose tissue. "Adipocytes" are
also known as
"lipocytes" and "fat cells".
"Adipose Tissue" as used herein means the connective tissue comprising
adipocytes (i.e.,
fat cells). Adipose tissue is generally where the body deposits and stores
excess fat. Adipose
tissue encompasses, without limitation, white, brown, and yellow adipose
tissue.
"Body's fat storage capacity" as used herein means the body's ability to store
energy as
fat for the body in adipose tissue. The body fat's storage capacity increases
with increasing
numbers of adipocytes.
Referenced herein are trade names for components including various ingredients
utilized
in embodiments of the invention. The inventors herein do not intend to be
limited by materials
under a certain trade name. Equivalent materials (e.g., those obtained from a
different source
under a different name or reference number) to those referenced by trade name
may be
substituted and utilized in the descriptions herein.
Compositions Comprising a Mannoheptulose (mHep)
Specifically, the present invention provides for a composition comprising an
effective
amount of a mHep for treating overweight and obesity in a mammal. In one
embodiment, the
compositions of the present invention are food compositions intended for oral
ingestion by the
mammal, preferably a human or a pet (e.g., cats, dogs). In certain aspects,
the compositions are
intended for consumption by a pet, wherein the compositions are selected from
the group
consisting of a pet food, a supplement, and a liquid.
"Pet food" is a composition intended to be ingested by a pet, and preferably a
domesticated pet such as, for example, a cat, a kitten, a puppy, or a dog. As
used here "pet food"
is intended to include things like treats (e.g., biscuits), chews, raw hides,
and the like. In an
embodiment, the "pet food" is designed specifically for a growing pet (e.g.,
puppy food) or In
another embodiment, the "pet food" is a "complete and nutritionally balanced
pet food". This
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means that it contains all known required nutrients in appropriate amounts and
proportions based
on recommendations of recognized authorities in the field of pet nutrition,
and is therefore
capable of serving as a sole source of dietary intake to maintain life or
promote production,
without the addition of supplemental nutritional sources. For an example of a
"nutritionally
balanced" dog food, see the guidelines in the National Research Council, 1985,
Nutritional
Requirements for Dogs, National Academy Press, Washington D.C., or Association
of American
Feed Control Officials, Official Publication 1996).
In another embodiment, the pet food composition may be a dry composition
(e.g., kibble,
and having a total moisture content of from about 0% to about 16%, by weight
of the product), a
moist or a semi-moist composition (i.e., having a total moisture content of
from about 16% to
about 50%, by weight of the product), a wet composition (i.e., having a total
moisture content of
greater than about 50%, by weight of the product), or any mixture thereof.
In yet another embodiment, the pet food composition may be a "high fat food",
preferably
a "high fat pet food", comprising a fat content present in the pet food
composition, on a dry
matter basis: a) of at least about 15% by weight of the composition; b) of at
least about 25% by
weight of the composition; c) of at least about 35% by weight of the
composition; or d) of at least
about 45% by weight of the composition. It is a common practice to
intentionally add some fat
to pet food compositions to improve palatability. However, when the levels of
fat begin to
exceed 10% of the pet food composition, then the pet food is considered "high
fat" by the
consumers. High fat pet food is hard to market given the general consumers
preference for low-
fat alternatives that will deliver the right balance of nutrition to their
pets.
Without wishing to be bound by theory, for example, with high fat pet food
composition,
it is believed that by adding an effective amount of a mHep into the high fat
pet food
composition, the mHep interacts with the adipocytes to negate the negative
effects of the fat.
Higher concentrations of mHep can be added to increasing concentrations of
fat. to a level where
the presence of the high fat content in the pet food composition has minimal
or nil impact on the
body fat accumulation of the animal consuming the food. In an embodiment, it
is believed that
the mHep is believed to be effective at mitigating the negative effects, even
at very high levels of
fat content, for example, to at least about 45% by weight of the composition.
Embodiments related to compositions, preferably pet food compositions, of the
present
invention may further comprise a source of carbohydrate. In one embodiment,
the compositions
may comprise from about 35%, by weight of the composition, up to about 50%, by
weight of the
composition, carbohydrate source. In other embodiments, the composition can
comprise a source
of carbohydrate at from about 35% to about 45%, by weight of the composition,
or from about
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40% to 50%, by weight of the composition. Non-limiting examples of
carbohydrate source
include, grains or cereals such as rice, corn, milo, sorghum, barley, wheat,
and the like are
illustrative sources of carbohydrate.
