The involvement of the hypothalamus in the regulation of food intake and energy expenditure has had experimental support for many decades. For example, it was shown in 1940 that hypothalamic lesions in the rat led to morbid obesity. It was also understood that the ability of mammals to maintain fairly stable body weight involves some type of communication between body fuel storage and the control of food intake. The identification of hyperphagic obese mice and the realization that their condition was due to a recessively inherited defect provided a model with which to further study the control of appetite. A series of important experiments with these mice (designated ob/ob) using parabiosis (joining two living systems) demonstrated that one or more humoral factors were involved in mediating the ob/ob phenotype. More specifically, it was found that the ob/ob mice are missing a satiety factor. A related mouse strain with an obese phenotype similar to diabetes mellitus, db/db was resistant to the satiety factor. Within the past twenty years, the satiety factor, the product of the ob gene, has been identified as the 167 amino acid hormone leptin, from the Greek “leptos” meaning thin. It is produced in the adipose tis sue and, as shown in Figure 1 the circulating levels of leptin show a logarithmic relationship to the amount of adipose tissue as a function of total body mass.
Fig1. Relationship between serum leptin levels and body fat. The relationship between serum leptin levels and the percent of body mass that is fat tissue is shown on a logarithmic scale.
Leptin is highly conserved among mammals and has been identified in birds as well. Lack of leptin in both humans and rodents leads to morbid obesity and neuroendocrine disruptions, which can be reversed by exogenous administration of the hormone. Leptin receptors, which transmit their signals through the JAK/STAT pathway, are found in several nuclei in the medial basal hypothalamus.
Leptin is not the only regulator of energy homeostasis and some other participants are summarized in Figure 2. In this figure, attention is focused on two important types of neurons in the arcuate nucleus of the hypothalamus. The first synthesizes the neuropeptides AgRP (Agouti related protein) and NPY (neuro peptide Y), which lead to increased food intake. The second type consists of POMC-synthesizing neurons whose product is α-MSH, leading to suppression of food intake. Leptin, from adipose tissue, affects both of these pathways, inhibiting the first and stimulating the second for an overall decrease in food intake. In addition to the regulation of appetite by lipid stores, or lipostatic regulation, glucostatic regulation is exerted by insulin, whose effects on the two sets of neurons is the same as those of leptin. Ghrelin, already discussed in this chapter as the endogenous ligand for the growth hormone secretagogue receptor, also functions as a “hunger” signal, so that, through action on the NPY/ AgRP neurons, feeding behavior increases.
Fig2. Pathways of appetite regulation in the hypothalamus. Three peripheral pathways are shown: stimulation of food intake by the stomach hormone, ghrelin and the two food intake suppressing pathways comprised of leptin from adipose tissue and insulin from the pancreas. These peripheral hormones interact with two sets of neurons in the arcuate nucleus of the hypothalamus. On the left is shown the AgRP (agouti-related protein/ NPY (neuropeptide Y)) neuron, which acts to stimulate appetite. On the right is shown the POMC (proopiomelanocortin) neuron which, through production of α-MSH, depresses food intake.
Understanding the pathways that control appetite, food intake, and energy utilization continues to be the subject of intensive investigation and many aspects remain to be elucidated. Table1 summarizes many of the peptides that are involved in these vital processes. The hormonal control of appetite and energy utilization is also discussed in Chapter 7.
Table1. Some Neuropeptides That Regulate Appetite
