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The Homeostatic Mechanisms of Obesity

Mallory Bramlett

Fall 2005

A Critical Literature Review submitted in partial fulfillment of the requirements for the

Senior Research Thesis.

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The Homeostatic Mechanisms of Obesity Mallory BramlettFall 2005

A Critical Literature Review submitted in partial fulfillment of the requirements for the Senior Research Thesis.

Abstract This paper examines the mechanisms that maintain body weight homeostasis in humans. Obesity is increasing at rapid rates in all age groups, achieving epidemic proportions. While single gene mutations cause morbid obesity and can easily be treated: however, most cases of obesity involve a genetic predisposition in which the phenotype is expressed through environmental factors. The modern environment creates a setting that promotes and perpetuates obesity and overweight. The hypothalamus is the section of the brain that controls food regulation and weight balance. The arcuate nucleus, ventromedial hypothalamus, lateral hypothalamus, paraventricular nucleus, and the dorsomedial hypothalamus are all important parts of the hypothalamus that are involved in weight homeostasis. These centers contain receptors for neuropeptides such as leptin, neuropeptide Y, Ghrelin, α-MSH, and CCK which can either stimulate or inhibit food intake and energy expenditure, depending on their nature. These hypothalamic regions and neuropeptides create a negative feedback loop which regulates body weight. This negative feedback loop defends body weight, regardless of whether it is obese, lean, or underweight. The body can handle small, brief perturbations in body weight, resetting the weight back to normal. However, chronic perturbations from body weight result in a seemingly irreversible state of body weight. This review examines all mechanism involved in the maintenance and defense of body weight and possible treatments and research directions.

An overweight condition transitions to obesity when surpluses of fat collect and begin to adversely affect health. The Body Mass Index (BMI) is the standard used to evaluate the presence and severity of obesity (Dixon and O’Brien, 2002). To calculate one’s BMI, weight in kilograms is divided by height in meters squared (kg/m^2 ) (National Center for Health Statistics, 1999). A BMI from 18 to 25 is considered normal body weight, a BMI of 25 to 30 is overweight, a BMI of 30 to 40 is obesity, and a BMI over 40 is extreme obesity (National Institute of Health, 1998). A BMI over 30 defines obesity according to both the World Health Organization and the National Institute of Health. By these standards, 27% of Americans are obese and an additional 34% are overweight (National Center for Health Statistics, 1999). BMI is based on the correlation between BMI and mortality; at a BMI of 30, the risk of mortality increases by 30% and at a BMI of over 40, the risk of premature death related to obesity is 100% (Manson et al, 1995). The epidemic of obesity adversely affects social, psychological, and economical aspects, as well as health concerns. Obesity creates a loss of productivity and mobility. Billions of dollars each year are spent on diet programs, exercise equipment, and dietary products. Obesity consumes 10% of all medical expenses (Antonio et al , 2005), which results in approximately $99.2 billion per year (Montague, 2003). Many people tend to eat in response to sadness, anger, or boredom, contributing to weigh gain. Obesity is also associated with depression and low self-esteem (Montague, 2003). There are numerous detrimental medical consequences of obesity: type two diabetes, hypertension, ischemic heart disease, stroke, asthma, gallstones, obstructive sleep apnea (OSA), depression, osteoarthritis of knees, hips, and feet, infertility, cancer of breasts, bowel, endometrium, and prostate, and gout. Obese women have 28 times

