Longterm control of food intake and energy expenditure

In addition to the immediate control of feeding by hunger and satiety, there is also long-term control of food intake and energy expenditure, in response to the state of body fat reserves. In 1994 it was shown that the normal product of the gene that is defective in the homozygous recessive mutant (ob/ob) obese mouse is a small peptide that is secreted by adipose tissue. Administration of the synthetic peptide to genetically obese mice caused them to lose weight, and administration of excessive amounts of the peptide to normal mice also caused weight loss. It was called leptin, from the Greek A,£TCTOO - lean or thin.

Further studies showed that the administration of leptin to the genetically obese diabetic ( fa/fa) rat had no effect on body weight, and indeed these rats secreted a normal or greater than normal amount of leptin. The defect in these animals is a mutation in the membrane receptor for leptin.

Initially, the leptin receptor was found in the hypothalamus, and because the circulating concentration of leptin is determined largely by the mass of adipose tissue in the body, it was assumed that the function of leptin is to signal the size of fat reserves in the body to the hypothalamus, in order to control appetite. Interestingly, subcutaneous adipose tissue secretes more leptin than does abdominal adipose tissue, which may be an important factor in the difference in health risks associated with central (abdominal) obesity and hip-thigh obesity, which is due to subcutaneous fat (section 6.3.2).

Control of food intake is certainly one of the functions of leptin - reduced food intake can be observed in response to direct injection of the peptide into the central nervous system, and in response to leptin there is increased secretion of a number of peptide neurotransmitters that are known to be involved in regulation of feeding behaviour. However, the weight loss seen in response to leptin is greater than can be accounted for by the reduced food intake alone. Furthermore, in response to leptin there is a specific loss of adipose tissue, whereas, as discussed in section 8.2, in response to reduced food intake there is a loss of both adipose tissue and lean tissue.

Leptin receptors are also found in a variety of tissues other than the hypothalamus, including muscle and adipose tissue itself. Leptin has a number of actions in addition to its action in the hypothalamus, which result in increased energy expenditure and loss of adipose tissue:

  • It causes increased expression of uncoupling protein (section 3.3.1.4) in adipose tissue and muscle. This results in relatively uncontrolled oxidation of metabolic fuel, unrelated to requirements for physical and chemical work, and increased heat output from the body (thermogenesis).
  • It increases the activity of lipase in adipose tissue (section 10.5.1), resulting in the breakdown of triacylglycerol reserves and release of non-esterified fatty acids for oxidation.
  • It decreases the expression of acetyl CoA carboxylase in adipose tissue (section 5.6.1). This results in both decreased synthesis of fatty acids and increased oxidation of fatty acids as a consequence of decreased formation of malonyl CoA (section 5.6.1 and section 10.5.2).
  • There is some evidence that leptin also promotes apoptosis (programmed cell death) specifically in adipose tissue, thus reducing the number of adipocytes available for storage of fat in the body.

The result of these actions of leptin on adipose tissue and muscle is that there is a considerable increase in metabolic rate, and an increase in energy expenditure, as well as a reduction in food intake.

Although most leptin is secreted by adipose tissue, it is also secreted by muscle and the gastric mucosa. The role of leptin secretion by muscle is unclear, but in response to a meal there is a small increase in circulating leptin, presumably from the gastric mucosa. This suggests that, in addition to its role in long-term control of food intake and energy expenditure, leptin may be important in responses to food intake. Insulin (which is secreted mainly in response to food intake; section 5.3.1) stimulates the synthesis and secretion of leptin in adipose tissue.

There is also a circadian variation in leptin secretion, with an increase during the night. This is in response to the glucocorticoid hormones, which are secreted in increased amount during the night. It is likely that the loss of appetite and weight loss associated with chronic stress, when there is increased secretion of glucocorticoid hormones, is mediated by the effect of these hormones on leptin synthesis and secretion.

When leptin was first discovered, there was great hope that, as in the obese mouse, human obesity (see Chapter 6) might be due to a failure of leptin synthesis or secretion, and that administration of synthetic leptin might be a useful treatment for severe obesity. However, most obese people secrete more leptin than lean people (because they have more adipose tissue), and it is likely that the problem is due not to lack of leptin, but rather to a loss of sensitivity of the leptin receptors. Only in a very small number of people has obesity been found to be genetically determined by a mutation in the leptin gene.

1.3.3 APPETITE

In addition to hunger and satiety, which are basic physiological responses, food intake is controlled by appetite, which is related not only to physiological need, but also to the pleasure of eating — flavour and texture, and a host of social and psychological factors.

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