Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

All organisms must adapt to changing nutrient availability, with nutrient surplus promoting glucose metabolism and nutrient deficit promoting alternative fuels (in mammals, mainly free fatty acids). A major function of glucose-sensing neurons in the hypothalamus is to regulate blood glucose. When these neurons sense glucose levels are too low, they activate robust counterregulatory responses to enhance glucose production, primarily from liver, and reduce peripheral metabolism. Some hypothalamic neurons can metabolize free fatty acids via β-oxidation, and β-oxidation generally opposes effects of glucose on hypothalamic neurons. Thus hypothalamic β-oxidation promotes obese phenotypes, including enhanced hepatic glucose output.