The compositions, preferably pet food compositions, of the present invention
may also
5 contain other materials such as, but not limited to, dried whey and other
dairy by-products, beet
pulp, cellulose, fiber, fish oil, flax, vitamins, minerals, flavors,
antioxidants, and taurine.
Optionally, other beneficial ingredients may be present in the compositions,
preferably
pet food compositions, of the present invention, for example, crude protein as
a percentage of the
composition in the range of from about 10% to about 90% by weight of the
composition, from
10 about 20% to about 50% by weight of the composition, from about 20% to
about 40% by weight
of the composition, or from about 20% to about 35%by weight of the
composition. Other
optional ingredients in the pet food composition mayinclude: probiotic
components
(Bifidobacteria and/or Lactobacillus), prebiotic components (e.g.,
fruct000ligosaccharides, PCT
Publication No.W02005/0158294, for example), omega-6 and omega-3 fatty acids,
carnitine,
hexametaphosphate, glucosamine, chondroitin sulfate, carotenoids including
beta carotene,
vitamin E, and lutein.
"Supplement" as used herein is intended to cover both "dietary supplement" and
"food
supplement" and means a product intended to be ingested separately in addition
to the normal
diet of the mammal, or added to a food, preferably a pet food, or added to a
liquid intended for
consumption by the animal.
"Liquid" as used herein means fillers, gravies, sauces, beverages,
supplemental water, and
combinations thereof The liquid is intended to be ingested separately in
addition to the normal
diet of the mammal, or added to a food, preferably a pet food.
Mannoheptulose (mHep)
The compositions of the present invention comprises an effective amount of an
mHep for
treating or preventing overweight and obesity in a mammal to which the
composition has been
administered. Where the composition is preferably a pet food, the amount of
mHep as a
percentage of the composition is in the range of from about 0.0001% to about
10% by weight of
the composition, from about 0.1% to about 5% by weight of the composition, or
from about 0.1%
to about 3% by weight of the composition, wherein the weight of the
composition is on a dry
matter basis.
Although it should be noted that greater percentages of mHep can be supplied
because it
has a high therapeutic window unlike other caloric restriction mimetics, such
as resveratrol,
which has a high effective dose but strong cytotoxic (50-100 p m) making it to
be more difficult
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to administer. In other various embodiments, the amount of mHep is about 1.0%,
1.5%, 2.0%,
2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%,
8.0%, 8.5%,
9.0%, 9.5%, or 10.0% by weight of the composition.
When the composition is formulated as a dietary supplement, the composition
may be
formulated to contain mHep at higher concentrations (i.e., 2X, 3X, 4X, 5X,
etc.) to be amenable
for administration to a mammal in the form of a tablet, capsule, liquid
concentrated, or other
similar dosage form, or to be diluted before administrations, such as by
dilution in water,
spraying or sprinkling onto a composition such as, for example, a pet food,
and other similar
modes of administration.
The mHep used in the present invention can be derived from any suitable
source.
Preferred sources of mHep include:
i. a naturally-derived source of mHep;
ii. a synthetically-derived source of mHep;
iii. a microbial-derived source of mHep;
iv. a combination of a) and b);
v. a combination of a) and c);
vi. a combination of b) and c); or
vii. a combination of a), b) and c).
Naturally-Derived mHep
The mHep may be obtained from a "naturally-derived source", such as, a
component of
plant matter such as an avocado, avocado extract, avocado meal, avocado
concentrate, or other
enriched source of mHep. Non-limiting examples of enriched sources of mHep
include alfalfa,
fig, or primrose. The plant matter may include the fruit, seed (or pit),
branches, leaves, or any
other portion of the relevant plant or combinations thereof.
Avocado (also commonly referred to as alligator pear, aguacate, or palta)
contains
unusually enriched sources of mHep, as well as related sugars and other
carbohydrates. Avocado
is a sub-tropical evergreen tree fruit, growing most successfully in areas of
California, Florida,
Hawaii, Guatemala, Mexico, the West Indies, South Africa, and Asia.
