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GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues.

Lipina, Christopher; Walsh, Sarah K.; Mitchell, Sharon E.; Speakman, John R.; Wainwright, Cherry L.; Hundal, Harinder S.


Christopher Lipina

Sharon E. Mitchell

John R. Speakman

Harinder S. Hundal


Emerging evidence indicates that G-protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L-α-lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function and energy metabolism. We examined how GPR55 deficiency and modulation affects insulin signaling in skeletal muscle, adipose tissue, and liver alongside expression analysis of proteins implicated in insulin action and energy metabolism. We show that GPR55-null mice display decreased insulin sensitivity in these tissues, as evidenced by reduced phosphorylation of PKB/Akt and its downstream targets, concomitant with increased adiposity and reduced physical activity relative to wild-type counterparts. Impaired tissue insulin sensitivity coincided with reduced insulin receptor substrate-1 abundance in skeletal muscle, whereas in liver and epididymal fat it was associated with increased expression of the 3-phosphoinoistide lipid phosphatase, phosphatase and tensin homolog. In contrast, GPR55 activation enhanced insulin signaling in cultured skeletal muscle cells, adipocytes, and hepatocytes; this response was negated by receptor antagonists and GPR55 gene silencing in L6 myotubes. Sustained GPR55 antagonism in 3T3-L1 adipocytes enhanced expression of proteins implicated in lipogenesis and promoted triglyceride accumulation. Our findings identify GPR55 as a positive regulator of insulin action and adipogenesis and as a potential therapeutic target for countering obesity-induced metabolic dysfunction and insulin resistance.


LIPINA, C., WALSH, S.K., MITCHELL, S.E., SPEAKMAN, J.R., WAINWRIGHT, C.L. and HUNDAL, H.S. 2019. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues. FASEB journal [online], 33(1), pages 1299-1312. Available from:

Journal Article Type Article
Acceptance Date Jul 26, 2018
Online Publication Date Aug 27, 2018
Publication Date Jan 1, 2019
Deposit Date Sep 25, 2018
Publicly Available Date Sep 25, 2018
Journal FASEB journal
Print ISSN 0892-6638
Electronic ISSN 1530-6860
Publisher Federation of American Society of Experimental Biology
Peer Reviewed Peer Reviewed
Volume 33
Issue 1
Pages 1299-1312
Keywords Endocannabinoid; Cannabinoid receptor; Skeletal muscle; Liver; Adipogenesis
Public URL


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