-36 -24 -12 0 12 24 36 48 60 72 84 96 108 120 132 Study Duration (Hours)

FIGURE 17 Effect of fasting and refeeding on leptin concentrations in the plasma of normal human subjects. (From Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF. Responses of leptin to short-term fasting and refeeding in humans: A link with ketogenesis but not ketones themselves. Diabetes 1996;45:1511-1515).

post-translational processing (see Fig. 3 in Chapter 38) gives rise to ^-melanocyte stimulating hormone (a-MSH). As a neuropeptide, a-MSH is a potent negative regulator of food intake and activates melanocortin receptors in neurons in the dorsomedial and paraven-tricular nuclei of the hypothalamus and the lateral hypothalamic area. Expression of a-MSH in rodents is increased by leptin and suppressed by overfeeding. Pharmacological blockade or genetic depletion of brain melanocortin receptors results in obesity.

• In the skin, a-MSH increases expression of a black pigment in hair follicles. A protein, called agouti, competes with a-MSH for the melanocortin receptor, and under its influence, a yellow pigment is expressed. The observation that a mutation that results in ubiquitous inappropriate expression of the agouti gene in mice also produces obesity led to the discovery that neurons in the arcuate nucleus express a similar protein, the agouti-related protein (AGRP), which competes with a-MSH for binding to the melanocortin receptor in the brain. AGRP and neuropeptide Y are coexpressed in arcuate neurons, and their combined actions provide a strong drive for food intake. Expression of AGRP is increased in leptin deficiency and decreased by leptin treatment.

• Melanin concentrating hormone (MCH) was originally described as the factor that opposes the melano-phore dispersing activity of MSH in fish, but MCH is also expressed in neurons in the lateral hypothalamus of mammals. When administered to rodents, MCH stimulates feeding behavior and antagonizes the inhibitory effects of a-MSH. Unlike AGRP, MCH does not bind to the same receptor as a-MSH. Fasting increases MCH expression, and absence of the MCH gene in mice results in reduction in body fat content.

• Another appetite-suppressing peptide is the cocaine and amphetamine regulated transcript (CART) whose discovery arose out of studies of drugs of abuse. It is widely expressed in the brain and other endocrine tissues including some neurons in the arcuate nuclei that also express a-MSH. Administration of CART inhibits the feeding response to NPY. Mice that are deficient in CART become obese.

Other neuropeptides and amine transmitters that originate in neurons in various brain loci and the gastrointestinal tract also participate in the complex regulation of feeding behavior. A complete ''wiring diagram'' cannot yet be drawn, but some of the relationships are shown in Fig. 18.




FIGURE 18 Proposed negative feedback control of leptin secretion, a-MSH, a melanocyte stimulating hormone; CART, cocaine and amphetamine regulated transcript; NPY, neuropeptide Y; AGRP, agouti-related peptide; MCH, melanin concentrating hormone.

Adipocyte fFood Intake * Energy expenditure

FIGURE 18 Proposed negative feedback control of leptin secretion, a-MSH, a melanocyte stimulating hormone; CART, cocaine and amphetamine regulated transcript; NPY, neuropeptide Y; AGRP, agouti-related peptide; MCH, melanin concentrating hormone.

Other Effects of Leptin

Through its actions on neurons associated with autonomic and anterior pituitary functions, leptin affects temperature regulation, reproduction, and adrenal cortical function. Leptin receptors are also found in many cells outside of the central nervous system. Adipocytes express leptin receptors and respond to leptin in an autocrine manner with an increase in lipolysis. Leptin acts directly on pancreatic beta cells to inhibit insulin secretion and thus forms one arm of a negative feedback arrangement between beta cells and adipocytes in which stimulation of leptin secretion by insulin leads to inhibition of insulin secretion by leptin.

The presence of leptin receptors in the gonads suggests that peripheral actions of leptin may complement the fertility-promoting effects exerted at the hypothalamic level. Other peripheral effects of leptin include actions in bone marrow to promote hemato-poiesis and actions in capillary endothelium to increase angiogenesis (blood vessel formation). Leptin is also produced by the placenta and may play a role in fetal development.

Role of Insulin

Although insulin promotes the storage of excess metabolic fuels in adipose tissue, it may also serve as an indicator of total body fat and signal to the hypothalamus to limit food intake and fat storage. Insulin sensitivity decreases as fat storage depots increase. Therefore, higher concentrations of insulin are required to maintain blood glucose within normal limits, and hence insulin levels in blood increase or decrease in parallel with changes in body fat. Insulin receptors are present in neurons in the arcuate nucleus where insulin acts to inhibit NPY synthesis and produce other leptin-like effects. Insulin also stimulates leptin synthesis in adipocytes and in typical negative feedback fashion, leptin inhibits insulin secretion. While understanding of the interplay between insulin and leptin is incomplete, it is likely that both hormones play a major roles in long term regulation of fat storage.

Role of Gastrointestinal Hormones

Secretions from the intestinal tract also influence appetite and satiety, and influence both meal size and the frequency of eating. Although discovered for its actions to increase GH secretion, ghrelin (see Chapters 38 and 44), secreted by endocrine cells in the mucosal lining of the stomach may also play an important role in signaling hunger. Its concentrations in blood increase with fasting and are promptly reduced by food ingestion. Ghrelin stimulates cells in the arcuate nuclei to secrete NPY and AGRP. The duodenal hormone cholecystokinin (CCK) which is secreted by the intestinal mucosa upon ingestion of proteins and fat (see Chapter 32) acts as a satiety signal to limit meal size. Genetic defects in the CCK receptor produce abesity in rodents. Leptin and insulin may increase the sensitivity to CCK.

Suggested Reading

Ahima RS, Flier JS. Leptin. Ann Rev Physiol 2000;62:413-437. Felig P, Sherwin RS, Soman V, Wahren J, Hendler R, Sacca L, Eigler N, Goldberg D, Walesky M. Hormonal interactions in the regulation of blood glucose. Rec Prog Horm Res 1979;35: 501-528.

Jefferson LS, Cherrington AD. The endocrine pancreas and regulation of metabolism, in Handbook of physiology, Section 7, Vol II, The endocrine pancreas and regulation of metabolism, Oxford University Press, New York, 2001. Randle PJ, Kerbey AL, Espinal J. Mechanisms decreasing glucose oxidation in diabetes and starvation: Role of lipid fuels and hormones. Diabetes/Metab Rev 1988;4:623-638. Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 1999;276:E1-E18. Schwartz, M, Woods, SC, Porte, D, Jr., Seeley, RJ, Baskin, DG, Central nervous system control of food intake. Nature 2000;404:661-671

Wasserman DH, Cherrington AD. Regulation of extramuscular fuel sources during exercise. In Rowell LB, Shepherd JT, eds., Exercise: Regulation and integration of multiple systems, Handbook of physiology, Section 12, Oxford University Press, New York, 1996, pp 1036-1074.)

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