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Recent Advances in Nutritional Sciences

Energy Homeostasis, Obesity and Eating Disorders: Recent Advances in Endocrinology¹

Diagnostic Systems Laboratories, Incorporated, Webster, TX 77598 and ^* Beth Israel Deaconess Medical Center, Department of Endocrinology Diabetes and Metabolism, RN 325, Boston, MA 02215

²To whom correspondence should be addressed. E-mail: cmantzor{at}bidmc.harvard.edu.

	ABSTRACT

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Health problems resulting from obesity could offset many of the recent health gains achieved by modern medicine, and obesity may replace tobacco as the number one health risk for developed societies. An estimated 300,000 deaths per year and significant morbidity are directly attributable to obesity, mainly due to heart disease, diabetes, cancer, asthma, sleep apnea, arthritis, reproductive complications and psychological disturbances. In parallel with the increasing prevalence of obesity, there has been a dramatic increase in the number of scientific and clinical studies on the control of energy homeostasis and the pathogenesis of obesity to further our understanding of energy balance. It is now recognized that there are many central and peripheral factors involved in energy homeostasis, and it is expected that the understanding of these mechanisms should lead to effective treatments for the control of obesity. This brief review discusses the potential role of several recently discovered molecular pathways involved in the control of energy homeostasis, obesity and eating disorders.

KEY WORDS: • obesity • energy homeostasis • leptin • ghrelin • insulin • adiponectin • resistin • peptide YY3-36

In the early 1950s, it was first postulated that food intake is closely linked to the amount of stored energy (fat mass) in the body. During the 1970s and 80s, gut peptide cholecystokinin, bombesin, gastrin-releasing peptide, neuromedin B (1) and glucagon (2) were identified as "immediate" satiety signals released from the gastrointestinal tract in response to the presence of food. During the 1990s, leptin was recognized as a longer-term adiposity signal, secreted in proportion to body fat stores. Moreover, in addition to modulating immediate peripheral satiety signals, insulin and leptin were shown to directly target the central nervous system and inhibit food intake (3). The currently accepted model of energy homeostasis proposes that peripheral signals become integrated with other regulators of food intake, such as the presence of food, habits or social behavior. Similarly, meal termination may be governed by extrinsic factors and intrinsic factors, the latter including signals generated in the organism in response to the consumption of food.

	Leptin.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
The discovery of leptin, the product of the obese gene (4), and soon thereafter, the characterization of the leptin receptor (5) and the circulating leptin binding protein (soluble extracellular domain of the leptin receptor) (6) renewed interest in the hormonal regulation of energy balance. Leptin is a 16-kDa glycosylated protein of 146 amino acids produced predominantly by adipose tissue, although low levels of expression were also detected in the hypothalamus, pituitary, placenta, skeletal muscle, and gastric and mammary epithelia (7). Leptin may play a role in many diverse physiologic processes, but it is primarily involved in energy homeostasis and satiety. Leptin levels in the circulation are increased in proportion to fat mass, and circulating leptin conveys information to the hypothalamus regarding the amount of energy stored in adipose tissue, suppressing appetite and affecting energy expenditure (8).

Initial studies investigating the physiologic role of leptin in mice demonstrated that leptin was directly involved in the regulation of satiety, energy balance and feeding behavior. Ob/ob mice, which do not produce functional leptin, become enormously obese when feeding regimens allow ad libitum consumption; they reach four times normal body weight compared with controls. The administration of leptin can reverse this weight gain in this and other mouse models of obesity, indicating that leptin plays an important role in the regulation of food intake.

Rare genetic mutations resulting in leptin or leptin receptor deficiencies in humans also support the notion that leptin plays an important role in satiety. Leptin-deficient children exhibit ravenous feeding behavior and develop extreme obesity. Administration of exogenous leptin to these children results in a remarkable decrease in their energy intake and a dramatic loss of fat mass while maintaining lean body mass (9,10). Although these studies demonstrate that leptin can be a most effective pharmaceutical preparation for treating obesity in leptin-deficient states, the administration of exogenous leptin fails to reduce adiposity significantly in most cases of human obesity that are characterized by increased adipocyte leptin content and high circulating leptin levels, reflecting a state of leptin resistance. The mechanisms underlying leptin resistance in obese humans may include defective transport of leptin into the brain, and/or reduced hypothalamic leptin signaling, which is in part due to up-regulation of specific inhibitors of leptin signaling. The pathogenesis of leptin resistance is currently under intense investigation, and it is expected that elucidation of the mechanisms underlying leptin resistance may lead to the development of new therapeutic options for the treatment of obesity.

