2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism

Kwang-Mook Jung, Jason R. Clapper, Jin Fu, Giuseppe D'Agostino, Ana Guijarro, Dean Thongkham, Agnesa Avanesian, Giuseppe Astarita, Nicholas V. DiPatrizio, Andrea Frontini, Saverio Cinti, Sabrina Diano, Daniele Piomelli

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84 Citations (Scopus)


The endocannabinoid system plays a critical role in the control of energy homeostasis, but the identity and localization of the endocannabinoid signal involved remain unknown. In the present study, we developed transgenic mice that overexpress in forebrain neurons the presynaptic hydrolase, monoacylglycerol lipase (MGL), which deactivates the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). MGL-overexpressing mice show a 50% decrease in forebrain 2-AG levels but no overt compensation in other endocannabinoid components. This biochemical abnormality is accompanied by a series of metabolic changes that include leanness, elevated energy cost of activity, and hypersensitivity to β(3)-adrenergic-stimulated thermogenesis, which is corrected by reinstating 2-AG activity at CB(1)-cannabinoid receptors. Additionally, the mutant mice are resistant to diet-induced obesity and express high levels of thermogenic proteins, such as uncoupling protein 1, in their brown adipose tissue. The results suggest that 2-AG signaling through CB(1) regulates the activity of forebrain neural circuits involved in the control of energy dissipation.
Original languageEnglish
Pages (from-to)299-310
Number of pages12
JournalCell Metabolism
Issue number3
Publication statusPublished - 7 Mar 2012

Bibliographical note

Copyright © 2012 Elsevier Inc. All rights reserved.


  • animals
  • arachidonic acids
  • endocannabinoids
  • energy metabolism
  • glycerides
  • hypothalamus
  • immunohistochemistry
  • mice
  • mice, transgenic
  • monoacylglycerol lipases
  • nerve tissue proteins
  • prosencephalon
  • signal transduction


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