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Regulation of energy homeostasis by peripheral signals

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The increased incidence of obesity makes it imperative to understand the regulation of food intake and body weight. We review the signals that interact with the brain to control energy homeostasis, i.e. energy intake and expenditure. Three broad categories can be distinguished. Signals generated in the gastrointestinal tract during meals (‘satiety’ signals, e.g. cholecystokinin) elicit satiation and contribute to stopping the meal. The potency of these acutely acting signals must be increased if they are to be used therapeutically. Hormonal signals whose secretion is proportional to body fat (adiposity signals, leptin and insulin) robustly reduce food intake and body weight by directly stimulating receptors locally in the brain. Therapeutic applications will have to find ways to circumvent the systemic actions of these hormones, targeting only the brain. Satiety and adiposity signals interact with neuronal circuits in the brain that utilize myriad neurotransmitters to cause net catabolic or anabolic responses. Considerable effort is being directed towards finding ways to intervene in specific circuits to help accomplish weight loss.

Section snippets

The energy equation and the obesity epidemic

Food intake is one of the commonest behaviors we undertake on a daily basis, and one with profound consequences because food intake also comprises one side of the energy equation. The energy equation holds that if body weight is to remain stable, food intake (i.e. energy intake) must equal energy expenditure (i.e. metabolism plus the effects of exercise) over long intervals. If the energy equation is not in balance, body weight will drift upwards or downwards over time.1 In point of fact, there

Meals

Food intake in mammals, including humans, occurs in distinct bouts or meals, and the number and size of meals over the course of a day comprises the meal pattern. Most humans are quite habitual in that they eat approximately the same number of meals, and at the same time of day, on a daily basis.15., 16. There is, however, a considerable variation among individuals, with some having three meals a day, others four, others with small snacks interspersed, and so on. It is generally accepted that

Body fat regulation

The other important information needed to regulate body weight pertains to the amount of fat stored in the body (see Figure 1 above). That is, it is well known that if an individual loses body weight (e.g. by dieting), there is a tendency to eat more food and restore body weight when conditions allow. Analogously, if an individual voluntarily overeats, or is forced to overeat, and gain weight, there is a tendency to reduce food intake and lose the gained weight when conditions allow. This is

Integration of satiety and adiposity signals

The information about total body fat derived from insulin and leptin must be integrated with satiety signals as well as with other signals related to myriad other factors, including learning, the social situation, stress and so on, for the control system to be maximally efficient. Although the nature of these interactions is not well understood, several generalizations or conclusions can be made. For one, the negative feedback circuits related to body fat and meal ingestion can easily be

Central signals related to energy homeostasis

As an oversimplification, the neural circuits in the brain that control energy homeostasis can be subdivided into those which receive relevant sensory information (afferent circuits), those which integrate the information and those which control motor, autonomic and endocrine responses (efferent circuits). The discussion above has focused upon some of the relevant afferent satiety and adiposity signals and how they influence food intake. Peptides such as insulin, leptin and CCK can be

Melanocortins

This is a rapidly expanding area of research and beyond the scope of this review. Because of this, only a few generalizations will be made. As discussed above, the arcuate nucleus of the hypothalamus comprises a hub, where many kinds of signals related to energy homeostasis converge. Adiposity signals from the circulation interact with specific insulin and leptin receptors in the arcuate nucleus. Satiety signals entering the hindbrain are relayed to the arcuate and other hypothalamic areas. The

Summary

Several types of signal are involved in the regulation of energy homeostasis by the brain. Because appetite and meal initiation are generally not under homeostatic control, body weight is regulated by how much food is eaten once a meal begins. Satiety signals generated as ingested food interacts with the stomach and intestine contribute to satiation. Adiposity signals are detected directly in the brain and work by changing the sensitivity of satiety signals such that when individuals lose

Acknowledgements

The preparation of this review was supported by several grants from the United States National Institutes of Health.

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