The long-term objective of this fellowship to elucidate molecular, biochemical, and physiological mechanism(s) coupling the sensing of (macro-) nutrients within the hypothalamus to the regulation of liver glucose metabolism. Here we tested the hypothesis that the metabolism of lactate within the mediobasal hypothalamus is a pivotal (required) step in the central sensing of carbohydrates, which in turn induces robust changes in liver glucose fluxes. First, we enhance the hypothalamic availability and metabolism of lactate and pyruvate by increasing levels of either glucose or lactate (Aim 1). Since the entry of lactate-derived carbons in the TCA cycle requires its conversion to pyruvate (catalyzed by the enzyme lactate dehydrogenase) we wish to examine whether this biochemical step is indeed required for the sensing of both lactate and glucose within the hypothalamus (AIM 2). Next we investigate whether activation of hypothalamic KATP channels is required for the effects of central glucose and lactate (Aim 3). Lastly, we wish to explore the physiological impact of these observations by negating the hypothalamic sensing mechanism during physiological elevations in the circulating lactate levels (Aim 4). [unreadable] [unreadable]