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Hypothalamic glucagon signals through the KATP channels to regulate glucose production.

ABSTRACT: Insulin, leptin and GLP-1 signal in the mediobasal hypothalamus (MBH) to lower hepatic glucose production (GP). MBH glucagon action also inhibits GP but the downstream signaling mediators remain largely unknown. In parallel, a lipid-sensing pathway involving MBH AMPK?malonyl-CoA?CPT-1?LCFA-CoA?PKC-? leading to the activation of KATP channels lowers GP. Given that glucagon signals through the MBH PKA to lower GP, and PKA inhibits AMPK in hypothalamic cell lines, a possibility arises that MBH glucagon-PKA inhibits AMPK, elevates LCFA-CoA levels to activate PKC-?, and activates KATP channels to lower GP. We here report that neither molecular or chemical activation of MBH AMPK nor inhibition of PKC-? negated the effect of MBH glucagon. In contrast, molecular and chemical inhibition of MBH KATP channels negated MBH glucagon's effect to lower GP. Thus, MBH glucagon signals through a lipid-sensing independent but KATP channel-dependent pathway to regulate GP.

SUBMITTER: Abraham MA

PROVIDER: S-EPMC3953686 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Hypothalamic glucagon signals through the KATP channels to regulate glucose production.

Abraham Mona A MA Yue Jessica T Y JT LaPierre Mary P MP Rutter Guy A GA Light Peter E PE Filippi Beatrice M BM Lam Tony K T TK

Molecular metabolism 20131128 2

Insulin, leptin and GLP-1 signal in the mediobasal hypothalamus (MBH) to lower hepatic glucose production (GP). MBH glucagon action also inhibits GP but the downstream signaling mediators remain largely unknown. In parallel, a lipid-sensing pathway involving MBH AMPK→malonyl-CoA→CPT-1→LCFA-CoA→PKC-δ leading to the activation of KATP channels lowers GP. Given that glucagon signals through the MBH PKA to lower GP, and PKA inhibits AMPK in hypothalamic cell lines, a possibility arises that MBH gluc ...[more]

PMID: 24634823

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Project description:ObjectiveHypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production.Research design and methodsWe implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK ?2 [D¹??A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo.ResultsMBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production.ConclusionsMolecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.

Dataset Information

Hypothalamic glucagon signals through the KATP channels to regulate glucose production.

Publications

Hypothalamic glucagon signals through the KATP channels to regulate glucose production.

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