Throughout the world, more than a billion people are overweight and more
than 300 million are obese (Gunter, 2006). In the past four decades, the
percentage of Americans who are obese has increased from 13% to 30%. Two
thirds of Americans are overweight. This increasing trend of weight gain
is similar to what is occurring in other Western countries (Gunter, 2006).
For the first time in recent history, the average lifespan of Americans
is expected to decline and the negative health effects of obesity is one
of the primary reasons for this (Cota, 2006).
1) SIGNALS SECRETED BY ADIPOSE
Adipose cells secrete a number of hormones which are collectively referred
to as adipocytokines. These adipocytokines are generating greater interest
because of their roles in obesity, diabetes, cardiovascular disease, atherosclerosis,
and immune function (Koerner, 2005; Avogaro, 2005).
Given that weight gain and obesity are represent a serious health concern
throughout the world, especially in industrial nations, the hormone leptin
has attracted a great deal of attention because it reduces appetite and
increases metabolic rate. Leptin is a cytokine gene family member which
is secreted by adipose, the placenta, the ovaries, the pituitary gland,
the stomach, and the liver. As greater amounts of adipose are stored in
the body, greater amounts of leptin are secreted. Leptin thus serves as
a "lipostat" which provides feedback on the amount of fat in
the body to the feeding centers of the brain. The hypothalamus and hippocampus
are the regions of the brain which absorb the greatest amounts of leptin
(Ahima, 2005). Leptin undergoes cyclical variation in its secretion, with
maximal secretion occurring at night. A number of signals (such as insulin,
glucose, extrogen, glucocorticoids, inflammatory signals, and interleukin)
increase leptin levels while others (such as androgens, ligands of adrenoreceptors,
and cigarette smoking) decrease leptin levels (Koerner, 2005; Lopez, 2005;
Moschos, 2002; Yildiz, 2006).
In humans, several polymorphisms of the leptin gene have been linked to
obesity. Nonfunctional leptin genes cause a rare form of obesity which
has been successfully treated with gene therapy. Unfortunately, increases
in leptin levels seem to reduce weight in only a small percentage of obese
individuals (Koerner, 2005). While leptin treatments do not significantly
affect most obese patients, it does improve the levels of insulin and
reaction to insulin in those who suffer from congenital leptin deficiency
and a few other specific lipid disorders (such as lipodystrophy) (Yildiz,
If leptin inhibits weight gain in normal individuals, why wouldn't artificially
elevated leptin levels be effective in combating obesity? Although obese
individuals have higher levels of leptin in their plasma (given the greater
amount of adipose in their bodies), this leptin is not effective in reducing
food intake. It may be that high levels of leptin induce the gene SOC3
(suppressor of cytokine signaling 3) which inhibits leptin receptor activity.
Increased expression of tyrosine phosphatase PTPIB may also decrease the
effectiveness of leptin. The resistance to leptin in obese individuals
had been compared to the resistance to insulin in diabetes (Koerner, 2005).
Leptin also is involved in the regulation of puberty, reproduction, and
immune function. Increased leptin levels increases risk for cardiovascular
disease. Leptin also induces mitosis in some cell types and increased
leptin levels contribute to breast cancer, gynecological cancers, leukemia,
and cancers of the digestive tract. Leptin also inhibits bone formation
(Koerner, 2005). Leptin is produced in the epithelia of mammary glands
(Moschos, 2002). Leptin is produced by the placenta and elevated levels
are associated with abnormalities of pregnancy such as pre-eclampsia (Sagawa,
2002). Leptin is required for normal reproductive development. The infertility
and sexual underdevelopment of mutant mice which lack leptin can be treated
with leptin administration. Obese children who are deficient in leptin
restore normal pubertal development and gonadotropin secretion patterns
with leptin treatment (Pasquali, 2006). Mutant mice with lowered levels
of leptin have lower brain weights, neuronal activity, and abnormal myelination
The leptin receptor (OB-R) is a member of the family of cytokine class
I receptors. Leptin receptors are expressed in the ovary, testis, endometrium,
and the cells of the pituitary which secrete gonadotropins (Moschos, 2002).
Alternate splicing can produce at least 4 variants in humans and 6 in
rodents. One of the receptors is soluble in plasma and may protect leptin
from degradation, contributing to increased leptin activity in thin and
anorexic individuals. Individual variations in the leptin receptor have
also been linked to obesity (Koerner, 2005).
Adiponectin is a hormone that belongs to the gene family which includes
collagen, complement proteins, and the inflammatory signal TNF alpha.
Only adipose cells secrete adiponectin. Adiponectin is a factor in determining
risk of heart disease since it inhibits inflammation, atherosclerosis,
and insulin resistance. Increased expression of adiponectin can reduce
atheroscelerosis and insulin resistance in mice and some gene variants
(which presumably reduce the protein's function) in humans are associated
with obesity, elevated insulin levels, and increased insulin resistance
(Gable, 2006; Koerner, 2005; Gil-Campos, 2004).
Adiponectin levels are higher in those who are lean or lose weight and
lower in diabetics, those with cardiovascular disease, and the obese (Gable,
2006). Women have higher levels of adiponectin apparently due to the influence
of sex steroids on its synthesis (Gable, 2006).