Species of avocado include, for example, Persea Americana and Persea nubigena,
including all cultivars within these illustrative species. Cultivars may
include 'Anaheim,' Bacon,'
'Creamhart,"Duke,"Fuerte,"Ganter,"Gwen,"Hass,"Jim,"Lula,"Lyon,"Mexicola
Grande,'
'Murrieta Green,'
Nabal,"Pinkerton,"Queen,"Puebla,"Reed,"Rincon,"Ryan,"Spinks,' opa
Topa,"Whitsell," Wurtz,' and 'Zutano.' The fruit of the avocado is
particularly preferred for use
herein, which may contain the pit or wherein the pit is removed or at least
partially removed.
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Fruit from Persea Americana is particularly preferred for use herein, as well
as fruit from
cultivars which produce larger fruits (e.g., about 12 ounces or more when the
fruit is mature),
such as Anaheim, Creamhart, Fuerte, Hass, Lula, Lyon, Murrieta Green, Nabal,
Queen, Puebla,
Reed, Ryan and Spinks.
Other examples of naturally-derived sources of mHep may include plant matter
from
alfalfa, fig, or primrose, which has been reported to provide relatively high
levels of mHep.
Alfalfa is also referred to as Medicago sativa. Fig or Ficus carica (including
Cluster fig or
Sycamore fig, for example) may also be used, as well as primrose or Primula
officinalis.
Synthetically-Derived mHep
The mHep may be obtained from a "synthetically-derived source". Synthetic mHep
is
commercially available (Glycoteam GmbH (Hamburg, DE)) in highly purity forms.
However,
the highly purified synthetic mHep have the same activity level as the
naturally-derived source of
mHep, such as avocado extract.
Microbial Derived mHep
The mHep may be obtained from a "microbial derived source".
One skilled in the art will understand how to determine the appropriate amount
of mHep
to be added to a given composition. Non-limiting examples of some of the
factors that may be
taken into consideration include: (i) the type of composition (e.g., pet food
composition vs.
dietary supplement), (ii) the average consumption of specific types of
compositions by different
animals, and (iii) the manufacturing processes and conditions under which the
composition is
prepared. The compositions of the present invention can be made according to
any method
suitable in the art such as, for example, that described in Waltham Book of
Dog and Cat
Nutrition, Ed. ATB Edney, Chapter by A. Rainbird, entitled "A Balanced Diet"
on pages 57 to
74, Pergamon Press Oxford.
In another aspect, the present invention is directed to a pet food composition
comprising a
mHep for promoting or maintaining a healthy body fat of growing pets, and
wherein the mHep is
present in the composition at from about 0.0001% to about 10% by weight of the
composition,
from about 0.01% to about 5% by weight of the composition, or from about 0.1%
to about 3% by
weight of the composition. By the term "healthy body fat", it is intended to
mean age-adjusted
percentage of body fat that is considered healthy for the mammal. For example,
if the mammal is
a human, one could refer to the World Health Organization (WHO) "Age-Adjusted
Body Fat
Percentage Recommendations" as a guideline. They have separate charts for men
and women, as
women tend to have higher percentage of body fat for reproductive reasons.
Table 1: Body Fat Percentage Recommendations
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Women
Age Healthy
Underfat Overweight Obese
Range
20-40 yrs Under 21-33% 33-39% Over 39%
21%
Under
41-60 yrs 23-35% 35-40% Over 40%
23%
Under
61-79 yrs 24-36% 36-42% Over 42%
24%
Men
Age Healthy
Underfat Overweight Obese
Range
20-40 yrs Under 8-19% 19-25% Over 25%
8%
41-60 yrs Under 11-22% 22-27% Over 27%
11%
61-79 yrs Under 13-25% 25-30% Over 30%
13%
Administration of the Compositions
The composition of the present invention can be administered to the mammal by
a variety
of routes of administration. Such routes include, for example: oral,
intranasal, intravenous,
intramuscular, intragastric, transpyloric, subcutaneous, rectal, and the like.
In an embodiment, the
preferred administration route is "oral" administration of the composition.
"Oral" administration
means that the mammal ingests the composition or a human feeds the mammal the
composition
of the present invention, and wherein the "human" that feeds the composition
may be, for
example, a pet owner, physician, veterinarian or other health professionals
(e.g., pharmacists).
