Energy intake

Evidence that there is regulation of energy intake has long been available from studies of laboratory animals. For instance, rats or mice have been underfed from an early age. Then, when their weight is significantly less than control animals allowed ad libitum feeding (feeding as much as they want), the underfed animals are returned to ad libitum feeding. The result is always that their weight rapidly increases until it reaches the same value as control animals of a similar age. This led many years ago to the concept of a 'set-point' for body weight (as there is a set-point for temperature in a system with a thermostat: see Fig. 6.2). What determines this set-point? Some people argued for a 'pon-derostat', a system that responds according to ponderal index or the degree of overweight. The British physiologist G.C. Kennedy, in the 1950s, argued for a 'lipostat', a system that responds according to the size of the body's fat stores. The discovery of leptin (see Section 5.6 and Fig. 5.11) proved this conjecture to be basically correct. Leptin, as described in Section 5.6, is a signal from adipose tissue. Its plasma concentration reflects the size of the fat stores, and signals to the hypothalamus to restrict energy intake (and also, in small animals, to increase energy expenditure).

The discovery of leptin in 1994 led to an explosion of work in the field of energy intake regulation. It is now recognised that there are several pathways within the central nervous system that regulate food intake in both positive and negative directions. Some of these are summarised in Box 11.1.

Box 11.1 Regulation of energy intake

Most of the detail of appetite regulation has been worked out in laboratory animals, but the discovery of some relatively rare single-gene mutations causing obesity in humans gives support to the idea that the pathways are basically similar.

There are short-term and long-term regulatory pathways. These converge within the central nervous system.

Long-term signals feed information on the 'energy status' of the organism to the brain. Those clearly identified are leptin and insulin: leptin signals the state of the fat stores, insulin the state of 'carbohydrate repleteness'. These act through complex pathways in the hypothalamus that involve a variety of neurotransmitters and neuropeptides. They inhibit hunger pathways and stimulate satiety pathways. Conversely, if leptin and insulin concentrations are low, signalling a need for energy, hunger pathways are stimulated and satiety is suppressed. Some key peptides involved in these hypothalamic pathways are:

• Neuropeptide Y (NPY): this is a powerful hunger signal; injection of neuropeptide Y into the brains of rats brings about eating.

• Peptides related to pro-opiomelanocortin (POMC) (see Section 5.3.1): POMC is a large peptide that is cleaved to generate a number of biologically active peptides including ACTH and melanocyte-stimulating hormone (MSH) (one of a family of peptides known as melanocortins). MSH was, as its name suggests, first identified as a stimulator of pigment (melanin) production in the skin, but also acts on a variety of receptors in the hypothalamus to suppress appetite. One of these receptors in particular is the melanocortin-4 receptor (Mc4 receptor). Mice lacking the Mc4 receptor overeat and become obese, and recently some children with early-onset obesity have been found to have mutations in the Mc4 receptor.

Short-term signals arise from the intestinal tract, the hepatic portal vein and the liver. Generally they serve to produce satiety, bringing about the end of a meal. These signals are transmitted partly in afferent fibres of the vagus nerve (see Section 7.2.2.2) and partly through the blood. There are many candidate 'satiety' hormones including glucagon-like peptide-1 (Section 5.7) and chole-cystokinin (CCK, Section 3.2.3.2), and also apolipoprotein-AIV secreted from the small intestine as a component of chylomicrons. Ghrelin is a peptide released from the stomach (ghrelin gets its name from its first-recognised action of stimulating growth hormone release) that stimulates appetite: its secretion rises during fasting and is suppressed following feeding.

These pathways and their interaction are summarised in Fig. 11.1.1. Note that this is very over-simplified; see Further Reading for more detailed accounts.

Hypothalamic nuclei . NPY _ pathways

+ POMC _ pathways

+ POMC _ pathways

Brainstem —Hunger

Suppression of appetite

Nutrient-related signals transmitted via vagal afférents and circulation

Nutrient-related signals transmitted via vagal afférents and circulation

Longer-term regulation Satiety signals

Fig. 11.1.1 Summary of central pathways regulating appetite.

There has been some scepticism over whether these systems, mostly discovered in small animals, operate in humans. Plasma leptin concentrations in obese humans are almost always elevated compared with lean people: there is a positive relationship, as expected, with fat mass (Fig. 11.1). Therefore the majority of human obesity is not explained by a defect in leptin secretion (as is seen in the ob/ob mouse); in fact, people remain obese despite high levels of leptin.

Fig. 11.1 Relationship between serum leptin concentration and percentage body fat in 179 subjects with a wide range of fatness. There is generally a positive relationship: the more fat one has, the higher the leptin concentration. However, for any particular value of body fat (40%, for instance), there is a wide range of leptin concentrations, so generalisations are dangerous. Adapted from Considine, R.V., Sinha, M.K. & Heiman, M.L. et al. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334: 292-295. With permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved.

Fig. 11.1 Relationship between serum leptin concentration and percentage body fat in 179 subjects with a wide range of fatness. There is generally a positive relationship: the more fat one has, the higher the leptin concentration. However, for any particular value of body fat (40%, for instance), there is a wide range of leptin concentrations, so generalisations are dangerous. Adapted from Considine, R.V., Sinha, M.K. & Heiman, M.L. et al. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334: 292-295. With permission. Copyright © 1996 Massachusetts Medical Society. All rights reserved.

However, recent developments have shown that this system is, indeed, of fundamental importance to human energy balance. The group of Professor Stephen O'Rahilly in Cambridge, UK, have specialised in studying cases of severe childhood obesity. In 1997 they reported two young cousins who had shown phenomenal growth, and compulsive eating behaviour, since birth. When they attempted to measure the plasma leptin concentrations in these children, they could find none. Sequencing of their leptin genes showed that both are homozygous for a frameshift mutation1 in the leptin gene. They cannot produce functional leptin, and the impact for them is almost as severe as if they could not produce insulin (although quite different in nature). The cousins have now been treated with human leptin (produced by recombinant DNA techniques as discussed in Section 5.6). Data have been published for one of them. She has shown progressive weight loss, and remarkable normalisation of her eating behaviour, for the first time in her life (Fig. 11.2). Since that time, there have been reports of several further families with mutations either in the leptin gene or in the gene for the leptin receptor (although this is still an extraordinarily rare cause of obesity). The phenotype is similar, and, in older people, includes sexual immaturity, emphasising that leptin is an important signal to the reproductive system as well as to the systems regulating energy intake (see Section 5.6). We can no longer believe that human energy intake is not regulated by internal mechanisms, although clearly these mechanisms, when they are working normally, can easily be overridden.

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