Mice which lack adiponectin develop insulin resistance (even without weight
gain) when fed a diet high in sugar (Gable, 2006). In humans, several
polymorphisms in the adiponectin gene which lower its plasma levels increase
risk of diabetes and obesity (Gil-Campos, 2004).
Of the various signaling molecules secreted by adipose, adiponectin
is produced at the highest levels, composing about .01% of plasma protein
(which is higher than the levels of other adipocytokines by a factor of
a thousand and higher than levels of pro-inflammatory signals by a factor
of a million). Adiponectin (produced by the gene most abundant gene transcript
1 or APM1) is only secreted by mature adipocytes. Subcutaneous fat cells
produce more hormone than visceral fat cells (Koerner, 2005; Gable, 2006).
Adiponectin acts through cellular pathways which involve AMP-dependent
kinases and peroxisome proliferators receptor alpha (PPARa). Through these
pathways, triglycerides are oxidized (and their levels are subsequently
reduced), cells are more sensitive to insulin (increasing their glucose
uptake), and gluconeogenesis declines. Adiponectin decreases the risk
of atherosclerosis by decreasing the production of monocytes, the production
of endothelial adhesion receptors for monocytes (thus decreasing monocyte
migration), decreasing the conversion of macrophages to foam cells, decreasing
signaling from macrophages, decreasing the hypertrophy of smooth muscle,
decreasing levels of blood lipids, and increasing production of NO (Gable,
2006). Adiponectin increases uptake of glucose in muscle and reduces liver
gluconeogenesis through AMPK and PPAR alpha proteins (Gil-Campos, 2004).
Two GPCRs function as adiponectin receptors. One (AdipoR1) interacts with
insulin receptors to increase their effectiveness. Adiponectin receptor
production and activity decrease in obese individuals (Koerner, 2005).
Adiponectin receptors are expressed in heart muscle cells, adiponectin
is involved in the control of cardiac remodeling, and low levels of adiponectin
promote cardiovascular disease (Ouchi, 2006).
Resistin is a cytokine secreted by adipose cells in rodents and secreted
by bone, leukocytes, and pancreatic beta cells in humans. Increased levels
of resistin inhibit insulin function while lower levels decrease plasma
glucose levels and gluconeogenesis in the liver. Some variants contribute
to obesity and to insulin resistance in diabetes. It also appears to affect
pubertal development in adolescents. The placenta produces resistin which
may inhibit insulin action during pregnancy (Sagawa, 2002; Koerner, 2005;
Visfatin is a newly discovered adipocytokine that can interact with insulin
receptors (Koerner, 2005). Visfatin is only secreted by adipose and its
levels are associated with levels of visceral fat (Matsuzawa, 2006).
E) INFLAMMATORY SIGNALS FROM ADIPOSE
Chronic, low-grade activation of inflammatory mechanisms is thought to
contribute to atherosclerosis, diabetes, asthma, obesity, and other disorders
(Matarese, 2005). The accumulation of visceral fat results in increased
production of pro-inflammatory adipocytokines which include TNF alpha,
plasminogen activator inhibitor type 1, adipsin, interleukin 6, monocyte
chemotactic protein 1, haptoglobin, adipsin, complement 3, and heparin
binding epidermal growth factor-like growth factor (Matsuzawa, 2006; Gable,
2006). Mice with low levels of complement protein 3 (C3) were lower weight
and had lower leptin levels (Chen, 2006).
Macrophages (which are derived from monocytes such as those pictured below) accumulate in adipose where they migrate to areas near dead
adipocytes and fuse to form giant multinucleate syncytia. This formation
of syncytia is a feature associated with chronic inflammation which occurs
in multiple tissues. Preadipocytes can even differentiate into macrophages,
although it is unknown whether they do so in organisms (Chen, 2006).
2) HORMONES SECRETED FROM THE DIGESTIVE TRACT
Several hormones which affect our energy balance and the accumulation of adipose are produced by the organs of the digestive tract. Some neuropeptides which regulate hunger and body weight are secreted by the gastrointestinal tract such as cholecystokinin ( CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and ghrelin (GHRL).
Ghrelin is a hormone primarily produced in the stomach that increases
food intake and decreases energy usage. Ghrelin is also produced in both
the ovaries and testes. In men, the Leydig cells of the testes are also
targets for ghrelin action while in women, the corpus luteum is one of
the targets for ghrelin. Ghrelin is also expressed in the brain although
its function is not yet known. (Pasquali, 2006).
Ghrelin binds to a GPCR receptor known as the growth hormone secretagogue
receptor which increases growth hormone secretion. Ghrelin receptors are
primarily expressed in the hypothalamus (in the arcuate nucleus in cells
that produce both feeding signals such as neuropeptide Y and agouti gene-related
protein) and the pituitary. Receptors are also expressed in the brainstem
and in the vagus nerve (Ellacott, 2006; Xu, 2004).
B) CCK (CHOLESYCTEKININ)
CCK is released from the digestive tract after food intake (specifically
the absorption of fatty acids and amino acids). CCK increases satiety
and reduces food intake. The melanocortin receptor MC4R is a factor in
some of the effects exerted by CCK on food intake (Ellacott, 2006).
3) HORMONES FROM THE BRAIN
Several hormones which affect our energy balance and the accumulation of adipose are produced by the brain.
