Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Composition And Method For Inducing Lipolysis And Increasing The
Metabolism Of Free Fatty Acids
Related Applications
This application is related to co-pending U.S., Patent Application:
, entitled "Composition for facilitating a more favorable blood lipid
profile and increasing the metabolism of free fatty acids via increased nitric
oxide levels" filed on May 11, 2007, the contents of which are hereby
incorporated by reference in there entirety.
Field of the Invention
The present invention relates to a nutritional supplement for inducing
lipolysis and increasing the catabolism of free fatty acids via the
phosphorylation of perilipins. More specifically, the present invention
relates
to a nutritional supplement comprising a combination of green tea extract and
y-butyrobetaine.
Background of the Invention
Obesity, a condition of excessive body fat, generally results from more
food being consumed than is being used. Stemming from excessive body fat,
several health-related concerns have been linked to obesity and being
overweight, such as increased morbidity, hypertension, coronary heart
disease, type 2 diabetes mellitus, stroke and even some forms of cancer
(Curioni C, Andre C, Veras R. Weight reduction for primary prevention of
stroke in adults with overweight or obesity. Cochrane Database Syst Rev.
2006 Oct 18;(4):CD006062). Obesity has become an increasingly
widespread and predominant health concern. According to the World Health
Organization (WHO) obesity is considered a multifactorial chronic disease
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which is increasing in frequency (Curioni C, Andre C, Veras R. Weight
reduction for primary prevention of stroke in adults with overweight or
obesity.
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006062).
One of the main contributing factors in obesity is overeating, which
30 results in an excess of energy being consumed in relation to the amount of
energy being expended by an individual. This excess energy is then
commonly stored as fat. A simplified determination of an individual's body
weight is essentially governed by the net effect of energy consumed versus
energy expended. Daily energy expenditure consists of three components:
35 basal metabolic rate, adaptive thermogenesis and physical activity
(Westerterp KR. Diet induced thermogenesis. Nutr Metab (Lond). 2004 Aug
18;1(1):5). All of the aforementioned components must be in a balance with
energy expenditure in an individual, that is, energy or food intake being such
that an individual does not gain nor lose body weight. Therefore, in order for
40 a person to lose body weight from a reduction in adipose tissue, more
energy
must be expended by the individual than is taken into the body.
With the unprecedented rise in obesity throughout the world, there
exists both a need and want from individuals for improved aids, methods and
interventions directed to reducing body fat and maintaining lowered levels of
45 body fat. These needs have led to intensive study of the various mechanisms
of fat metabolism. One such mechanism that has shown promise is the
arginine-nitric oxide pathway. Nitric oxide (NO), which is synthesized from
arginine by all cell types, has been shown to be a key signal molecule
involved in adipose tissue biology by influencing adipogenesis and insulin-
50 stimulated glucose uptake.
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There are four major mechanisms by which NO has been shown to
influence energy metabolism. As a first mechanism, NO has been shown to
increase the phosphorylation of both hormone-sensitive lipase and perilipin.
Perilipin is a protein which coats lipid droplets in adipocytes and acts to
55 protect triglycerides from hormone-sensitive lipases, which break lipids
into
glycerol and free fatty acids. When the perilipin is phosphorylated its
conformation changes and the lipids stored within are exposed to hormone-
sensitive lipase, thus enacting hormone-senstive-mediated lipolysis.
Additionally, as a second mechaninsm of energy metabolism, NO has been
60 shown to stimulate the phosphorylation of adenosine-3',5'-monophosphate
activated protein kinases. Activation of these kinases causes a decrease in
levels of malonyl-CoA, which plays a key role in the chain elongation of fatty
acid biosynthesis by providing 2-carbon units to fatty acids. The fatty acids
are then comitted to fatty acid chain synthesis. Additionally, activation of
65 these kinases decreases the expression of genes related to lipogenesis and
gluconeogenesis. Thirdly, NO has been shown to increase blood flow to
insulin-sensitive tissue, thereby promoting substrate uptake and product
removal. Lastly, NO has been shown to activate the expression of
peroxisome proliferator-activated receptors leading to enhanced mitochondrial
70 biogenesis and oxidative phosphorylation.
Summary of the Invention
The present invention is directed towards a nutritional supplement,
comprising at least a therapeutically effective amount of green tea extract,
and a therapeutically effective amount of y-butyrobetaine. The composition of
75 the present invention may further comprise y-butyrobetaine ethyl ester or
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similar additional derivatives of y-butyrobetaine. The ingredients of the
present nutritional supplement act substantially simultaneously to induce
lipolysis, resulting in free fatty acid release, and to increase the
catabolism of
free fatty acids via the phosphorylation of perilipins. Both a composition and
a
80 method are provided by the present disclosure.
