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Although it is a widely held thought that direct hormone action on peripheral tissues is sufficient to mediate the control of nutrient handling, the role of the central nervous system in certain aspects of metabolism has long been recognized. Furthermore, recent findings have suggested a more general role for the central nervous system in metabolic control, and have revealed the importance of a number of cues and hypothalamic circuits. The brain's contributions to metabolic control are more readily revealed and play a crucial part in catabolic states or in hormone deficiencies that mimic starvation.
The survival of multicellular organisms depends on the appropriate uptake and release of nutrients by major metabolic tissues. In the absence of continuous feeding, the availability of metabolic fuels (for example, glucose, fatty acids and amino acids) for use in tissues is maintained by storing nutrients, which are later released at the appropriate time and rate. Hormones that are secreted by the pancreatic islets of Langerhans modulate important aspects of nutrient uptake and storage (insulin) or their release into the circulation (glucagon). They do this partly by acting directly on the tissues that are the main reservoirs for these nutrients (for example, liver, adipose and muscle tissue).
Although the direct actions of these hormones on metabolic tissues are crucial for whole-body metabolic homeostasis, several central nervous system (CNS)-regulated systems have long been recognized to control important aspects of metabolism. For instance, the elaboration of catecholamines by the sympathetic nervous system (SNS), along with hypothalamically controlled hormones (such as glucocorticoids and thyroid hormone), functions in concert with glucagon to mediate the counter-regulatory response, promoting nutrient release into the blood and favouring substrate use over storage1. Well-recognized CNS pathways mediate crucial aspects of this counter-regulatory response. Recent data reveal a more general role for CNS pathways in the modulation of metabolism: various nutrient, energetic and hormonal cues (such as insulin and the adipose-derived hormone leptin) function in the hypothalamus to control glucose and lipid metabolism, in addition to overall energy balance2,3 (Fig. 1). Several hypothalamic areas, especially the ventromedial nucleus and arcuate nucleus (including the arcuate melanocortin system), as well as the hindbrain, make important contributions to these effects. Although the peripheral response to the hormones that control metabolism (for example, insulin...