greater risk of developing Type 2 Diabetes than non-obese women with a BMI lower than 25 (Lawrence and Kopleman, 2004). Type 2 Diabetes exists because of obesity and with even modest weight loss, type 2 diabetes disappears. There are more than 14 million cases of Type 2 Diabetes in the United States and most are due to obesity. At a BMI of 25, one’s risk of developing Type 2 Diabetes is five times greater and at a BMI of over 30, one’s risk is thirty-five times greater than a non-obese person with a BMI lower than 25 (Dixon and O’Brien, 2002). Cardiovascular disease results from obesity in that the excessive fat increases the body’s demand for oxygen. This high demand for oxygen via blood increases cardiac output. Ventricular hypertrophy occurs as a physiological adaptation by the ventricle in response to stress in an increased volume load. This occurs in order to maintain normal volume, despite an overload in demand. Ventricular hypertrophy occurs as a normal response during exercise to increase blood flow due to an increase in oxygen demand. However, chronic ventricular hypertrophy associated with obesity can lead to inefficiency and cause leading to diastolic (pressure while heart rests between beats) and systolic (pressure while heart pumps blood) dysfunction. This causes a decrease in function of the heart and possibly heart failure (Dixon and O’Brien, 2002). Respiratory diseases are also common in the obese population. Obstructive Sleep Apnea (OSA) occurs with half of all obese patients. Breathing is hindered by increased fat deposits in the abdominal and chest walls, leading to periods of apnea and oxygen destruction (Lawrence and Kopelman, 2004). OSA occurs mainly with central adiposity in the gut, but can also occur in other forms of obesity. OSA can lead to daytime drowsiness and cognitive dysfunction. Asthma is common in obese patients, especially

decrease in energy expenditure include leptin, neuropeptide Y (NPY), and ghrelin. The catabolic pathways that decrease food intake and increase energy expenditure include cholecystokinin (CCK) and melanocortins. The interaction of these two pathways in the hypothalamus creates a negative feedback loop which defends an individual’s current body weight. This paper reviews the current understanding of the homeostatic mechanisms of body weight. Genetics Research shows that obesity has a heritability of 70-85% (Bouchard et al , 1998), which is greater/equal to height and other disorders that are considered to have a genetic basis (Friedman, 2002). The genes that would effect weight regulation are genes with encoding proteins and are thought to be numerous due to the complexities of body weight homeostasis (Loos et al , 2005). BMI correlations are higher between monozygotic twins (74%) than dyzogtic twins (32%), regardless of shared environment (Barsh et a l, 2000). Genes are responsible for variabilities in resting metabolic rate, weight gain in response to excess calories, and body fat distribution (Bouchard, 1994). The single genes that produce obesity are rare and are called susceptibility genes (Perusse et a l, 2001) and at least five single-gene defects are known (Barone et a l, 1994). These rare genes involve leptin deficiency, defects in the leptin receptor, and defects in the processing of pro-opiomelancortin, pro-convertase 1, TSH-β, and PPAR- y. These genes occur in a very small portion of the population, but are very powerful. The most common single gene defects involve the melanocortin receptor system (Perusse et al, 2001), especially MC4R (Lee et a l, 2004). 5% of all childhood obesity can be attributed to MC4R genetic mutations (Friedman, 2004). For leptin mutations and defects, leptin

injections can cure obesity (Berthoud, 2004). A few specific genes involved in weight regulation are known. The beta-2 adrenergic receptor (ADR) gene encodes a 413 amino- acid protein which has a role in regulating energy balance by mediating glycogen breakdown and lipid mobilization (Loos et al , 2005). A study with monozygotic male twins with no family history of obesity, hyperlipidemia (an increase of lipids, e.g. Cholesterol, in the blood stream), or diabetes showed similar body responses to overfeeding. The subjects ate an excess of 1,000kcal each day, six days a week, for 100 days. Researchers found at least three times more variance in weight and fat mass between pairs of twins than within pairs of twins. The different genetic makeup responded differently in gaining and distributing of fat mass. In abdominal visceral fat, there was six times more variance between pairs than within pairs. This study showed that different genetic dispositions respond differently to overfeeding; some individuals are more likely to gain weight than others and individuals gain weight in different areas. Weight responses are most similar within similar genetics than among indivudals of different genetic backgrounds (Loos and Rankinen, 2005). A similar study examined 14 pairs of female monozygotic twins whose caloric intake was restricted for four weeks. The individuals consumed a low-calorie diet of 380kcal/day. On average, the subjects lost 8.8kg of body weight and 6.5kg of body fat during the four weeks. However, there was 12.8 times more variability of body weight changes between genetic pairs than within and the variability in body fat loss was even greater. This study shows that certain genetic dispositions loose weight more easily and individuals with the same genetic makeup will respond similarly to caloric deficits (Loos and Rankinen, 2005). Both the overfeeding study and the caloric restriction study show

