title: 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-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 glucagon-PKA inhibits AMPK, elevates LCFA-CoA levels to activate PKC-δ, and activates KATP channels to lower GP. We here report that neither molecular or chemical activation of MBH AMPK nor inhibition of PKC-δ 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.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Abraham
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Jessica T Y
authors.initials: JT
authors.lastname: Yue
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Mary P
authors.initials: MP
authors.lastname: LaPierre
authors.affiliation: Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College of London, South Kensington, London, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Filippi
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Physiology, University of Toronto, Toronto, Canada ; Departments of Medicine, University of Toronto, Toronto, Canada ; Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada.
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
keywords: Glucagon; Glucose production; Hypothalamus; KATP channels