Adipose and the cells of the digestive tract release hormones which provide
the brain with information about the nutritional status of the body. The
hypothalamus responds with signals (such as melanocortins and other neuropeptides)
which will regulate energy intake and metabolic rate. The hypothalamus produces several neuropeptides involved in energy balance such as agouti-related protein (AgRP), cocaine- and amphetamine-regulated transcript (CART), and neuropeptide Y (NPY). These three hypothalamic signals regulate appetite in diversevertebrates, including fish (Murashita, 2009).
A) PROOPIOMELANOCORTIN (POMC) AND MSH
The proopiomelanocortin POMC gene encodes a number of signal molecules:
ACTH (which stimulates secretion of hormones from the adrenal cortex),
MSH, MSH, MSH (which affect melanocytes, pigmentation, and food intake),
lipotropin, lipotropin, corticotropin-like intermediate lobe peptide (CLIP),
and endorphin. POMC is cleaved by prohormone convertase enzymes to create
these various signaling molecules. Mutations of the POMC gene can lead
to a host of effect such as insufficient production of adrenal hormones,
light skin, red hair, and obesity (Caroll, 2005; Todorovic, 2005; OMIM;
The neurons of the arcuate nucleus of the ventrolateral region of the
hypothalamus express the POMC gene. These neurons are influenced by hormones
such as insulin, ghrelin, peptide YY, glucocorticoids, and estrogen in
addition to glucose and fatty acids (Lopez, 2005). POMC is also expressed
in the nucleus of the tractus solitarius of the brainstem (Ellacott, 2006).
Alpha MSH binds to the melanocortin receptors MC3R and MC4R and through
them exerts control over food intake (Lopez, 2005).
Alpha MSH also has a variety of other roles other than the control of
food intake. Alpha MSH is an anti-pyretic signal that opposes the actions
of interleukin 1(IL-1) and TNF alpha (but not IFN alpha or PGE2) in promoting
fever (Getting, 2006). Alpha MSH and ACTH increase libido in lab animals.
Synthetic agonists of MC3R and MC4R receptors (such as MTII and PT-141)
cause erections in humans (Getting, 2006). Because TNF alpha promotes
the replication of the HIV virus, alpha MSH is being considered for AIDS
treatments since it inhibits TNF alpha (Getting, 2006).
In both humans and rodents, beta MSH binds MC4R better than alpha MSH
and is more likely to be its natural ligand. Beta MSH is produced in the
regions of the hypothalamus which control feeding (Harrold, 2006).
B) MELANOCORTIN RECEPTORS
In addition to their activity in the brian, melanocortin receptors and
POMC expression also occurs in other tissues such as the gonads, placenta,
small intestine, heart, lung, and kidney (Caroll, 2005).
The melanocortin system determines the production of pigment in skin and
hair through MC1R receptors which are expressed on melanocytes in the
epidermis and hair follicles. Stimulation of these MC1R receptors increases
the production of eumelanin resulting in brown to black pigmentation.
Inhibition of MSH binding by agouti signaling protein (ASIP) increases
the production of the pheomelanin pigment resulting in orange to yellow
pigmentation. Polymorphisms of the MC1R gene can cause lighter hair and
skin, red hair, and increased susceptibility to skin cancer. Some of the
polymorphisms result in receptors which do not bind alpha MSH as well
and no known mutations eliminate the function of the receptor. The frequency
of some polymorphisms can be high in populations of Caucasians (Caroll,
MC1R binds alpha MSH and ACTH best and interacts with gamma MSH to a lesser
degree. It is expressed on melanocytes, endothelia, fibroblasts, monocytes,
glia, and keratinocytes. Its activity regulates pigmentation and opposes
inflammation and fever (Getting, 2006). MC1R also functions in the control
of immune responses and is expressed on macrophages and mast cells. Evidence
indicates that alleles which result in fair skin and fair/red hair increase
susceptibility to allergies and inflammatory disorders (Caroll, 2005).
MC2R only binds ACTH. It is expressed in the adrenal cortex where it promotes
the synthesis of adrenal hormones (Getting, 2006). Mutations in MC2R receptors
cause half the cases of familial glucocorticoid deficiency which is associated
with decreased viability and hyperpigmentation (Caroll, 2005).
MC3R binds gamma MSH, alpha MSH, and ACTH with comparable efficacies.
It is expressed in the brain and heart where it is involved in energy
balance and opposes inflammation (Getting, 2006). Although MC3R polymorphisms
are known, none are strongly associated with obesity (Caroll, 2005).
Neurons in the arcuate, paraventricular, and ventromedial nuclei of the
hypothalamus express high levels of MC3R and MC4R receptors. The control
of these neurons over appetite and metabolic rate is regulated by leptin
and AGRP. Leptin increases the production of alpha MSH (from POMC) and
MSH action is inhibited by AGRP (Caroll, 2005).
MC4R binds alpha MSH and ACTH best and interacts with gamma MSH to a lesser
degree. A large number of mutations in the MC4R gene are known. Although
the lack of MC4R in mice causes both an increase in food intake and a
lower metabolism, human mutations have only been observed to affect food
intake. Many mutations are associated with obesity and an estimated 1-6%
of obese patients may carry polymorphic alleles of MC4R. A few variant
alleles seem to offer protection from obesity (MacKensie, 2006; Todorovic,
2005; Caroll, 2005).
MC4R is expressed in the brain where it controls food intake, energy balance,
the control of erections, and combats fever. Both MC3R and MC4R are expressed
in regions of the brain which control erection in males (Getting, 2006).