Detailed Description of the Invention
In the following description, for the purposes of explanations, numerous
specific details are set forth in order to provide a thorough understanding of
the present invention. It will be apparent, however, to one of ordinary skill
in
85 the art that the present invention may be practiced without these specific
details.
The present invention is directed towards a nutritional supplement, for
inducing lipolysis and increasing the catabolism of the resultant free fatty
acids via the phosphorylation of perilipins. The composition of the present
90 invention comprises at least a combination of green tea extract and y-
butyrobetaine.
The term 'y-butyrobetaine' as used herein is understood to represent
gamma-butyrobetaine, also known as, butyrobetaine, deoxycarnitine, actinine,
4-butyrobetaine, or 4-trimethylamniobutyrate. Additionally, as used herein, 'y-
95 butyrobetaine' also includes derivatives of gamma-butyrobetaine wherein
said
derivatives are esterified forms of y-butyrobetaine, amides of y-
butyrobetaine,
and salts of y-butyrobetaine, as well as other derivatives of y-butyrobetaine
particularly those derivatives having similar pharmacoproperties to y-
butyrobetaine upon metabolism to an active form as defined by the scope of
100 the disclosure.
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A used herein, the term 'nutritional composition' includes dietary
supplements, diet supplements, nutritional supplements, supplemental dietary
and other compositions similarly envisioned and termed not belonging to the
conventional definition of pharmaceutical interventions as is known in the
art.
105 Furthermore, 'nutritional compositions' as disclosed herein belong to
category
of compositions having at least one physiological function when administered
to a mammal by conventional routes of administration.
Green Tea Extract (ECGC, Catechins and Polyphenols)
The active compounds of green tea are a family of polyphenois
110 wherein tannins are the largest of the subgroups the polyphenois contained
therein. The most active specific compound of the polyphenols is
epigallocatechin gallate (ECGC) which comprises 10-50% of the total
catechins found in green tea. Furthermore, caffeine is also a major active
component of green tea; however the percentage of caffeine contained in
115 extracts of green tea fluctuates significantly owing to several different
factors
such as processing, for example.
Green tea principally acts in a beneficial way through the polyphenols'
antioxidant activities as evidenced by several laboratory studies. One
clinical
study has shown that the ingestion of an extract of green tea results in a
rapid
120 increase in plasma antioxidant activity (Benzie IF, Szeto YT, Strain JJ,
Tomlinson B. Consumption of green tea causes rapid increase in plasma
antioxidant power in humans. Nutr Cancer, 1999. 34(1):83-7).
Moreover, green tea has also been shown to be effective in aiding
weight loss. This effect may be due to two activities. Green tea both reduces
125 fat digestion and increases energy expenditure (Berube-Parent S, Pelletier
C,
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Dore J, Tremblay A. Effects of encapsulated green tea and Guarana extracts
containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy
expenditure and fat oxidation in men. Br J Nutr, 2005;94(3):432-6). Fat stores
provide the energy necessary for the increase in energy expenditure via the
130 oxidation of fat, consequently leading to thermogenesis. In this regard,
the /3-
oxidation of fats resulting from administration of green tea extracts is a
result
of activities at adenosine receptors. The activation of adenosine receptors on
a cell's surface causes an increase in cyclic adenosine monophosphate
(cAMP), leading to lipolysis via an increase in epinephrine and
135 norepinephrine.
Additionally, the mechanism of action of green tea may also be, due to
an increase in norepinephrine. Catechins, found in green tea, are known to
inhibit catechol-O-methyl-transferase (COMT), an enzyme which degrades
norepinephrine. In turn, norepinephrine inhibits the degradation as well as
140 increases the production of cyclic adenosine monophosphate (cAMP).
Furthermore, increasing norepinephrine levels by the inhibition of
norepinephrine uptake results in increased weight loss in both lean and obese
mice as evidenced in animal studies (Billes SK, Cowley MA. Inhibition of
Dopamine and Norepinephrine Reuptake Produces Additive Effects on
145 Energy Balance in Lean and Obese Mice. Neuropsychopharmacology. 2007
Apr;32(4):822-34). Stemming from increased norepinephrine levels is the
result of an increased presence of cAMP which leads to greater activation of
protein kinase A, which subsequently activates lipases found in adipose
tissue.
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150 It is herein understood by the inventors that increasing the amount of
cAMP present in cells will lead to increased protein kinase A activity,
resulting
in increased activity of lipases and thus greater fatty acid release.
