Elsevier

Molecular Metabolism

Volume 3, Issue 7, October 2014, Pages 705-716
Molecular Metabolism

Original article
CB1 cannabinoid receptor in SF1-expressing neurons of the ventromedial hypothalamus determines metabolic responses to diet and leptin

https://doi.org/10.1016/j.molmet.2014.07.004Get rights and content
Under a Creative Commons license
open access

Abstract

Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change.

Keywords

CB1 receptor
Endocannabinoid
Ventromedial nucleus
Hypothalamus
Obesity
Leptin

Abbreviations

CB1
cannabinoid type-1
FDG
fluorodeoxyglucose
FISH
fluorescent in situ hybridization
PET
positron emission tomography
SF1
steroidogenic factor 1
vGlut2
vesicular transporter of glutamate 2 receptor
VMN
ventromedial nucleus

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Present address: Department of Biochemistry and Molecular Biology I and CIBERNED, School of Biology, Complutense University-IUIN, 28040 Madrid, Spain.