Regulation of Hunger

The possibility that adipose tissue secretes a hormonal satiety factor (a circulating chemical that decreases appetite) has been suspected for years on the basis of physiological evidence. According to this view, secretion of the satiety factor would increase following meals and decrease during fasting. Such a satiety factor could act through its regulation of the hunger centers in the hypothalamus.

The satiety factor secreted by adipose tissue has recently been identified. It is the product of a gene first observed in a strain of mice known as ob/ob (ob designates "obese"; the double symbol indicates that the mice are homozygous for this gene—they inherit it from both parents). Mice of this strain display hyperpha-gia (they eat too much) and decreased energy consumption. The ob gene has been cloned in mice and humans, and has been found to be expressed (produce mRNA) only in adipocytes. As expected, the expression of this gene is decreased during fasting and increased after feeding. The protein product of this gene, the presumed satiety factor, is a 167-amino-acid polypeptide now called leptin. The ob mice produce a mutated and ineffective form of leptin, and it is this defect that causes their obesity. When they are injected with normal leptin they stop eating and lose weight.

Scientists have also identified a few obese people with defective leptin genes. However, studies in humans show that the activity of the ob gene and the blood concentrations of leptin are raised in most obese people, and that weight loss results in a lowering of plasma leptin concentrations. Thus, unlike the case of the ob/ob mice, most cases of obesity in humans may be caused by a reduced sensitivity of the brain to the actions of leptin.

In the ob/ob mice, it was observed that injections of leptin caused a decreased amount of neuropeptide Y in the hypothalamus. This observation provides a clue about how leptin might work. As discussed in chapter 7, neuropeptide Y is a potent stimulator of appetite. It functions as a neurotransmitter of axons that extend within the hypothalamus from the arcuate nucleus to the paraventricular nucleus, two regions implicated in the control of eating behavior. When weight is lost, a reduced secretion of leptin from the adipocytes may result in increased production of neuropeptide Y, which then stimulates increased hunger and food intake and decreased expenditure of energy.

When weight is gained, conversely, an increased secretion of leptin may reduce hunger by inhibiting neuropeptide Y release in the hypothalamus. The control of hunger, however, appears to be more complex than this. Scientists have discovered that appetite can be suppressed by melanocyte-stimulating hormone (MSH) or by a related neuropeptide of the melanocortin family that binds to a specific melanocortin receptor in the hypothalamus. It has thus been proposed that when weight is gained, the rising levels of lep-tin may increase the activity of these melanocortin pathways, suppressing appetite and increasing energy expenditure.

In summary (fig 19.3), leptin is believed to target the arcuate nucleus of the hypothalamus, where it affects two populations of neurons. One population produces neuropeptide Y; these neurons are inhibited by leptin. The other population produces MSH and is stimulated by leptin. As a result, high leptin levels should suppress appetite, while lowered leptin levels should promote appetite. These effects are believed to help the body maintain its usual level of adiposity (fat storage).

Regulation of Metabolism

Adipose Mass

Hypothalamus

Hypothalamus

Neuropeptide Y Melanocortin peptides Neuropeptide Y (including MSH)

Adipose Mass

Neuropeptide Y Melanocortin peptides Neuropeptide Y (including MSH)

Secondary Hypothalamic Nuclei

Secondary Hypothalamic Nuclei

Endocrine changes; increased sympathetic nerve activity

Metabolic rate

Endocrine changes; increased sympathetic nerve activity

Metabolic rate

Figure 19.3 The action of leptin. Leptin crosses the blood-brain barrier to affect neurotransmitters released by neurons in the arcuate nucleus of the hypothalamus. This influences other hypothalamic nuclei, which in turn reduce appetite and increase metabolic rate. The figure also shows that insulin stimulates adipose cells to secrete leptin and is able to cross the blood-brain barrier and to act in a manner similar to leptin.

The actions of leptin and insulin (fig. 19.3) are important in the long-term regulation of eating and, by this means, in maintaining homeostasis of body weight. Other hormones are believed to be more involved in meal-to-meal feelings of hunger and satiety (a feeling of "fullness," and thus reduction of appetite). One of these is a recently discovered hormone called ghrelin, secreted by the stomach. Ghrelin secretion rises between meals, when the stomach is empty, and stimulates hunger. As the stomach fills during a meal, the secretion of ghrelin rapidly falls. Another hormone that regulates eating is the intestinal hormone cholecystokinin (CCK). Secretion of CCK rises during and immediately after a meal, and has been found to promote satiety. These two hormones thus act antagonistically on the arcuate nucleus of the hypothalamus (fig. 19.3) to promote feelings of hunger and satiety before and after a meal.

Intermediate between the long-term regulation of eating by leptin and insulin, and the short-term regulation by ghrelin and CCK, is a newly discovered hormone named PYY3-36. This hormone is secreted by the small intestine in proportion to the calorie content of a meal. In a recent study, injections of this hormone into humans was found to suppress appetite for up to 12 hours after a meal. Like leptin, PYY3-36 acts on the arcuate nucleus to decrease neuropeptide Y and increase melanocortin peptides (fig. 19.3). Through this action, PYY3-36 may regulate appetite to help determine the spacings between meals.

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