Weight-loss programs are well known to be ineffective long term, with most individuals regaining any weight lost within a short period of time, and it has been proposed that the corresponding decline in serum leptin levels due to the loss in fat mass may contribute to the inability of these subjects to maintain their weight loss. Exogenous leptin administration to replace leptin levels to preweight-loss levels prevented the regaining of weight and promoted loss of fat mass while preserving fat-free mass (11) in a small group of subjects participating in a weight loss program, but these findings have to be replicated by larger studies.

In this context, it was shown recently that decreasing leptin levels in response to food deprivation are responsible for the starvation-induced suppression of the hypothalamic-pituitary-gonadal axis (12), as well as the malfunction of several other neuroendocrine axes. Thus, it seems that leptin may act as the critical link between adipose tissue and not only hypothalamic centers regulating energy homeostasis but also the reproductive system, indicating whether adequate energy reserves are present for normal reproductive function (13).

	Insulin.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Insulin and leptin share many properties as adiposity signals. Although insulin is secreted from pancreatic ß cells rather than adipocytes, the circulating concentration of insulin is also proportional to adiposity (14). In a manner similar to leptin, insulin also crosses the blood-brain barrier and interacts with specific receptors in the arcuate nucleus of the hypothalamus (15). Moreover, through interaction with specific neurons in the arcuate nucleus, both leptin and insulin reduce food intake and body weight in a dose-dependent manner when administered directly into the central nervous system (16). Unlike leptin, insulin secretion from the pancreas is stimulated acutely in response to meals, whereas leptin is not, and it has been shown that prolonged hyperinsulinemia may stimulate the secretion of leptin. Finally, obesity in the vast majority of obese humans is associated with both hyperinsulinemia and hyperleptinemia, which are indicative of insulin and leptin resistance, respectively. Adiponectin and resistin are two recently identified molecules that were reported to enhance or impair insulin sensitivity, respectively.

	Adiponectin.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Adiponectin, also called gelatin-binding protein-28, apM1, AdipoQ and Acrp30, is a 244-amino acid protein expressed and secreted exclusively from white adipose tissue. Adiponectin circulates at high levels in human plasma as a homopolymer comprising up to 18 monomeric units; the basic unit is a homotrimer, whereas the monomeric unit has never been described under natural conditions.

Adiponectin acts as an insulin-sensitizing hormone whose blood concentrations are reduced in obesity and type 2 diabetes. Administration of recombinant adiponectin to rodents increases glucose uptake and fat oxidation in muscle, reduces fatty acid uptake and hepatic glucose production in liver, and improves whole-body insulin resistance (17). In rhesus monkeys, the decrease in plasma adiponectin levels parallels the development of insulin resistance and type 2 diabetes (18). Moreover, thiazolidinediones, drugs that enhance insulin sensitivity, increase plasma adiponectin and mRNA levels in mice (19). In support of these findings, adiponectin was shown to be negatively correlated with body weight, body fat mass and insulin levels in humans.

	Resistin.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Resistin, also called "adipose-tissue-specific secretory factor" (20) and "FIZZ3" (21), is a unique signaling polypeptide secreted by adipocytes. The resistin gene encodes a 114-amino acid polypeptide with a 20-amino acid signal sequence, and is secreted as a 94-amino acid polypeptide with 11 cysteine residues. Resistin is secreted as a dimer, with a single di-cysteine residue required for dimerization, whereas the remaining 10 cysteine residues are involved in determining the structure of the resistin monomeric unit. Currently available data from studies in rodents are conflicting, however, and studies in humans are still required to confirm a role for resistin in regulating insulin sensitivity.

In 2001 Steppan and colleagues (22) reported that resistin secretion is decreased by the antidiabetic drug rosaglitazone and is increased in diet-induced and genetic mouse models of obesity. Moreover, administration of anti-resistin antibody improves blood sugar and insulin action in obese mice, and administration of recombinant resistin impairs glucose tolerance and insulin action in normal mice. These observations have not been confirmed by other investigators, however; thus, the role of resistin in mice remains controversial. Studies in humans to fully elucidate the role of resistin are still required, but initial observational and interventional studies have failed to support a role for circulating resistin in regulating insulin resistance in humans (23).

	Ghrelin.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Ghrelin was originally discovered by Kojima and co-workers (24) during their search for an endogenous growth hormone secretagogue. This hormone is a 28-amino acid lipophilic peptide with a labile octanoic acid side chain at the serine residue three, which is expressed primarily in specialized enterochromaffin cells located mainly in the mucosa of the fundus of the stomach (24). Ghrelin has metabolic effects opposite to those of leptin. It stimulates food intake, enhances the use of carbohydrates and reduces fat utilization, increases gastric motility and acid secretion and reduces locomotor activity.

Although ghrelin has potent growth hormone-releasing properties comparable to those of growth hormone-releasing hormone (24), it also has powerful effects that are independent of growth hormone (25). Administration of ghrelin peripherally or centrally into the cerebral ventricles induces weight gain in rodents (26); in humans, ghrelin levels peak before each meal and then fall to lower levels immediately upon food consumption.