Feeding instructions that which informs and/or directs the human about the use
and how
to feed the composition to the mammal may include, for example, oral or
written direction (e.g.,
from a physician, veterinarian, other healthy professional); radio, intemet or
television media
(e.g., advertisement); and/or packaging associated with the composition (e.g.,
label present on the
packaging). Additionally, administration in accordance with the present
invention may be
continuous or intermittent, and will vary depending upon the subject/patient.
For example, upon
review of the subject's/patient's physiological condition, and whether the
purpose of the
administration is therapeutic or prophylactic, and others factors that become
known to the skilled
practitioners.
Methods of Using the Compositions
It has been discovered in accordance with the present invention that mHep
inhibits the
differentiation process of fat stem cells, specifically, mesenchymal stem
cells (MSC), into
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adipocytes when cultured in the presence of differentiation medium. After
culturing, the
inventors discovered that the mHep treated fat stem cells have an overall gene
expression pattern
that is similar to the undifferentiated cells that were not given the
differentiation medium. It has
also been discovered that mHep effectively inhibit the ability of
differentiating fat stem cells to
accumulate lipid. These results indicate that mHep might be able to protect
adipose tissue from
biological changes induced by the excessive accumulation of body fat through
reduction in the
body's fat storage capacity.
In an aspect of the present invention, the present invention is directed to a
method of
treating or preventing overweight and obesity in a mammal, wherein the method
comprises
administering to the mammal a composition comprising an effective amount of a
mHep.
In an embodiment, the mammal is consuming more than the minimum caloric
requirements or is not on a diet regimen.
In another embodiment, the mammal is a human (e.g., woman, man). When
referring to a
human, the terms "overweight" and "obesity" may be used to identify states of
body weight/ body
fatness based on the human subject's Body Mass index (BMI). Table 2 below sets
out ranges of
BMI for each body state according to the guidelines provided by the U.S. CDC.
BMI is
determined by taking the subject's weight and dividing it by the height.
Table 2: BMI and Weight Status for Humans
BMI (kg/m2) Weight Status
Below 18.5 Underweight
18.5-24.9 Normal
25.0-29.9 Overweight
30.0 and above Obese
In another embodiment, the mammal is a pet selected from:
a) a growing pet selected from the group consisting of a reproductively-intact
puppy, a
reproductively-intact kitten, an overweight or obese puppy, an overweight or
obese
kitten, a spayed or neutered puppy, and a spayed or neutered kitten;
b) an adult pet selected from the group consisting of a reproductively-intact
adult dog, a
reproductively-intact adult cat, an overweight or obese adult dog, an
overweight or
obese adult cat, a spayed or neutered adult dog, a spayed or neutered adult
cat; or
c) a senior pet selected from the group consisting of a reproductively-intact
senior dog, a
reproductively-intact senior cat, an overweight or obese senior dog, an
overweight or
obese senior cat, a spayed or neutered senior dog, and a spayed or neutered
senior cat.
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When the mammal is a pet, the terms "overweight" and "obesity" refer to states
of body
weight/ body fatness based on an assessment of the animal's body using the
Body Condition
Chart (BCS) for Assessing Obesity in Cats and Dogs, developed by Greg Sunvold
from JAMS
(1998), as reproduced in FIGS. 1A (dogs) and 1B (cats). The chart provides 5
types of body
5 weight/ fatness status: (1) thin, (2) underweight, (3) ideal, (4)
overweight, and (5) obese, with
defining physical characteristics for each type to help with the assessment.
The benefit of the
chart approach is that it provides some uniformity to the assessment.
It has also been discovered that the degree of the adipocyte's response is
dependent on the
timing of the mHep administration relative to the stage of adipocyte
differentiate, since mHep
10 appears to have limited effect on adipocytes once they have
differentiated and are accumulating
lipids. Accordingly, the benefit of mHep on adipocyte functionality is
dependent on early mHep
administration prior to the initiation of adipocyte differentiation. Once fat
stem cells have
differentiated into adipocytes it is difficult to get rid of them. Therefore,
the objective of early on
administration of mHep to a mammal is to inhibit the differentiation process
and limit your
15 body's reserve of adipocytes.
In another embodiment, the mammal is a growing pet such as, for example, a
kitten or a
puppy. The kitten may be a domesticated cat that is 3 years old or less, 2
years old or less, or 1
year old or less. The puppy may be a domesticated dog that is 3 years old or
less, 2 years old or
less, or 1 year old or less. Preferably, the growing pet is in need thereof
such treatment since the
animal is overweight or obese, or the method is a prophylactic to prevent the
mammal from
becoming overweight or obese. Non-limiting examples of a growing pet in need
of such
treatment include an overweight puppy, an obese puppy, an overweight kitten,
or an obese kitten.
