WEIGHT GAIN, OBESITY, AND DIABETES

 

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).

adiposeadipose

A) LEPTIN
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, 2006).
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 (Ahima, 2005).
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).

FAT CELL

B) ADIPONECTIN
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).

C) RESISTIN
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; Ahima, 2005).

D) VISFATIN
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).

monocytemonocyte

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).

digestive system
A) GHRELIN
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.

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).

hypothalamus

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; Hillebrand, 2006).
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).

MC1R
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, 2005).
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
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
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).

MC4R
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
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 (Caroll, 2005).
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, 2006).
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).

F) OREXINS
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.

neuronsneurons
A) SEROTONIN
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).

B) CANNABINOIDS
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, 2006).
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).

PREPRONOCICEPTIN; PNOC
The PNOC gene produces two neuropeptides, nociceptin and nocistatin which are both involved in pain pathways. Nociceptin may also be involved in memory formation.

PROENKALPHIN; PENK
Enkalphin is produced in the brain and adrenal glands and is involved in responses to pain and stress and in aggression.

PRODYNORPHIN; PDYN
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).

5) GENDER
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 (Geary, 2004).


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).

6) DIET
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, 2006).

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).

B) FIBER
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, 2005).

7) FAT CELLS AND OBESITY

adipose
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, 2003).

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, 2002).
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 (Moschos, 2002).

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 fat.
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).

SOCIETAL FACTORS
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, 2005).
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 (Popkin, 2005).
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, 2002).
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, 2006).
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, 2006).

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, 2006).
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 (Unger, 2002).

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).

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