An embodiment of the present invention comprises Green Tea extract.
A serving of the nutritional supplement contains from about 0.05 g to about
155 1.00 g of Green Tea extract. In a preferred embodiment, the Green Tea
extract is standardized to about 45% EGCG, about 75% catechins, and about
90% polyphenols.
y-butyrobetaine (GBB) and Derivatives
y-butyrobetaine is an intermediate in carnitine biosynthesis in
160 mammals. It is synthesized, from trimethyl lysine, in almost all cell
types and
then excreted into the blood to be reabsorbed by the kidney and liver. After
reabsorption, GBB is converted to carnitine by y-butyrobetaine dioxygenase.
This conversion to carnitine is extremely efficient, thus presence of y-
butyrobetaine in urine is very small (Vaz FM, Wanders RJA. Carnitine
165 biosynthesis in mammals. Biochem J. 2002;361:417-429).
Since y-butyrobetaine is a precursor to carnitine, its administration has
been studied as a way to increase carnitine levels in the body. Carnitine acts
as a carrier molecule for fatty acids across the inner mitochondrial membrane.
In order for free fatty acids to be catabolized, they must first enter the
170 mitochondria of a cell such that a-oxidation may take place to produce
energy.
Fatty acids are first activated with the addition of coenzyme A(CoA), then
bound to carnitine and transferred across the mitochondrial inner membrane.
After transport across the mitochondrial membrane, the carnitine is removed
and the fatty acid is oxidized to produce energy.
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175 Additionally, the administration of y-butyrobetaine to rats (Sjakste N,
Kleschyov JL, Baumane L, Dzintare M, Meirena D, Sjakste J, Sydow K,
Munzel T, Kalvinsh I. Endothelium- and nitric oxide-dependent vasorelaxing
activities of gamma-butyrobetaine esters: possible link to the antiischemic
activities of mildronate. Eur J Pharmacol. 2004 Jul 8; 495(1):67-73
(Abstract)),
180 provides vasodilating activities. These vasodilating activities were
attributed
to increases in nitric oxide concentrations in blood. Since nitric oxide has
been shown to increase energy metabolism, it is herein understood by the
inventors that increases in NO levels will lead to increased catabolism of
fatty
acids being released from adipocytes, thereby reducing the fat content in the
185 body. The mechanisms of which have been previously discussed above.
An embodiment of the present invention comprises y-butyrobetaine or
derivatives thereof. A serving of the nutritional supplement contains from
about 0.005 g to about 0.050 g of y-butyrobetaine or derivatives thereof.
Since fatty acids which have been release can be reabsorbed and re-
190 stored. again as fat, it is desirable to eliminate the fatty acids which
have been
released before they are reabsorbed. As such, the present invention aims to
not only release fatty acids stored in the body, but to substantially
simultaneously oxidized them to energy which can be emitted from body of an
individual as heat. The oxidized fatty acids cannot be reabsorbed and re-
195 stored as fat, thus weight loss results.
In an embodiment of the present invention, which is set forth in greater
detail in Example 1, the nutritional supplement comprises an extract of green
tea, y-butyrobetaine, and y-butyrobetaine ethyl ester. The nutritional
supplement is provided in any acceptable and suitable oral dosage form as
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200 known in the art. Lipolysis via cAMP signaling and the metabolism of free
fatty
acids via increased nitric oxide levels and ,6-oxidation is substantially
simultaneously induced and carried out in an individual by administration of
the composition of the present invention.
The nutritional supplement of the present invention may be
205 administered in a dosage form having controlled release characteristics
i.e.
time-release. Furthermore, the controlled release may be in forms such as a
delayed release of active constituents, gradual release of active
constituents,
or prolonged release of active constituents. Such active constituents release
strategies extend the period of bioavailability or target a specific time
window
210 for optimal bioavailability. Advantageously the nutritional supplement may
be
administered in the form of a multi-compartment capsule which combines both
immediate release and time-release characteristics. Individual components of
the nutritional supplement may be contained in differential compartments of
such a capsule such that specific components are released rapidly while
215 others are time-dependently released. Alternatively, a uniform mix of the
various components of the present invention may be divided into both
immediate release and time-release compartments to provide a multi-phasic
release profile.
While, not wishing to be bound by theory, the present invention is
220 comprised of components which have been shown to inhibit the activity of
enzymes which degrade norepinephrine. The resulting increase in the
presence of norepinephrine will lead to inhibition of the degradation of cAMP
as well as the increased production of cAMP. Increased levels of cAMP
present in cells will lead to elevated protein kinase A activity, resulting in
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225 increased activity of lipases and thus greater fatty acid release in the
body of
an individual upon administration of the composition of the present invention.