The composition comprising mHep is administered to growing pets before they
have fully
developed to the normal adult weight, so it is not possible or healthy to
suppress weight gain
altogether. The method of the present invention allows for a net weight gain
of lean body mass
yet at the same time treats or prevents weight gain derived from excessive fat
accumulation.
Accordingly, for growing pets, the overweight or obesity being targeted by
this new method is
characterized by a weight gain derived substantially from excessive fat
accumulation in adipose
tissues. It is desirable that the composition of the present invention has a
sparing effect on lean
body mass.
In another embodiment, the growing pet may be reproductively-intact or
preferably, may
have been spayed or neutered. It is possible that after weaning but before
reaching sexual
maturity. The removal of sex organs results in markedly decreased levels of
endogenous sex
hormones (e.g., estrogen). Consequently, weight gain is common in mammals
following spaying
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or neutering. Accordingly, the methods of the present invention would benefit
growing pets that
have been spayed or neutered.
In another embodiment, the method is for preventing overweight and obesity in
a
mammal having a body that is characterized as thin, underweight or ideal. It
is clear that if the
mammal is obese with appreciable levels of body fat storage, due to its
mechanism of action,
mHep will not be able to treat that animal. However, it is believed that mHep
would be
beneficial to prevent overweight and obesity in adult/senior pets, if they
have not developed
appreciable levels of body fat. In this scenario, MH would help to
prevent/minimize the
"middle-age spread" and "age-related increase in body fat" leading to
overweight and obesity in
an otherwise lean adult/senior pet, irrespective of whether they are
reproductively-intact or
neutered.
Of this embodiment, the mammal that would be suitable for this preventative
method are
ones having percentages of total body fat between from about 0.1% to about
20%, or from about
0.5% to about 15%, or from about 1% to about 10%, of the total body weight.
Alternatively,
another way of identifying if a mammal is overweight or obese is by checking
if the mammal has
(i) a body condition characterized as thin, underweight, or ideal, as
determined based on a body
condition chart as disclosed herein; or (ii) a body condition score (B CS) of
1 to 3 based on a
scale from 1 to 5, wherein the BCS is deteremined according to the Body
Condition Score Test as
disclosed herein.
For example, FIGS. 1A & 1B provide the body condition chart for dogs and cats
(available from IAMS (1998)). The body condition chart lists 5 body
conditions (thin,
underweight, ideal, overweight and obese) along with physical criteria that
may be easily viewed
and measurable by anyone such as, for example, non-professionals (e.g., pet
owner), and
professionals (e.g., veterinarian and animal practiconer).
The BCS method is the most accessible and commonly used method for estimating
obesity in a pet. Under the BCS method, physical examination, visual
observation, and palpation
may be used to assign a body condition score. The body condition score is a
semi-quantitative
assessment of body fat with the following scale 1 to 5 by 0.25 points;
1=emaciated, 2=thin, 3=
average, 4= fat, and 5=obese.In another embodiment, wherein the method
administration to the
mammal of a composition comprising an effective amount of an mHep inhibits or
reduces the
differentiation process of fat stem cells into adipocytes in the mammal. In
the present invention,
"an effective amount" of a mHep refers to the amount of mHep in a composition
of the present
invention, when administered to a mammal, preferably a human or a domesticated
animal such
as, for example, a pet or companion animal (e.g., cats, dogs) sufficient to
effect treatment or
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prevention of overweight and obesity. This "effective amount" of a mHep, which
is a component
of the composition of the present invention, will vary depending upon the
condition and its
severity, the manner/route of administration, the age of the mammal to be
treated and its overall
health, but can determined routinely by one of ordinary skill in the art
having regard to his own
knowledge and to this disclosure.
