Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

Ibrahim Knani, Brian J. Earley, Shiran Udi, Alina Nemirovski, Rivka Hadar, Asaad Gammal, Resat Cinar, Harry J. Hirsch, Yehuda Pollak, Itai Gross, Talia Eldar-Geva, Daniela P. Reyes-Capo, Joan Han, Andrea M. Haqq, Varda Gross-Tsur, Rachel Wevrick, Joseph Tam

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objective Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Original languageEnglish (US)
Pages (from-to)1187-1199
Number of pages13
JournalMolecular Metabolism
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2016

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Cannabinoid Receptor CB1
Endocannabinoids
Obesity
Cannabinoid Receptor Antagonists
Cannabinoid Receptors
Hyperphagia
rimonabant
Energy Metabolism
Body Weight
Phenotype
Morbid Obesity
Arachidonic Acid
Weight Loss
Fats
Ligands
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Knani, I., Earley, B. J., Udi, S., Nemirovski, A., Hadar, R., Gammal, A., ... Tam, J. (2016). Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome. Molecular Metabolism, 5(12), 1187-1199. https://doi.org/10.1016/j.molmet.2016.10.004

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome. / Knani, Ibrahim; Earley, Brian J.; Udi, Shiran; Nemirovski, Alina; Hadar, Rivka; Gammal, Asaad; Cinar, Resat; Hirsch, Harry J.; Pollak, Yehuda; Gross, Itai; Eldar-Geva, Talia; Reyes-Capo, Daniela P.; Han, Joan; Haqq, Andrea M.; Gross-Tsur, Varda; Wevrick, Rachel; Tam, Joseph.

In: Molecular Metabolism, Vol. 5, No. 12, 01.12.2016, p. 1187-1199.

Research output: Contribution to journalArticle

Knani, I, Earley, BJ, Udi, S, Nemirovski, A, Hadar, R, Gammal, A, Cinar, R, Hirsch, HJ, Pollak, Y, Gross, I, Eldar-Geva, T, Reyes-Capo, DP, Han, J, Haqq, AM, Gross-Tsur, V, Wevrick, R & Tam, J 2016, 'Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome', Molecular Metabolism, vol. 5, no. 12, pp. 1187-1199. https://doi.org/10.1016/j.molmet.2016.10.004
Knani, Ibrahim ; Earley, Brian J. ; Udi, Shiran ; Nemirovski, Alina ; Hadar, Rivka ; Gammal, Asaad ; Cinar, Resat ; Hirsch, Harry J. ; Pollak, Yehuda ; Gross, Itai ; Eldar-Geva, Talia ; Reyes-Capo, Daniela P. ; Han, Joan ; Haqq, Andrea M. ; Gross-Tsur, Varda ; Wevrick, Rachel ; Tam, Joseph. / Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome. In: Molecular Metabolism. 2016 ; Vol. 5, No. 12. pp. 1187-1199.
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AU - Knani, Ibrahim

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AU - Hadar, Rivka

AU - Gammal, Asaad

AU - Cinar, Resat

AU - Hirsch, Harry J.

AU - Pollak, Yehuda

AU - Gross, Itai

AU - Eldar-Geva, Talia

AU - Reyes-Capo, Daniela P.

AU - Han, Joan

AU - Haqq, Andrea M.

AU - Gross-Tsur, Varda

AU - Wevrick, Rachel

AU - Tam, Joseph

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N2 - Objective Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

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