MC5R binds alpha MSH and ACTH best and interacts with gamma MSH to a lesser
degree. It is expressed in lymphocytes and exocrine glands where it affects
the secretion of sebaceous glands and immune responses (Getting, 2006).
C) ACTH AND GLUCOCORTICOIDS
Hypothalamic secretion of CRH increases the pituitary production of ACTH
which stimulates hormone production in the adrenal glands. ACTH secretion
is controlled through a negative feedback loop as cortisol levels affect
the production of CRH in the hypothalamus. ACTH is released from the anterior
pituitary, binds to MC2R receptors, and stimulates cells to convert cholesterol
into glucocorticoid, mineralcorticoid, estrogen, and androgen hormones
Chronic overproduction of cortisol is associated with obesity and diabetes.
Cortisol not only increases the availability of energy-rich molecules
(through gluconeogenesis in the liver and the breakdown of triglycerides
in fat cells), it also increases food intake and thus weight gain (in
both humans and other animals). Those who display non-normal stress responses
are at increased risk for obesity (Gluck, 2006). Under stress, individuals
consume more sweet and high fat foods (Gluck, 2006).
D) AGOUTI-RELATED PROTEIN, AGRP
The gene agouti was first described for its action in mouse hair follicles
where it opposes the action of alpha MSH (at receptor MC1R) resulting
in yellow fur. Mutations in the gene can not only cause yellow fur but
also obesity in mice (Stutz, 2005). In mice, the elevated expression of
the agouti protein (which antagonizes the action of MSH at MCR receptors)
led to the same obese phenotype cause by mutations in the MC4R receptor
gene. Heterozygotes expressed an intermediate condition of obesity (MacKensie,
In humans, a homolog of agouti, the agouti-related protein, is primarily
expressed in the arcuate nucleus hypothalamus. The neurons which produce
POMC and AGRP are influenced by hormones such as insulin, ghrelin, peptide
YY, glucocorticoids, and estrogen in addition to glucose and fatty acids
(Lopez, 2005). AGRP-secreting neurons also secrete Neuropeptide Y which
is also involved in the control of food intake. The agouti-related protein
(AGRP) is more highly expressed during fasting conditions and direct injection
into cerebrospinal fluid increase food intake (in both humans and mice).
Mice which overexpress AGRP ingest more food, become obese, are hyperglycemic
and suffer from hyperinsulinemia. AGRP is one of the predominant orexigenic
signals in energy metabolism and it can continue to increase food intake
a week after secretion. Reduction in the levels of AGRP increase metabolic
rate and lower weight even when food intake levels are maintained. Increased
plasma AGRP are associated with obesity. Polymorphisms of the AGRP gene
are known which are correlated with decreased weight, lower food intake,
and decreased susceptibility to obesity, one being responsible for anorexia.
There are certain polymorphisms which are known only in certain ethnic
groups (Stutz, 2005; Caroll, 2005; Hillebrand, 2006).
AGRP exerts its influence by binding the melanocortin receptors MC3R,
MC4R, and MC5R, thus blocking the binding of the anorexigenic neuropeptide
alpha MSH. Some of the effect of AGRP seems to occur through a second
pathway other than the blocking of melanocortin at melanocortin receptors,
perhaps through the binding of co-receptors such as syndecan (Stutz, 2005).
AGRP is not only an antagonist of alpha MSH, it functions directly as
an inverse agonist by binding the MC4R receptor (Todorovic, 2005).
The hypothalamic neurons of the paraventricular nucleus secrete the hormone
TRH which increases thyroid activity and metabolic rate. AGRP inhibits
TRH neurons while alpha MSH and leptin stimulates these neurons (Stutz,
2005). AGRP affects adipose cells, increasing the activity of fatty acid
synthase (Stutz, 2005).
Leptin and insulin are produced after feeding and both decrease the expression
of AGRP. If leptin and insulin levels are maintained artificially at normal
levels during fasting, the typical increase in AGRP which occurs during
fasting does not occur. The peptide ghrelin (produced in the digestive
tract) increases AGRP and NPY and its promotion of food intake is dependent
on AGRP and NPY action (Stutz, 2005). Outside the hypothalamus, the highest
expression of AGRP and POMC in humans is the adrenal gland (Stutz, 2005).
Increased levels of glucocorticoids increase AGRP and NPY expression and
food intake. In response to the secretion of leptin, hypothalamic neurons
produce alpha MSH which binds to MC3R and MC4R receptors. As leptin levels
drop, AGRP is secreted by the hypothalamus which competes with MSH for
binding sites on MC3R and MC4R receptors and increases food intake and
lowers metabolic rate (Caroll, 2005). Leptin inhibits AGRP/NPY neuron
activity while promoting the activity of neurons expressing POMC. Decreased
expression of leptin has the opposite effects (MacKensie, 2006).
AGRP is secreted cyclically and this diurnal cycle depends on glucocorticoid
secretion. Eliminating the production of glucocorticoids (such as in adrenalectomy)
decreases the activity of/response to AGRP and NPY, increases the response
to alpha MSH and leptin, and results in weight loss (Stutz, 2005).
Levels of fatty acids in plasma can affect AGRP secretion (Stutz, 2005).
Animal data indicates that AGRP levels increase during pregnancy and lactation,
periods associated with increased food intake (Stutz, 2005).