The dose of the mHep will depend upon the form in which the mHep is delivered
to the
mammal. The dose will vary depending on the size and condition of the pet to
which mHep is to
be administered. Dosage in the range of from about 0.0001 or about 0.001 g/kg
to about 1g/kg
can be beneficial in some embodiments. As used herein, when dosage in mg/kg is
used, the mg
refers to the level of the mHep and kg refers to kilograms of body weight of
the mammal,
preferably where the mammal is a human or pet such as, for example, a cat or
dog. In one
embodiment, the dosage of the component provided to a pet on a daily basis may
be from about
0.1, 0.5, 1, 2, or 5 mg/kg to about 15, 20, 50, 100, 150, or 200 mg/kg, and
all combinations of
these ranges, wherein "mg" refers to the level of the mHep and "kg" refers to
kilograms of body
weight of the mammal. In one embodiment, the daily dosage to the pet may be
from about 0.1
mg/kg to about 50 mg/kg, from about 1 mg/kg to about 20 mg/kg, 1 mg/kg to
about 15 mg/kg,
from about 2 mg/kg to about 10 mg/kg, or from about 2 mg/kg to about 5 mg/kg,
or about
2mg/kg. In certain embodiments, these amounts may translate to compositions
comprising less
than about 5%, or less than about 2%, or from about 0.0001% to about 0.5%, or
from about 0.1%
to about 10%, or from about 5%, of mHep, all by weight of the composition. In
certain
embodiments, the mHep is present in the compositions in the range of from
about 0.0001% to
about 10%, or from about 0.01% to about 5%, or from about 0.1% to about 3%, by
weight of the
compositions. All ranges therebetween are envisioned. The level of mHep may be
determined
by one of ordinary skill in the art based on a variety of factors, for
example, the form of the
composition. For example, when the composition is a pet food composition it is
selected from a
dry composition, a smei-moist composition, wet composition, or supplement, or
any other form
or mixture thereof. The ordinarily skilled artisan will be able to utilize the
preferred dosage and
determine the optimal level of mHep within a given composition.
In another embodiment, wherein the administration of the mHep results in the
inhibition
or reduction of the differentiation process of fat stem cells into adipocytes
results in lower levels
of adipocytes such that the mammal's body's fat storage capacity decreases by
about at least 5%,
about at 10%, or about at least 20%, relative to an untreated mammal.
In another aspect, the present invention is directed to a method to promote or
maintain a
healthy body weight in a mammal, wherein the method comprises administering to
the mammal
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an effective amount of a composition comprising a mHep to prevent or reduce
excessive body fat
in the mammal. "Excessive body fat" may be any amount that qualifies the
mammal to be
considered overweight or obese.
In yet another aspect, the present invention is directed to a method for
preventing or
ameliorating overweight and obesity in a mammal comprising feeding to the
mammal a
composition comprising a mHep present in the composition. The mHep is present
at from about
0.0001% to about 10% by weight of the composition, from about 0.01% to about
5% by weight
of the composition, or from about 0.1% to about 3% by weight of the
composition. The
composition is selected from the group consisting of a pet food, a supplement
and a liquid,
wherein the supplement or the liquid can be taken separately or added to the
pet food, and
wherein the mammal is an adult pet or a senior pet.
In yet another aspect, the present invention is directed to a method for
preventing or
ameliorating overweight and obesity in a mammal comprising feeding to the
mammal a
composition comprising a mHep. The mHep is present in the composition at from
about
0.0001% to about 10% by weight of the composition, from about 0.01% to about
5% by weight
of the composition, or from about 0.1% to about 3% by weight of the
composition., wherein the
composition is selected from the group consisting of a pet food, a supplement
and a liquid,
wherein the supplement or the liquid can be taken separately or added to the
pet food, and
wherein the mammal is an adult pet or a senior pet.
In yet another aspect, the present invention is directed to a method for
increasing lifespan
of a mammal, comprising administering to the mammal a composition comprising a
daily dosage
amount of 1 mg/kg to about 50 mg/kg, or 1 mg/kg to about 15 mg/kg, or 1 mg/kg
to about 5
mg/kg, of a mHep. It is expected that mammals that are exposed to longer
duration of the mHep,
for example, by starting with the treatment shortly after birth, will reap
more benefits in terms of
increased lifespan. In an embodiment, the administration starts when the
mammal is about 1
month old or less, about 6 months old or less, about 1 year old or less, about
2 years old or less,
or about 3 years old or less.
In an embodiment, the reduction of caloric intake by the mammal is at least
about 5%, at
least about 10%, at least about 20%, at least about 30%, at least about 40%,
or at least about
50%. In another embodiment, the lifespan increases by about 10% or higher,
about 15% or
higher, about 20% or higher, about 25%, about 30% or higher, or about 35% or
higher.