reproduction. The development of obesity was very rare because these high caloric meals were sporadic and large amounts of energy were needed to obtain these meals (Berthoud, 2004). Research has also shown that genes can affect an individual’s response to the environment, as well as behavioral affinities and preferences. Networks of genes can influence hunger and meal size, frequency of meals, amounts of carbohydrates, fats, and proteins consumed, and response to social context of eating, and time of day of eating (De Castro, 1999). Similar genes cause similar body type responses to energy surpluses and deficits and the distribution of fat mass. The basic understanding of obesity is that genes predispose an individual to develop obesity, but environmental influences are necessary in expressing the phenotype (Loos et al , 2005). Environment Environmental factors are necessary in developing obesity. Since obesity did not become a prevalent medical issue until the last thirty years and the drastic rise in its incidence, it is more likely that our environment has led to these changes more than our genetics. The “obesity-promoting environment” is necessary to show the phenotype. Evidence of this can be seen when individuals move from “restrictive environments,” environments in which food is not readily available, to “obesigenic environments,” environments that have high access to high-caloric foods, they gain significant amounts of body weight and body fat. However, those with the greatest genetic predispositions will gain the most weight, whereas some individuals are more resistant to gaining weight, possibly due to higher metabolic rates (Loos and Rankinen, 2005).

The obesigenic environment is also called the “toxic environment.” This type of environment is one that high caloric diets are easily accessible and a sedentary lifestyle is promoted (Colditz et al , 1996). Fast food restaurants, buffets, mini-markets in gas stations, fast food and soft drink contracts in schools, and advertisement of cheap, dense foods all contribute to the availability of high-fat foods. This environment perpetuates obesity and is still expanding; therefore the rise of obesity prevalence is on a steep increase (Foreyt and Goodrick, 1995). Studies have shown that a sedentary lifestyle and a high-fat diet are the key predictors in developing and maintaining obesity. Individuals who ingest a high-fat diet paired with physical inactivity gain significantly more weight than do individuals who ingest high-carbohydrate diets paired with physical inactivity. The amount of fat intake is the main cause of obesity, not just a high-calorie diet alone. This is due to the high palatability of fat as compared to other types of food (Bell et al , 2001). One study examined overfeeding in rodent pups. The rodent litter was reduced from 10-14 pups per litter to 3 pups per litter in order to increase access in postnatal feeding. During the postnatal period (before weaning), the overfed pups gained 10% more body weight than the controls who were in a normal sized litter. They also developed hyperglycemia and insulin resistance. The increase of body weight included two times more body fat and increased plasma leptin levels compared to the controls. Increases in NPY and AgRP mRNA in the ARH were responsible for maintaining the obesity after the postnatal period. This is likely due to alterations in the hypothalamic neuropeptide activity created by early onset obesity (Glayas et a l, 2005). This study shows that overfeeding is a main source of obesity and overweight. This study also

regions in the hypothalamus are the arcuate nucleus (ARC) and the paraventricular nucleus (PVN). Both are located near the third ventricle in the brain (Chen et a l, 2004). Other hypothalamic regions important in weight regulation are the ventromedial hypothalamus (VMH), the dorsomedial hypothalamus (DMH), and the lateral hypothalamus (LH) (Bing et al , 2001). The ARC acts as a controlling center for insulin, leptin, ghrelin, NPY, and α- MSH (Chen et al , 2004). This network of neruopeptides regulates signals for chemical release. This allows a balance of the anabolic and catabolic pathways. The anabolic pathways stimulate food intake (orexigenic) and decrease energy expenditure, resulting in weight gain. Catabolic pathways suppress food intake (anoresigenic) and increase energy expenditure, resulting in weight loss (Benedict et al, 2004). The ARC also has connections with the PVN, DMH, and VMH. Endocrine and duodenal signals meet between hypothalamic nuclei and the caudal brainstem. The PVN acts as an integrating system, where many neural pathways that modify energy balance diverge. The PVN receives metabolic signals and then initiates appropriate responses in order to maintain body weight homeostasis via food intake or energy expenditure (Glayas et al , 2005). It contains NPY, α-MSH, serotonin (5HT), galanin, nonadrenaline, and opiod peptides. The PVN is very sensitive to the effects that the neurotransmitters have on weight regulation (Bing et al , 2001). The PVN can activate the hypothalamic-pituitary adrenal axis and the anterior and posterior pituitary signal (HPA axis), creating an afferent feedback loop that regulates weight balance (Chen et al , 2004).