A number of pharmacological drugs have been developed which act on the
E) AGOUTI-SIGNALING PROTEIN, ASIP
In addition to AGRP, the agouti signaling protein (ASIP) also binds to
melanocortin receptors to prevent the binding of MSH, thus acting as an
antagonist (Caroll, 2005). Although polymorphisms of the agouti signaling
protein do not seem to be responsible for as many variations in human
pigmentation as in some other mammals, one polymorphism is associated
with darker hair and eyes in Africans (Caroll, 2005).
The hypothalamus produces two peptides named Orexin A (hypcretin 1) and
Orexin B (hypocretin 2). Orexin is produced in the lateral and posterior
hypothalamus and orexin receptors are expressed in a variety of brain
regions which are involved in the control of feeding. Increased levels
of orexin increase food intake and risk of obesity while antagonists of
orexin receptors reduce food intake (Xu, 2004).
G) MELANIN-CONCENTRATING HORMONE
Melanin-concentrating hormone (MCH) increases food intake and risk of
obesity. Mutations in its receptors and precursor decrease food intake
and increase metabolic rate (Xu, 2004). Melanin concentrating hormone
was originally described in fish where it is only involved in skin color.
In mammals, it has not yet been shown to affect skin color although receptors
are expressed on skin cells and there is some evidence for a role in the
pigment disorder vitiligo. Instead, MCH is almost exclusively expressed
in the brain and its expression increases food intake and the accumulation
of fat. Mice which lack MCH are thinner with higher metabolic rates. Leptin
levels are inversely correlated with MCH levels. Although MCH functions
downstream of leptin, it represents only one of several pathways since
MCH loss in mice can correct some of the effects of leptin deficiency
(such as obesity) but not others (such as overeating and elevated insulin
expression) (Shi, 2004).
There are two receptors for melanin-concentrating hormone: MCHR1 and MCHR2.
Inhibition of MCHR1 causes a reduction in weight and an increase in metabolic
rate. MCHR2 is only expressed in carnivores and primates (Shi, 2004).
H) NPY FAMILY
NEUROPEPTIDE Y; NPY
Neuropeptide Y (NPY), gut endocrine peptide YY (PYY), pancreatic polypeptide
PP (PP) and pancreatic polypeptide PY (PY) are all composed of 36 amino
acids. All vertebrates possess neuropeptide Y in central and peripheral
nervous systems (Larhammar, 1993). Mutations in the NPY gene cause the
obesity in mice indicating that NPY involved in the control of lipid metabolism.
In humans, polymorphisms of this gene have been correlated to variations
in serum cholesterol, LDL levels, atherosclerosis, and serum triglyceride
levels. NPY also has other roles: it is expressed in the olfactory epithelium
and, in mice, affects alcohol intake. One polymorphism in humans is observed
more frequently in those who are alcohol dependent (OMIM).
PANCREATIC POLYPETIDE PPY
PPY regulates pancreatic secretions and has a role in weight gain. It
is secreted from the endocrine tissue of the pancreas.
PANCREATIC POLYPETIDE PPY2
PEPTIDE YY; PYY
The large intestine releases peptide YY which decreases appetite and inhibits
the AGRP/NPY producing neurons (MacKensie, 2006).
PEPTIDE YY2; PYY2
PYY2 is secreted from enteroendocrine cells of the pancreas and small
intestine and it inhibits the activity of the stomach. Decreased activity
may be a factor in obesity.
Increased production of neuropeptide W decreases weight gain and increases
metabolic rate (Xu, 2004).
4) BRAIN CIRCUITS INVOLVED IN FEEDING
The neurons and neuronal pathways which are involved in the control of food intake, the reward associated with eating, and predispoition to overeating utilize specific neurotransmitters and neuropeptides.
Neuronal circuits which secrete serotonin increase secretion of alpha
MSH from the hypothalamus. Increasing serotonin production decrease food
intake while the inhibition of serotonin action increases food intake.
Drugs such as d-Fenfluramine (d-Fen) increase brain serotonin activity
to cause weight loss (Zhou, 2005).
CB1 and CB2 are the GPCRs which respond to marijuana and endocannabinoids
(those produced by the body). CB1 is most highly expressed in the hippocampus
and cerebellum but is also expressed outside the brain in the spleen,
testis, and white blood cells. CB2 is primarily expressed in white blood
cells. Both are expressed in the placenta (Onaivi, 2002). The cannabinoid
receptor CB1 is one of the most abundant receptors in mammalian brains,
with concentrations similar to receptors for GABA and glutamate (Cota,
Endocannibinoids are a set of signals produced from long-chain polyunsaturated
fatty acids. Five are known to exist: arachidonoethanolamide (also known
as anandamides, it is produced in the brain and a variety of other tissues),
2-arachidonoylglycerol (2-AG; it is the most effective ligand of the receptor
CB1), noladin (known only from the brains of pigs thus far), virodhamine
(an agonist of CB2 with a partial agonist/antagonist role acting on CB1),
and N-arachidonoyldopamine (which acts on VR1 receptors with the same
efficacy as capsacian from hot peppers) (Cota, 2006).
C) OPIOID FAMILY
Opioids are signals which function in pain stimuli, feeding, sexual behavior,
learning, thermoregulation, development, and the physiology of the cardiovascular
and respiratory systems. The opioid met-enkalphin promotes cell proliferation
in several bacteria and protists which possess opioid receptors (Zagon,
1992; Danielson, 1999).