In another embodiment, the method of increasing lifespan wherein:
(i) the administration of mHep begins when the mammal is about 1 month old and
the
lifespan increase is about 30% or higher;
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(ii) the administration of mHep begins when the mammal is about 6 months old
and the
lifespan increase is about 25% or higher;
(iii)the administration of mHep begins when the mammal is about 1 year old and
the
lifespan increase is about 20% or higher;
(iv)the administration of mHep begins when the mammal is about 2 years old and
the
lifespan increase is about 15% or higher; and
(v) the administration of mHep begins when the mammal is about 3 years old and
the
lifespan increase is about 10% or higher.
Combination Therapy
The composition comprising an effective amount of mHep or an effective amount
of
mHep of the present invention may be usefully combined with one or more other
therapeutic
agent or as any combinations thereof, in the treatment of overweight or
obesity.
Packages
The present invention also covers an article of commerce, preferably in form
of a
package, containing a composition comprising an effective amount of a mHep as
described
hereinabove together with a feeding manual with instructions for how to orally
administer
composition to the feline companion animal. Any standard packaging that is
suitable for delivery
and sale of the compositions as disclosed herein can be used. The package can
also include
specific written benefit statements related to the treatment or prevention of
overweight or obesity
in a mammal, preferably where the mammal is a pet, and more preferably where
the pet is a
growing pet such as, for example, kitten or puppy.
The benefit statements can also relate to the health benefits resulted from
such treatment
or prevention, such as decrease body weight, healthy body weight, healthy body
fat, and
prolonged life span.
Examples
The following examples are provided to illustrate embodiments of the invention
and are
not intended to limit the scope thereof in any manner.
Example 1 ¨ Preparation of Avocado Extract
Avocado extract containing enhanced levels of mannoheptulose is prepared in
accordance
with the following optional process, and utilized in compositions of
embodiments of the
invention.
Whole avocado fruit (about 900 kg) is provided. The fruit is split and the
pits are
removed, either partially or wholly, providing about 225 kg of pitted avocado
halves. The raw
avocado is charged to a disintegrator, whereupon some agitation, water (about
3000 kg) and
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CELLUBRIX (commercially available from Novozymes A/S) (about 1 liter) is
further charged.
The mixture is further agitated and concurrently heated to about 66 C. Upon
completion of the
charge, further CELLUBRIX (about 1 L) is added, and the entire mixture is
CELLUBRIX held
under agitation for about 12 hours at a controlled pH of about 5.5. The
temperature is then further
5 increased to about 80 C and then held for at least about 2 hours. The
resulting digested plant
mixture is then filtered at 80 C to provide the carbohydrate extract as the
filtrate. The
carbohydrate extract is then evaporated in a simplified recirculation system
at 80 C, under
vacuum, to provide the carbohydrate extract having from about 10% to about 20%
solids and a
pH of about 5.5. The extract is then further concentrated using a refractance
window dryer to
10 provide about 100 kg of the extract as a crystalline or powder (a yield
of about 11% carbohydrate
extract, based on the starting mass of the whole avocado fruit, which is
analyzed as a yield from
about 0.25% to about 4.5% mHep, based on the starting mass of the whole
avocado fruit). It
should be noted the amount of mHep found in avocados varies with the
particular strain and state
of ripeness of the fruit. The extract may be used in the compositions of
embodiments of the
15 invention.
Example 2 ¨ Effect of mHep on Mesenchymal Stem Cells (MSC) Differentiation
Study 1 ¨ This study describes an in vitro assay for testing the impact of
mHep on the
terminal differentiation of Mesenchymal Stem Cells (MSC) (i.e., fat stem
cells) into functional
adipocytes. MSC (C57BL/6) (Gibco) is cultured in adipocyte differentiating
medium (Invitrogen)
20 in the presence of palmitate at 37 C, with 5% CO2, to induce MSC
differentiation from pre-
adipocytes into functional adipocytes. A control plate of MSC is cultured in
Basal Medium
without ADP (BP) as a negative control (i.e., reflect undifferentiated MSC).