In humans, circulating ghrelin levels are decreased in acute states of positive energy balance and in chronic obesity, but elevated during fasting and in anorexia nervosa. These data further support the hypothesis that the secretion of ghrelin not only has effects opposite to leptin, but is also regulated antipodal to leptin. Whether increased ghrelin levels in anorexia nervosa reflect a pathophysiologic state of ghrelin resistance analogous to that of leptin resistance in obesity remains to be elucidated. In addition, the development of a ghrelin antagonist, or the development of a mechanism to inhibit ghrelin release to control appetite, may be an important pharmaceutical development for the management of obesity.

Finally, recent evidence suggests that ghrelin may play a role in reproductive function, a scenario that is analogous to the elucidation of a role of leptin in the control of reproductive function (13).

	Peptide YY3-36.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
Another gastrointestinal tract-derived peptide, which was first identified in 1980 (27) and has only recently been appreciated as a hormonal regulator of appetite, is peptide YY3-36 (28). Peptide YY3-36 is produced by the gut in response to the presence of food and is found to decrease food intake. In common with leptin, this peptide has been shown to cross the blood-brain barrier and act on the arcuate nucleus of the hypothalamus, stimulating neurons that create a sensation of satiety and inhibiting neurons that stimulate feeding behavior (28). In a recent study (29), the effect of an infusion of peptide YY3-36 on appetite and food intake in 12 obese and 12 lean subjects demonstrated that, unlike leptin, there was no evidence of resistance to peptide YY3-36 in obese subjects. Endogenous levels of peptide YY3-36 were low in the obese subjects, suggesting that peptide YY3-36 deficiency may contribute to the pathogenesis of obesity, and infusion of peptide YY3-36 significantly decreased the cumulative 24-h energy intake in both obese and lean subjects. The same group of investigators recently reported that pancreatic polypeptide has similar effects on energy homeostasis. These results are certainly of great interest and warrant further investigation.

	The Link between the Periphery and the Brain: Metabolic Circuitry in the Hypothalamus.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
It is currently accepted that appetite is regulated by an interplay of hormonal and neural mechanisms, discussed comprehensively in several recent publications (30,31). In brief, the arcuate nucleus of the hypothalamus houses two opposing sets of neuronal circuitry, i.e., an appetite-stimulating circuit and an appetite-inhibiting circuit (see Fig. 1). The two circuits send signals mainly to the paraventricular nucleus (PVN)³ but also to other nuclei of the hypothalamus, which then directly modulate feeding behavior. The appetite-stimulatory and appetite-inhibitory circuits are influenced by peripheral hormonal signals that are able to cross the blood-brain barrier, such as leptin, insulin, ghrelin and peptide YY3-36.

View larger version (58K): [in this window] [in a new window]   FIGURE 1 The link between the periphery and the brain: endocrine and neuronal interaction in the regulation of energy homeostasis and appetite.

Leptin and insulin alike trigger the appetite-inhibitory circuit through up-regulation of -MSH and inhibit the appetite-stimulatory neuron by suppressing NPY and AgRP mRNA expression in the hypothalamus, whereas ghrelin has largely the opposite effect.

In studies in animals, peptide YY3-36 released from the intestinal tract after the ingestion of food, inhibits the hypothalamic NPY- and AgRP-expressing neurons, thereby disinhibiting adjacent proopiomelanocortin-expressing neurons and decreasing food intake.

Ghrelin and leptin receptors were also demonstrated in brainstem nuclei, and direct injection of leptin into the dorsal vagal complex reduces food intake and body weight in rats (32). Thus, although it has been established that the hypothalamus is central to the control of energy balance, accumulating evidence suggests that neural circuits originating in the caudal brainstem are also involved (33), and this area represents the focus of intense research efforts at this time.

	Concluding Remarks.

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 
This brief review has covered recent advances in the area of molecules regulating energy homeostasis and obesity. Other related hormones are expected to be added to this list in the near future as well as synthetic analogs developed by the pharmaceutical industry for the management of obesity. Further studies in obesity regulation will require the performance of appropriate animal studies to test the effectiveness of future putative antiobesity drugs as well as well-designed trials in humans to provide a better understanding of the role of any new antiobesity treatments.

	FOOTNOTES

 
¹ Manuscript received 14 October 2003.

³ Abbreviations used: AgRP, agouti-related peptide; -MSH, -melanocyte-stimulating hormone; NPY, neuropeptide Y; PVN, paraventricular nucleus.

	LITERATURE CITED

TOP ABSTRACT Leptin. Insulin. Adiponectin. Resistin. Ghrelin. Peptide YY3-36. The Link between the... Concluding Remarks. LITERATURE CITED

 

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