The PNOC gene produces two neuropeptides, nociceptin and nocistatin which
are both involved in pain pathways. Nociceptin may also be involved in
Enkalphin is produced in the brain and adrenal glands and is involved
in responses to pain and stress and in aggression.
This gene encodes the neuropeptidedes neoendorphin, dynorphin, and leumorphin.
Cannabinoids and opiates both function in reward pathways, adding to
the pleasant experience of eating. They also can affect specific aspects
of eating such as food preference. Marijuana has long been known to increase
the desire to eat more food, particularly sweet food. Mice treated with
opioids increase their intake of high-fat foods compared to other food
items. Opioids also seem to function in increasing the duration of a meal
and thus meal size (Cota, 2006). Drugs which block the action of endocannabinoids
and opiates are in use to combat obesity with success reported in early
studies. There is reason to believe that some of the same pathways (such as those
of cannabinoids and opiates) are involved in addiction to drugs function
in response to natural food rewards as well. Neurological responses to
overeating may parallel changes observed in drug addition (Cota, 2006).
There are gender differences in the biological mechanisms which control
food intake and metabolism. Estrogen increases leptin levels while androgens
decrease leptin levels and, as a result, leptin levels are higher in females
once other variables (such as weight and the amount of adipose) are taken
into account. More leptin is produced in subcutaneous fat (more abundant
in females) than in visceral fat and women have higher levels of free
plasma since their levels of leptin binding protein are reduced. In women,
leptin levels vary throughout the menstrual cycle and reach their peak
in the middle of the postovulatory perios (Moschos, 2002; Koerner, 2005).
Women with central obesity tend to have lower levels of sex hormone binding
globulin (SHBG) than those with peripheral obesity, perhaps because higher
insulin levels in women with central obesity inhibit hepatic SHBG synthesis.
This exposes tissues to higher levels of free estrogens and androgens
(Pasquali, 2006). Food intake varies over the menstrual cycle in humans
and other mammals, with its lowest value between the end of menstruation
and ovulation (Geary, 2004). Eating disorders such as anorexia nervosa
and bulimia nervosa are nine times more frequent in females than males
In the late 1990s, 18% of women in America were obese and the frequency
of obesity has increased in adults has increased by more than half since
the early 1990s. Statistically, women who are the greatest risk of obesity
following a pregnancy are those that gain excess weight during the pregnancy
and those that fail to lose the pregnancy-associate weight gain within
6 months of birth (Rooney, 2002). On average, women at 6 months after
birth have gained almost 2 kg compared to prepregnancy levels (Rooney,
2002). Unlike women, the levels of androgens in male plasma decrease as weight
increases. Obese men also have lower LH levels (Pasquali, 2006). In lab
animals, removal of the gonads decreases food intake and weight in males
but increases these processes in females (Geary, 2004).
A) DIVERSITY OF FATTY ACIDS
The omega-3 polyunsaturated fatty acids are more abundant in fish and
shellfish than in plants and land animals. These fatty acids have been
shown to reduce the risk of heart disease, clot formation, and inflammation.
In lab animals, replacing omega-3 fatty acids with other lipids increases
weight gain and the risk of diabetes and insulin resistance. These fatty
acids modify the makeup of membrane phospholipids and through them affect
cellular responses to insulin, eicosanoids and other signals (Lombardo,
Long chain fatty acids (LCFAs, such as oleic acid) but not medium length
fatty acids (MCFAs) reduce food intake by decreasing the production of
AGRP and neuropeptide Y (Lopez, 2005).
Americans consume about half the recommended amounts of fiber and fiber
levels are lower still among those who partake in popular low-carbohydrate
diets (Slavin, 2005).Dietary fiber increases satiation by decreasing the caloric concentration
of food, increasing chewing, increasing the volume of material in the
digestive tract, and lowering gastric emptying. Increased satiation results
in lower energy intake and reduction of adipose stores. Increased dietary
fiber can lessen the risk of obesity, cardiovascular disease, and type
2 diabetes (Slavin, 2005).
C) MALONYL CO-A
In response to high levels of glucose, cells can convert glucose into
lipid. In this process, acetyl CoA (from glucose catabolism) is converted
to malonyl-CoA by the enzyme acetyl coenzyme A carboxylase (ACC) and the
enzyme malonyl-CoA decarboxylase (MCD) can catalyze the reverse reaction.
Fatty acid synthase (FAS) then converts acetyl Co-A and malonyl-CoA into
fatty acids (Lopez, 2005).
As malonyl-CoA levels inside cells rise, the enzyme which transfers long
chain fatty acids (LCFAs) to the mitochondria, carnitine palmitoyltransferase-1,
is inhibited. Evidence suggests that levels of malonyl-CoA are signals
which inhibit the activity of FAS. Inhibiting FAS activity in the arcuate
nucleus of the hypothalamus results in increasing the production of anorexigenic
neuropeptides and decreasing the production of orexigenic neuropeptides.