The following samples are added to the MSC cultures with ADP to assess their
effect on
adipocyte differentiation: (i) mHep at 3 concentrations of 1.16 nM, 11 mM and
22 mM; (ii)
whole-fruit avocado extract added at 0.2% with 25% mHep enrichment; and (iii)
Resveratrol at
50 p M. Endpoint measures include: (i) oil red staining as a measure of
accumulated fat; (ii)
visual inspection of adipocytes; and (iii) an ATP assay to measure cell
viability. Assay
sensitivity allows for the testing of millimolar levels of mHep on adipocyte
differentiation.
Results 1
Results indicate the addition of palmitate in the differentiation cocktail
increases lipid
accumulation over the basal medium. MSC cultures with mHep (11 mM and 22 mM)
or whole-
fruit avocado extract (0.2%) present in the medium reverses lipid accumulation
to near basal
levels. These results imply mHep inhibits fat cell differentiation and the
ability of differentiated
adipocytes to accumulate lipid based on oil red staining (FIG. 2). Results are
supported by the
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reduced effectiveness of a lower mHep dose (1.16 mM) or a heat-inactivated
source of whole-
fruit avocado extract (0.2%) to prevent fat cell differentiation and oil
accumulation.
Study 2 ¨ In this study the impact of delaying the administration of mHep on
MSC
differentiation. 22 mM mHep was added to MSC cultures at 0, 4 and 7 days, and
end-point
measurements were taken with oil red staining as a measure of accumulated fat.
A control is
cultured in Basal Medium without ADP (BP) as a negative control (i.e.,
reflects undifferentiated
MSC).
Results 2
The inhibitory effects of mHep appear to be lost if mHep addition occurs after
differentiation and the adipocytes are accumulating lipid. The following table
shows the impact
on MSC differentiation due to delay of mHep (22 mM) addition until days 4 or
7. The results in
similar oil red-staining as MSC-derived control cells grown in differentiation
media devoid of
MH. In contrast, MH addition at day 0 results in similar inhibitory effects on
lipid accumulation
as noted previously. These results imply MH directly impacts the
differentiation process of
adipocytes to prevent lipid accumulation. MH appears to have no effect on
adipocytes once they
are differentiated and accumulating lipid. As such, any benefit of MH on
adipocyte functionality
is dependent on early MH administration prior to the initiation of adipocyte
differentiation.
Table 3:
MH (22 mM) addition Percentage of oil red staining in MH-treated
to differentiation media cells vs. differentiated fat cells ( SD)
Day 0 58%( 16%)
Day 4 97%( 25%)
Day 7 87%( 11%)
It should be understood that every maximum numerical limitation given
throughout this
specification includes every lower numerical limitation, as if such lower
numerical limitations
were expressly written herein. Every minimum numerical limitation given
throughout this
specification includes every higher numerical limitation, as if such higher
numerical limitations
were expressly written herein. Every numerical range given throughout this
specification
includes every narrower numerical range that falls within such broader
numerical range, as if
such narrower numerical ranges were all expressly written herein.
All parts, ratios, and percentages herein, in the Specification, Examples, and
Claims, are
by weight and all numerical limits are used with the normal degree of accuracy
afforded by the
art, unless otherwise specified. All documents cited in the Detailed
Description of the Invention
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are, in relevant part, incorporated herein by reference; the citation of any
document is not to be
construed as an admission that it is prior art with respect to the present
invention.
The dimensions and values disclosed herein are not to be understood as being
strictly
limited to the exact numerical values recited. Instead, unless otherwise
specified, each such
dimension is intended to mean both the recited value and a functionally
equivalent range
surrounding that value. For example, a dimension disclosed as "40 mm" is
intended to mean
"about 40 mm."
Every document cited herein, including any cross referenced or related patent
or
application, is hereby incorporated herein by reference in its entirety unless
expressly excluded or
otherwise limited. The citation of any document is not an admission that it is
prior art with
respect to any invention disclosed or claimed herein or that it alone, or in
any combination with
any other reference or references, teaches, suggests or discloses any such
invention. Further, to
the extent that any meaning or definition of a term in this document conflicts
with any meaning
or definition of the same term in a document incorporated by reference, the
meaning or definition
assigned to that term in this document shall govern.
While particular embodiments of the present invention have been illustrated
and
described, it would be obvious to those skilled in the art that various other
changes and
modifications can be made without departing from the spirit and scope of the
invention. It is
therefore intended to cover in the appended claims all such changes and
modifications that are
within the scope of this invention.
