Nutritional Factors in Central Metabolic Regulation

The control of metabolism by direct negative feedback of macronutrients detected centrally has been until recently an attractive, though unconfirmed, hypothesis in the homeostatic model of energy regulation. Research advances in the last decade have greatly expanded our knowledge of how circulating carbohydrates, lipids, and proteins, reflecting amounts of recently ingested macronutrients, are detected in hypothalamic areas to not only regulate food intake, but also direct metabolic processes responsible for energy balance and anabolic pathways. For example, plasma glucose sensed centrally is a major regulator of hepatic glucose production, a process most likely mediated by ATP-sensitive potassium channels. More surprising, circulating lipids detected by hypothalamic structures also act as potent negative feedback regulators of glucose mobilization in the liver, independent of their peripheral detection in the intestines. Finally, central detection of circulating postprandial leucine levels has been shown to decrease abdominal fat mass mobilization and thermogenesis. These findings are consistent with the hypothesis that recognition of macronutrients directly by hypothalamic receptors plays a pivotal role in central regulation of metabolic processes. Moreover, the elucidated mechanisms suggest promising potential sites for pharmacological intervention in the treatment of obesity, already at epidemic proportions, although our modern environment is clearly the major cause.