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