Central control of body weight and appetite

Abstract

Context: Energy balance is critical for survival and health, and control of food intake is an integral part of this process. This report reviews hormonal signals that influence food intake and their clinical applications.

Evidence acquisition: A relatively novel insight is that satiation signals that control meal size and adiposity signals that signify the amount of body fat are distinct and interact in the hypothalamus and elsewhere to control energy homeostasis. This review focuses upon recent literature addressing the integration of satiation and adiposity signals and therapeutic implications for treatment of obesity.

Evidence synthesis: During meals, signals such as cholecystokinin arise primarily from the GI tract to cause satiation and meal termination; signals secreted in proportion to body fat such as insulin and leptin interact with satiation signals and provide effective regulation by dictating meal size to amounts that are appropriate for body fatness, or stored energy. Although satiation and adiposity signals are myriad and redundant and reduce food intake, there are few known orexigenic signals; thus, initiation of meals is not subject to the degree of homeostatic regulation that cessation of eating is. There are now drugs available that act through receptors for satiation factors and which cause weight loss, demonstrating that this system is amenable to manipulation for therapeutic goals.

Conclusions: Although progress on effective medical therapies for obesity has been relatively slow in coming, advances in understanding the central regulation of food intake may ultimately be turned into useful treatment options.

Figure 1

Model summarizing different levels of control over energy homeostasis. During meals, signals such as CCK, GLP-1, and distension of the stomach that arise from the gut (stomach and intestine) trigger nerve impulses in sensory nerves traveling to the hindbrain. These satiation signals synapse with neurons in the nucleus of the solitary tract (NTS) where they influence meal size. Ghrelin from the stomach both acts on the vagus nerve and stimulates neurons in the ARC directly. Signals related to body fat content such as leptin and insulin, collectively called adiposity signals, circulate in the blood to the brain. They pass through the blood-brain barrier in the region of the ARC and interact with neurons that synthesize POMC or NPY and AgRP. ARC neurons in turn project to other hypothalamic areas including the PVN and the LHA. The net output of the PVN is catabolic and enhances the potency of satiation signals in the hindbrain. The net output of the LHA, on the other hand, is anabolic, suppressing the activity of the satiation signals. In this way body fat content tends to remain relatively constant over long intervals by means of changes of meal size.

Figure 2

Satiation signals arising in the GI system converge on the dorsal hindbrain (D) where they are integrated with taste and other inputs. The dorsal hindbrain makes direct connections with the ventral hindbrain (V) where neural circuits direct the autonomic nervous system to influence blood glucose and where the motor control over eating behavior is located. The dorsal hindbrain also conveys information on satiation and other factors anteriorly to the hypothalamus and other brain areas. These areas in turn integrate satiation and adiposity signals as well as available nutrients with experience, the social situation and stressors, and with time of day and other factors. The integrated information is then conveyed posteriorly back to the ventral hindbrain as well as to the pituitary to influence all aspects of energy homeostasis. Animals lacking neural connections between the hindbrain and the hypothalamus reduce the intake of individual bouts of eating when the stomach is distended or they are administered CCK. However, those animals cannot regulate their body weight and are not sensitive to past experience, time of day, or social factors (243).