Additionally, the present invention comprises components which have
been shown to lead to, via increased nitric oxide levels, increased
phosphorylation of hormone-sensitive lipase and perilipin. It is herein
230 understood by the inventors that increased phosphorylation of perilipin
will
result in a greater likelihood of lipids being broken down by lipases, leading
to
increased release of free fatty acids in the body of an individual upon
administration of the composition of the present invention.
Furthermore, increased nitric oxide levels will yield greater
235 phosphorylation of adenosine-3',5'-monophosphate activated protein kinase,
which will cause a decrease in levels of malonyl-CoA and decrease the
expression of genes related to lipogenesis and gluconeogenesis. It is herein
understood by the inventors that decreased malonyl-CoA levels will result in
reduced chain elongation of fatty acids and thus a decrease in fatty acid
240 biosynthesis in the body of an individual upon administration of the
composition of the present invention.
In addition, the present invention comprises components that have
been shown to lead to, via increased nitric oxide levels, elevated expression
of peroxisome proliferator-activated receptors. It is herein understood by the
245 inventors that increased expression of peroxisome proliferator-activated
receptors will enhance mitochondrial biogenesis and oxidative
phosphorylation, resulting in elevated metabolism of free fatty acids in the
body of an individual upon administration of the composition of the present
invention.
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250 Further to the aforementioned functions, the present invention
comprises components that have been shown to lead to, via increased nitric
oxide levels, elevated blood flow to insulin-sensitive tissue. It is herein
understood by the inventors that increased blood flow will promote substrate
uptake and product removal, thus increasing the movement of free fatty acids
255 throughout the body of an individual of the composition of the present
invention.
Additional embodiments of the present invention may also include
portions of the composition as fine-milled ingredients. U.S. Non-Provisional
Patent Application 11/709,526 entitled "Method for Increasing the Rate and
260 Consistency of Bioavailability of Supplemental Dietary Ingredients" filed
Feb
21, 2007, which is herein fully incorporated by reference, discloses a method
of increasing the rate of bioavailability following oral administration of
components comprising supplemental dietary compositions by the.process of
particle-milling.
265 Furthermore, additional embodiments of the present invention may be
incorporated into specific controlled-release solid dosage forms. U.S. Non-
Provisional Patent Application 11/709,525 entitled "Method for a
Supplemental Dietary Composition Having a Multi-Phase Dissolution Profile"
filed Feb 21, 2007, which is herein fully incorporated by reference, discloses
a
270 method of achieving a solid oral dosage form with multiple dissolution
characteristics for the release of active ingredients.
According to various embodiments of the present invention, the
nutritional supplement may be consumed in any form. For instance, the
dosage form of the nutritional supplement may be provided as, e.g., a powder
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275 beverage mix, a liquid beverage, a ready-to-eat bar or drink product, a
capsule, a liquid capsule, a tablet, a capiet, or as a dietary gel. The
preferred
dosage forms of the present invention are as a capiet or as a liquid capsule.
Furthermore, the dosage form of the nutritional supplement may be
provided in accordance with customary processing techniques for herbal and
280 nutritional supplements in any of the forms mentioned above. Additionally,
the nutritional supplement set forth in the example embodiment herein
disclosed may contain any appropriate number and type of excipients, as is
well known in the art. By way of ingestion of the composition of the present
invention, a method for substantially simultaneously inducing lipolysis and
285 increasing the catabolism of free fatty acids via the phosphorylation of
perilipins. The method of the present invention comprises at least the step of
administering to an individual a therapeutically acceptable amount of the
composition of the present invention.
Although the following example illustrates the practice of the present
290 invention in one of its embodiments, the example should not be construed
as
limiting the scope of the invention. Other embodiments will be apparent to one
of skill in the art from consideration of the specifications and example.
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Example
A nutritional supplement comprising the following ingredients per serving is
295 prepared for consumption as a caplet to be administered before meals:
About 0.46 g of green tea extract which is standardized for 90% polyphenols,
75% catechins, 45% epigallocatechin gailate, about 0.01 g of y-butyrobetaine
(GBB), and about 0.2 g of y-butyrobetaine ethyl ester.
300
Extensions and Alternatives
In the foregoing specification, the invention has been described with a
specific embodiment thereof; however, it will be evident that various
modifications and changes may be made thereto without departing from the
305 broader spirit and scope of the invention.
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