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UCP2-dependent redox-sensing in POMC neurons regulates feeding

ABSTRACT: Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic POMC neurons. Here we show 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. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Cultured Cells

SUBMITTER: Sabrina Diano

PROVIDER: ST002361 | MetabolomicsWorkbench | Mon Nov 28 00:00:00 GMT 2022

REPOSITORIES: MetabolomicsWorkbench

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UCP2-dependent redox-sensing in POMC neurons regulates feeding

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