As malonyl-CoA levels rise, POMC and CART expression increases, AGRP and
NPY levels decrease, and food intake decreases. Malonyl-CoA levels may
thus be a central mechanisms to measuring lipid levels in the body (Lopez,
7) FAT CELLS AND OBESITY
One of the early steps in the formation of new adipose tissue is the stimulation
of preadipocytes which were in a stage a growth arrest so that they reenter
the cell cycle. Proteins such as retinoblastoma, E2F, and cyclin dependent
kinases are involved in this transition. As preadipocytes begin to differentiate
into adipocytes, they express transcription factors C/EBP beta, C/EBP
delta, C/EBP alpha, and nuclear transcription factor PPAR gamma (peroxisome
proliferators activated receptor gamma). PPAR gamma is activated by pharmaceutical
products such as thiazolideinediones (TZDs) to make more adipose tissue
in diabetics. Although creating additional adipose in diabetics may seem
harmful, it actually alleviates diabetes symptoms because triglycerides
can be stored in adipose rather than non-adipose tissues where pathophysiological
mechanisms result. It may also modify the hormone secreted by adipose
in a way that improves health in diabetics (Camp, 2002).
The differentiation and hyperplasia of adipose cells in weight gain and
obesity involve MAPK pathways (Bost, 2005).
Abdominal adipose stores contribute to cardiovascular disease moreso than
subcutaneous stores elsewhere in the body (Avogaro, 2005).
Weight gain during the first week of life is associated with increased
risk of later obesity. An overabundance of nutrients in prenatal and early
postnatal life increase the risk of obesity (Prentice, 2005).
Those who are addicted to alcohol are more likely to suffer from eating
disorders, both obesity and anorexia/bulimia. There are a number of signals
which seem to be involved in both the control of feeding/weight gain and
voluntary alcohol consumption (at least in mice) which include melanocortin,
cholecystokinin, neuropeptide Y, and leptin. In is possible that common
neurological pathways determine both feeding and alcohol consumption (Thiele,
Between the 1960s and the early 1990s, the average of menarche has decreased
by 3 months in Caucasian girls and 5 ½ months in African-American
girls in the United States (Himes, 2006).
By eight years of age, about 48% of African-American girls and 15% of
Caucasian girls have begun breast development and/or the growth of pubic
hair. This degree of pubertal development is higher than values determined
in the past and the increasing frequency of overweight and obesity in
children is being considered as a possible factor causing this change
(Himes, 2006). Leptin increases GnRH production indirectly through intermediates
such as the cocaine and amphetamine transcript peptide (CART) (Moschos,
In mice, leptin is important in pubertal development and can accelerate
the onset of puberty. In humans, leptin expression in boys reaches its
highest point just prior to puberty while in girls it increases throughout
puberty. Higher levels of leptin are associated with an earlier age of
menarche. Women athletes have lower levels of leptin and delayed pubertal
onset (Moschos, 2002). Obese girls enter puberty earlier than thin girls
Colon cancer is highest in developed nations and abdominal fat is a
risk factor for colon cancer. Men with higher levels of abdominal fat
have twice the colon cancer risk as those with lower amounts of abdominal
As adipose levels increase, levels of insulin, glucose, triglycerides,
and inflammatory hormones increase. These changes can promote the growth
of cancer cells, particularly those of the colon (Gunter, 2006).
ETHNIC/INDIVIDUAL DIFFERENCES AND THE "THRIFTY GENOTYPE"
The "thrifty phenotype" could be caused by lower metabolic rates,
the ability to gain adipose quickly, the desire to increase food intake,
and inactivity. There is evidence that long-lasting differences in energy
regulation can result from undernourishment during fetal development (Prentice,
2005). Polymorphisms in a variety of genes (such as FABP2, MTP, CAL10,
apo-E, UCP2, and PPAR?2) which affect energy balance are thought to contribute
to the "thrifty genotype" (Kagawa, 2002).
The average recommended caloric intake varies among different nationalities,
reflecting overall ethnic differences in metabolic patterns.
Large body size in Caucasians may reflect an adaptation to colder temperatures
and increased need for heat generation. One variant of angiotensiogen
which causes sodium retention (Met235Thr) is more common among those of
African descent which may reflect the lower sodium content in tropical
foods. A different allele (235Thr) which results in greater sodium release
is more Caucasians. Increased meat consumption in ancestral Caucasians
would have resulted in hypertension with the sodium-retaining variant
(Kagawa, 2002).Ethnic differences in the ability to metabolize alcohol may reflect the
likelihood that ancestral food stores underwent fermentation (such as
tropical fruits or starches stored over winter) (Kagawa, 2002).
The LSC*P allele of lactase results in the production of lactase after
weaning. This allele's frequency ranges from 72-100% in Caucasians but
only 0-10% in Africans and Asians. Two African groups and one Asian group
which raise cattle also have high levels of lactase persistence (up to
93%) in Tsuti Africans (Kagawa, 2002).
Japanese Americans suffer diabetes rates 3 times that of Japanese living
in Japan Pima Indians on a Western diet suffer diabetes rates 2.5 times
that of Pima Indians on a traditional diet. The prevalence of obesity
in African-Americans is much higher than in Africans (Kagawa, 2002).
In developed countries, obesity is associated with lower socioeconomic
status, especially among women. In contrast, obesity is associated with
higher socioeconomic status in developing nations. The global increase
in obesity is an enormous drain on health care systems. During the 1990s,
the percentage of those in China suffering from obesity doubled (Ball,
Overall trends indicate that caloric consumption is increasing in all
groups of American society. A greater percentage of these calories come
from snack foods which are rich in calories and poor in nutrients. More
meals are being consumed away from home. Fruit and vegetable consumption
is declining (Popkin, 2005).
