Nutrient sensing in POMC neurons

About This Grant

Changes in metabolic states require the rapid and synergistic interaction between the brain and periphery to maintain homeostasis. Circulating factors such as nutrients play fundamental roles in these processes. Hunger and satiety are controlled by food intake and related hormonal and metabolic adaptations. After a meal, an important signal that has been attributed to drive satiety is glucose, which activates the anorexigenic pro- opiomelanocortin (POMC) neurons in the hypothalamus. Interestingly, only a subpopulation of POMC neurons shows activation by increased levels of glucose. In addition to glucose, lactate, the circulating redox indicator and glucose metabolite, has been shown to affect POMC activity. Indeed, lactate derived either from the circulation or locally by glial cells has been shown to regulate neuronal function, including that of POMC neurons, thus modulating peripheral glucose metabolism as well as feeding. Changes in circulating lactate levels occur in response to feeding, when glucose levels are elevated, and fasting when glucose levels decrease. While administration of lactate has been shown to affect feeding and metabolism via the hypothalamus and POMC neurons, the mechanism(s) via which this process plays a role in physiological control of whole-body energy metabolism in association with glucose is ill-defined. We have recently shown that lactate levels in the circulation and in the cerebrospinal fluid are elevated in fed state and addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. In support of this, MPC deletion in POMC neurons does not alter metabolism. Furthermore, our preliminary metabolic tracing data clearly showed that pyruvate derives predominantly from lactate and that similarly to lactate fatty acids induced increased mitochondrial respiration. Thus, we hypothesize that satiety promotion by POMC neurons require parallel processing of glucose, lactate, and fatty acids. During positive energy balance, glucose in POMC neurons undergo glycolysis thus generating ATP. ATP will then close the KATP channels inducing depolarization and initial activation of POMC neurons. As the ADP:ATP ratio increases, it will drive mitochondrial function which will be supported by lactate oxidation and, thus, generation of NADH to drive the ETC, and by fatty acids oxidation (in addition to lactate) to further drive the TCA cycle. We will determine the role of cytoplasmic (Aim 1) and mitochondrial (Aim 2) redox state in the regulation of POMC neuronal function and associated metabolic adaptations. In Aim 3 we will determine a) the role of fatty acids oxidation in POMC neurons and b) whether glucose, lactate and fatty acids synergistically or uniquely affect POMC neurons. The proposed studies are a logical extension of our preliminary data, and their completion will unmask a fundamental mechanistic principle in the central regulation of metabolism.