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

Research output: Contribution to journalArticle

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Abstract

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
Volume15
Issue number3
DOIs
Publication statusPublished - 7 Mar 2012

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Endocannabinoids
Prosencephalon
Energy Metabolism
Monoacylglycerol Lipases
Cannabinoid Receptors
Brown Adipose Tissue
Thinness
Thermogenesis
Hydrolases
Compensation and Redress
Adrenergic Agents
Transgenic Mice
Hypersensitivity
Homeostasis
Obesity
Diet
Neurons
Costs and Cost Analysis
2-arachidonylglycerol
Proteins

Keywords

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

Cite this

Jung, K-M., Clapper, J. R., Fu, J., D'Agostino, G., Guijarro, A., Thongkham, D., ... Piomelli, D. (2012). 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metabolism, 15(3), 299-310. https://doi.org/10.1016/j.cmet.2012.01.021

2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. / Jung, Kwang-Mook; Clapper, Jason R.; Fu, Jin; D'Agostino, Giuseppe; Guijarro, Ana; Thongkham, Dean; Avanesian, Agnesa; Astarita, Giuseppe; DiPatrizio, Nicholas V.; Frontini, Andrea; Cinti, Saverio; Diano, Sabrina; Piomelli, Daniele.

In: Cell Metabolism, Vol. 15, No. 3, 07.03.2012, p. 299-310.

Research output: Contribution to journalArticle

Jung, K-M, Clapper, JR, Fu, J, D'Agostino, G, Guijarro, A, Thongkham, D, Avanesian, A, Astarita, G, DiPatrizio, NV, Frontini, A, Cinti, S, Diano, S & Piomelli, D 2012, '2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism' Cell Metabolism, vol. 15, no. 3, pp. 299-310. https://doi.org/10.1016/j.cmet.2012.01.021
Jung K-M, Clapper JR, Fu J, D'Agostino G, Guijarro A, Thongkham D et al. 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metabolism. 2012 Mar 7;15(3):299-310. https://doi.org/10.1016/j.cmet.2012.01.021
Jung, Kwang-Mook ; Clapper, Jason R. ; Fu, Jin ; D'Agostino, Giuseppe ; Guijarro, Ana ; Thongkham, Dean ; Avanesian, Agnesa ; Astarita, Giuseppe ; DiPatrizio, Nicholas V. ; Frontini, Andrea ; Cinti, Saverio ; Diano, Sabrina ; Piomelli, Daniele. / 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. In: Cell Metabolism. 2012 ; Vol. 15, No. 3. pp. 299-310.
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AU - Thongkham, Dean

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AU - Cinti, Saverio

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N2 - 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.

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