The proximity of supermarkets and health stores is a positive factor affecting
obesity while the number of fast food restaurants is a negative factor.
Those who live in higher socioeconomic neighborhoods are more likely to
eat healthy food no matter what their individual socioeconomic level is
Areas vary in the access to safe recreation and transportation option
to recreational sites. There is unequal access to physical recreation
activities (Popkin, 2005).
There can be ethnic differences in the body weights which are perceived
to be ideal and overweight. In the United States, women of different ethnic
groups can differ as the levels of dissatisfaction they feel with body
sizes within the normal and overweight range (Padgett, 2003).
Some of the success one may have in achieving a desired weight or avoiding
relapse into obesity involves psychological factors such planning realistic
weight goals, self-efficacy, and successful problem-solving skills (Byrne,
Some individuals who suffer from obesity are binge eaters who eat large
amounts of food and feel as if they cannot control overeating. Those who
suffer from binge eating disorder are more likely to suffer from other
psychiatric disorders as well (Gluck, 2006).
INSULIN RESISTANCE AND TYPE 2 DIABETES
About a third of new diabetes cases in children are type 2 diabetes. The
growth in new cases is highest in those who have a family history of diabetes
and who have passed puberty. Minority youths are at a slightly higher
risk (Gil-Campos, 2004).
Type 2 diabetes covers a number of related conditions which differ in
the genetic causes. Insulin resistance can occur without obesity and obesity
can occur without insulin resistance (Summers, 2006). Typically, the condition
results in insulin resistance (reduced action of insulin) which decreases
the amount of glucose absorbed by muscle and fat, increases novel glucose
production from the liver and results in the hypersecretion of insulin
from the pancreas. At some point, the hypersecretion from the pancreatic
beta cells may no longer compensate for the high levels of glucose, resulting
in hyperglycemia and diabetes (Chen, 2006).
The primary environmental factors affecting diabetes are obesity and an
inactive lifestyle. Increased food intake and decreased levels of physical
activity are the primary risk factors for type 2 diabetes. Diets rich
in sugar, fat and saturated fatty acids with a high glycemic index also
increase risk. An estimated 80-90% of individuals who suffer from type
2 diabetes are obese and 80% suffer from metabolic syndrome (Uusitupa,
2005; Chen, 2006).
When insulin binds its receptor, it activates insulin receptor substrates
IRS-1 and IRS-2 which then activate other molecular pathways such as the
PI3K and AKT2 pathways. A number of pro-inflammatory molecules (such as
IKK beta, JNK1, PKC, nitric oxide synthase, and SOCS) affect insulin sensitivity,
often through the activity of insulin receptors and IRS substrates (Chen,
Insulin resistance is greater in visceral fat than in subcutaneous fat
(Matsuzawa, 2006). In experimental conditions, the storage of triglycerides
in tissues other than adipose increases susceptibility to insulin resistance
(Summers, 2006). Low birth weight is associated with increased risk of
developing type 2 diabetes (Kagawa, 2002). Increased leptin levels can
decrease the transcription of insulin in pancreatic beta cells (Yildiz,
Two mechanisms have been proposed through which cells could develop insulin
resistance in diabetes:
1) As adipose cells exceed their maximal storage levels, triglycerides
are stored in other tissues which differ in their responses to insulin.
2) The chronic inflammation associated with obesity produces cytokine
signals which induces insulin resistance (Summers, 2006).
Animals which lack certain inflammatory signal elements (TNFalpha or
its receptors, inhibitor of B kinase, and Jun N-terminal kinase) are
less likely to develop insulin resistance. Adipose secretes TNF alpha
and this cytokine increases the risk of insulin resistance. Interleukin
6 and plasminogen activator inhibitor type 1 are other inflammatory signals
which seem to promote insulin resistance (Summers, 2006).
Most of the sphingolipids in animals are synthesized rather than being
utilized from dietary sources. A series of reactions converts palmitoyl
CoA and serine into ceramide which can be converted into a variety of
products including sphingosine and sphingomyelin. Ceramide production
is increased by increased long chain saturated fatty acids in the diet
(but not polyunsaturated or short chain triglycerides). Ceramide is a
potent antagonist of insulin action and seems to contribute to the development
of insulin resistance. Ceramide damages cells and may contribute to a
variety of disorders ranging from atherosclerosis to diabetes (Summers,
Tissues other than adipose can oxidize fatty acids, especially after the
influence of leptin. However, when nonadipose cells are exposed to high
levels of long-chain fatty acids, especially in the absence of leptin,
these fatty acids can enter chemical pathways other than the oxidative
ones which lead to energy production. Some are converted to toxic products,
such as ceramide. In obese rats which lack leptin, ceramide results in
lipapoptosis of cardiac muscle cells (through caspase activation) and
pancreatic beta cells. While some cells of the body such as the liver
or skeletal muscles can cope with excess fatty acids (through VLDL production
and increased contraction, respectively), other cells such as beta pancreatic
cells have no mechanism to remove fatty acids other than oxidative pathways
A number of genes which affect risk for type 2 diabetes are known to
interact with other factors. One allele of PPAR gamma increase risk when
combined with low birth weight. Mutant alleles of beta adrenergic receptors
and uncoupling proteins may act synergistically when both are present
to increase risk (Uusitupa, 2005).