Ventromedial Hypothalamic Nucleus Controls Glucose Metabolism through Adipose Tissue Lipolysis

The central nervous system (CNS) coordinates metabolic target organ function to optimize blood glucose levels, while dysregulation of this system leads to impaired glycemia. Attempts to improve glucose control through CNS targeting are hindered by a incomplete understanding of the specific neuronal populations involved and how these cells coordinate peripheral metabolic target organ function. We found that cholecystokinin b receptor-expressing neurons of the ventromedial nucleus of the hypothalamus (VMN; VMNCCKBR neurons) mediate glucose mobilization during counter-regulatory responses to hypoglycemia and regulate glucose levels in normal and diabetic mice. Silencing VMNCCKBR neurons with tetanus toxin (CCKBRTT) attenuates hyperglycemia in ob/ob mice and decreases baseline blood glucose by suppressing hepatic gluconeogenesis despite decreased insulin and elevated glucagon. CCKBRTT mice have elevated hepatic gluconeogenic enzyme expression and normal glycemic responses to exogenous gluconeogenic substrates, suggesting that silencing VMNCCKBR neurons decreases blood glucose through impaired gluconeogenic substrate mobilization. To determine which gluconeogenic substrates contribute to VMNCCKBR-neuron mediated glucose production, we expressed channel rhodopsin in VMNCCKBR neurons to optogenetically activate VMNCCKBR neurons in freely moving mice. In addition to elevating plasma glucose, optogenetic activation resulted in a β3-adrenergic receptor-dependent increase in plasma ketones and glycerol, suggesting that VMNCCKBR neurons increase lipolysis though SNS innervation of white adipose tissue (WAT) . Consistent with this observation, CCKBRTT mice exhibited decreased fasting plasma glycerol and in vivo lipolysis, while β3-agonist treatment elevated these appropriately. Hence, VMNCCKBR neuron-mediated SNS outflow to WAT promotes lipolysis to provide gluconeogenic substrates and support baseline blood glucose in mice. Disclosure A.Affinati: Other Relationship; Novo Nordisk A/S. J.Flak: Research Support; Eli Lilly and Company. N.Kodur: None. A.Hashsham: None. A.J.Tomlinson: None. N.Bozadjieva kramer: None. C.Li: Employee; Novo Nordisk. M.G.Myers: Advisory Panel; Regeneron Pharmaceuticals Inc., Research Support; AstraZeneca, Novo Nordisk. Funding National Institutes of Health (F32DK122660)