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Publication
Control of physiologic glucose homeostasis via hypothalamic modulation of
gluconeogenic substrate availability.
Authors Su J, Hashsham A, Kodur N, Burton C, Mancuso A, Singer A, Wloszek J, Tomlinson
AJ, Yacawych WT, Flak JN, Lewis KT, Oles LR, Mori H, Bozadjieva-Kramer N, Turcu
AF, MacDougald OA, Myers MG, Affinati AH
Submitted By Alison Affinati on 10/15/2024
Status Published
Journal Molecular metabolism
Year 2025
Date Published 9/1/2025
Volume : Pages 99 : 102216
PubMed Reference 40684983
Abstract The brain mobilizes glucose in emergency situations such as hypoglycemia as well
as during day-to-day physiology such as fasting. While most hypothalamic
neuronal populations that contribute to glucose mobilization also contribute to
other aspects of metabolism, neurons in the ventromedial nucleus of the
hypothalamus that express the cholecystokinin b receptor (VMHCckbr neurons)
support glucose production during hypoglycemia without controlling energy
homeostasis. However, their role in day-to-day glucose physiology and the
mechanisms they engage to support glucose mobilization is unclear., We used
continuous glucose monitoring in mice with chronically silenced VMHCckbr neurons
to establish whether these neurons are required during day-to-day glucose
homeostasis. Tetanus-toxin based chronic silencing and acute optogenetic
activation were followed by analysis of hepatic glucose metabolism and white
adipose tissue lipolysis., We found that VMHCckbr neurons support glucose
homeostasis during short fasts and contribute to gluconeogenic substrate
mobilization and lipolysis. VMHCckbr neurons mobilize glucose without depleting
hepatic glycogen or increasing gluconeogenic gene expression, but instead
mobilize glycerol in a ß3-adrenergic receptor (ß3-AR)-dependent manner.
Restoring glycerol availability following VMHCckbr neuron silencing restores
glucose. Finally, acute activation of VMHCckbr neurons mobilizes additional
gluconeogenic substrates beyond glycerol., VMHCckbr neurons represent a distinct
subset of glucose-mobilizing VMH neurons that support physiologic glucose
homeostasis, likely through control of ß3-AR-mediated gluconeogenic substrate
mobilization and lipolysis. The presence of different glucose-mobilizing
neuronal populations that engage distinct mechanisms in a context-dependent
manner may provide the brain with flexibility to coordinate the appropriate
glycemic response to different circumstances.




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