Another hypothalamic area involved in energy regulation is the ventromedial hypothalamus (VMH). It is one of the largest nuclei in the hypothalamus. There is a large amount of leptin receptors present, suggesting that the VMH is an important leptin target for stimulating food intake and decreasing energy expenditure. Stimulation of the VMH inhibits food intake and lesioning the VMH results in weight gain (Bing et al , 2001). The DMH has an abundance of direct connections with the PVN, LH, and brainstem. This suggests that the DMH has a powerful role in influencing other hypothalamic regions. Research has suggested the DMH and the PVN work together to initiate and maintain food intake. There is a large number of neuropeptide receptors found the DMH. Therefore the DMH has a role in influencing other hypothalamic regions via its connections and abundance of neuropeptides (Bing at el , 2001). The DMH is also the nuclei that generates a response to hypothalamic stress and stimulates the HPA axis via its PVN projections. The DMH also activates the sympathetic nervous system. Therefore, the DMH is an integration center that induces responses through its projections to other hypothalamic nuclei, especially in times of perturbations from homeostasis (Bailey et al , 2003). Stimulation of the LH increases food intake and lesions cause a decrease in food intake, resulting in weight loss. The LH has a large number and variety of neurons that express orexins and MCH, both which stimulate food intake. NPY receptors are also abundant, which also stimulate food intake (Bing et al , 2001). Anabolic pathways in the hypothalamus stimulate food intake and decrease energy expenditure and metabolism, causing weight gain. The neuropeptides that exert

stimulated (Ahima, 2005). Leptin inhibits NPY and AGRP whose role is to increase food intake and decreases metabolism. Leptin also enhances POMC whose role is to decrease food intake (Friedman, 2004). In a normal individual, the amount of circulating leptin is directly proportional to the amount of body fat; the more fat mass, the more leptin is circulating to inform the body that there are enough fat stores. This is part of the negative feedback loop that helps maintain energy balance. Individuals produce specific amounts of leptin in order to maintain a set-point of body weight (Friedman, 2002). Leptin levels are increased in obesity and decreased during periods of fasting. The majority of obese individuals have increased levels of circulating leptin, which suggests an insensitivity or resistance to leptin compared to normal weight subjects. Reasons for the resistance of leptin include defects in the transportation pathway, defects in leptin signaling, inefficient uptake across the blood brain barrier, environmental medication of sensitivity, or a combination of all factors ( Friedman, 2002). CSF levels of leptin are lower in obese individuals than in normal weight individuals, supporting the idea that obesity is a result of inefficient uptake across the blood brain barrier (Ahima, 2005). Leptin sensitivity can be altered by environmental factors through a high lipid diet which modifies hypothalamus signaling or modification of reward pathways across the hypothalamic leptin pathways (Friedman, 2004). The ob/ob mouse is obese due to a mutation in the leptin gene. Therefore, the brain never receives the signal that there are enough fat stores so the mouse perceives a state of starvation. The mice are continually stimulated to eat and to decrease energy expenditure. In this case, direct injections of leptin cure obesity (Friedman, 2002).

Whereas, the db/db mouse has an inactivation of the leptin receptor (Campfield et a l,

and the fa/fa mouse has a mutated leptin receptor (Collum et al , 1996). Leptin can affect, and be affected, by many systems such as homeostatic, neuroendocrine, immune, reproductive and cardiovascular systems (Ahima, 2005). Leptin interacts with insulin at the post-receptor level. Insulin inhibits food intake in normal body weight individuals (Collum et al , 1996). Seratonin (5HT) can affect the hypothalamic pathways, as well as other hormones (Friedman, 2004). The rate of glucose uptake in adipose tissue can change levels in circulating leptin (Born et al, 2000). Leptin also might be involved with the immune system and sufficient amounts of leptin are needed for the onset of puberty. This could explain why anorexic girls do not have a menstrual cycle; their levels of leptin are too low due to extremely low amounts of fat mass (Friedman, 2002). Neuropeptide Y (NPY) is one of the most abundant and distributed neuropeptides in the brain (Gehlert, 1999), and possibly the most potent appetite stimulant (Cai et al, 2004). The 36 amino-acid peptide is part of the pancreatic polypeptide family. NPY is involved with energy homeostasis by stimulating feeding, decreasing energy expenditure, and increasing storage of energy as fat. It has been found that NPY stimulates mostly the intake of carbohydrates, but also stimulated moderate fat intake as well (Gehlert, 1999). Blood pressure, memory retention, and circadian rhythms can also be affected by levels of NPY since it is widely distributed throughout the brain and effects other process other than body weight regulation (Herzog, 2003). NPY levels are high before eating and are also elevated in obese individuals. NPY also increases the size of the meal, but not the frequency of meals (Gehlert, 1999). The storage of energy as adipose tissue is increased

