Adipose tissue

As mentioned earlier (Section 4.5.3.4), white adipose tissue is now recognised as an important endocrine organ, as well as a tissue involved in fat storage and mobilisation. Some the various products secreted by adipose tissue were covered in that section. Here we will discuss the secretion of one particular hormone, leptin.

The discovery of leptin is a fascinating story. In the 1950s, two animal breeders noticed a mutation in their mouse colony that led the affected animals to become naturally very obese. This mutation was the result of a change in one gene, which became known as the ob (for obese) gene. Mice heterozygous for the defective ob gene were normal. Only homozygous mutant mice (ob/ob mice) developed this spontaneous obesity. The question was, which single gene could so dramatically affect the body weight of an adult animal? Answering that question eventually required the techniques of molecular biology. In 1994 Jeff Friedman and colleagues at Rockefeller University (New York) showed that the single mutation leading to gross obesity in these mice was in a gene coding for a previously unknown protein, now known as leptin, and expressed only in white adipose tissue. The larger an adipocyte, the more leptin it produces and secretes, and of course the more adipocytes that are present in the body, the more leptin is produced. Leptin signals through receptors in the hypothalamus to restrict energy intake (i.e. to reduce appetite). In small animals it also signals to increase energy expenditure through activation of the sympathetic nervous system. The system is illustrated in Fig. 5.11 (and more details of appetite regulation by leptin and other signals will be given later, in Box 11.1). Leptin can be produced in bacteria by recombinant DNA techniques. When this recombinant leptin is injected into ob/ob mice, they become normal (they reduce their food intake and their energy expenditure increases).

Fig. 5.11 The leptin system and regulation of fat stores. Leptin is produced in, and secreted from, adipose tissue according to the extent of the fat stores. Leptin signals to the brain (hypothalamus) to (1) reduce energy intake, and (2) increase energy expenditure (the latter has only been shown convincingly in small animals). When fat stores are depleted, low leptin levels signal to the brain to (1) increase energy intake, and (2) reduce energy expenditure. The system was discovered in the spontaneously obese ob/ob mouse, which has a defective leptin gene. Therefore the brain of the ob/ob mouse 'thinks' that it is connected to a small fat mass and increases energy intake, while in fact the fat mass expands and expands.

^Energy expenditure

Fig. 5.11 The leptin system and regulation of fat stores. Leptin is produced in, and secreted from, adipose tissue according to the extent of the fat stores. Leptin signals to the brain (hypothalamus) to (1) reduce energy intake, and (2) increase energy expenditure (the latter has only been shown convincingly in small animals). When fat stores are depleted, low leptin levels signal to the brain to (1) increase energy intake, and (2) reduce energy expenditure. The system was discovered in the spontaneously obese ob/ob mouse, which has a defective leptin gene. Therefore the brain of the ob/ob mouse 'thinks' that it is connected to a small fat mass and increases energy intake, while in fact the fat mass expands and expands.

This story, as it emerged in 1994 and soon after, is now recognised to be an oversimplification. Leptin is produced in small amounts by other tissues including the stomach and placenta, and leptin receptors are found in many tissues. When leptin is injected into animals, there is an increase in glucose metabolism, probably implying effects in skeletal muscle. Leptin is also an important signal to the reproductive system. The ob/ob mouse is infertile, but becomes fertile when treated with leptin. It seems that low levels of leptin, implying low fat stores, signal to the reproductive system that the body does not have adequate energy reserves to embark upon child-bearing and rearing.

Leptin is a single-chain polypeptide hormone (16 kDa, 167 amino acids in humans). There are various isoforms of the leptin receptor, but one, known as OB-Rb or the long-form leptin receptor, seems to be the active form with an extracellular hormone-binding region and an intracellular signalling domain. Other, short-form leptin receptors may be involved with leptin transport. For instance, leptin must cross the blood-brain barrier to act on the long-form receptors expressed in the hypothalamus, and short-form receptors expressed in the choroid plexus (part of the blood-brain barrier) may facilitate this.

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