the Y1 receptor is disabled (Herzog, 2003) and some research shows increased body weight and fat mass with small caloric intake in the Y1 receptor knockout model (Gehlert, 1999). Therefore, the exact role of Y1 is not fully understood due to unreliable results. The Y2 receptor is pre-synaptically expressed and has a role in regulating synthesis and release of NPY and other neurotransmitters in energy homeostasis. The Y receptor is the least understood receptor, having little research conducted on its role. Researchers do know that it is found mostly in peripheral tissue, the PVN, and brainstem. The Y5 receptor has been called the “feeding receptor.” Y5 knockout models show that mice develop within a normal body weight when they are young, but develop late obesity by increasing food intake with an inactive Y5 receptor (Herzog, 2003). The Y5 receptor is expressed in the amygdala, hippocampus, PVN, and ARC (Cai et a l, 2004). Researchers believe that the Y1 and Y5 receptors are the most important role in feeding (Gehlert, 1999). The knockout models have also shown that a removal of one NPY receptor can cause other systems and neuropeptides, especially AgRP (Cai et al , 2004), to compensate for the dysfunction of NPY in maintaining energy homeostasis (Herzog, 2003). Ghrelin is an anabolic neuropeptide which stimulates feeding and decreases energy (Cai et al, 2004). This neuropeptide was first found in the stomach, but has now been found to be located in the hypothalamic areas of the ARC, PVN, LHA, VHM, and DL (Chen et al , 2005). There is special emphasis on the role of ghrelin in the ARC (Beck et al , 2004). Therefore it is both a peripheral and central nervous system peptide. Ghrelin is a natural ligand of the growth hormone secretagogue (GHSR), but the growth stimulation effect is independent of the energy homeostasis effect (Beck et al , 2004).

Circulating ghrelin from the gastrointestinal tract can stimulate the hypothalamic neural circuitry (Masaki et al , 2005). Ghrelin receptors are co-localized with Leptin receptors in the ARC, suggesting an interaction between lepting and ghrelin for the control of energy regulation (Beck et al , 2004). Ghrelin levels are high after fasting and before eating when there is an absence of food in the gut and decreased after eating when there is a food store. Administration of ghrelin causes increased fat mass and body weight through its stimulatory effects on food intake and inhibitory effects on energy expenditure, including decreased metabolic rate (Chen et al, 2005). A study with obese Zucker rats found that levels of Ghrelin change with age. At two months old, levels of Ghrelin were significanltly lower in the obese rats than in the lean rats. In the obese rats, the intake of ghrelin was inversely related to body fat. At two months old, the obese rats weighed 50% more than the lean rats. However, at six months old, Ghrelin levels of the obese rats had evened out with the levels in the lean rats. The body weight of the obese rats at six months old was not significantly different from the body weight of the obese rats at two months old. The two month old obese rats had lower levels of ghrelin than the six month old lean rats. The lean rats had 2.6% fat mass, where the obese rats had 12.1% fat mass. Rats can have low levels of Ghrelin and high levels of body fat mass (Beck et al, 2004). These results also show that the ghrelin functioning is down-regulated in obese rats and body composition is more important than body weight. Ghrelin also has roles in insulin secretion, adipogenesis, and lipid metabolism. Ghrelin stimulates differentiation of preadipocytes in adipose tissue, which transforms an undifferentiated cell into an adipose cell permanently, and antagonizes lipolysis, or

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