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

Christopher Lipina, Sarah K. Walsh, Sharon E. Mitchell, John R. Speakman, Cherry L. Wainwright, Harinder Hundal (Lead / Corresponding author)

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Abstract

Emerging evidence indicates that G-protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L-a-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 enhancedinsulin signalingin cultured skeletalmuscle cells, adipocytes, andhepatocytes;this response was negated by receptor antagonists and GPR55 gene silencingin L6myotubes. 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.

Original languageEnglish
Pages (from-to)1299-1312
Number of pages14
JournalFASEB Journal
Volume33
Issue number1
Early online date27 Aug 2018
DOIs
Publication statusPublished - Jan 2019

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Adiposity
G-Protein-Coupled Receptors
Insulin
Tissue
Insulin Resistance
Phosphoric Monoester Hydrolases
Adipocytes
Liver
Energy Metabolism
Muscle
Skeletal Muscle
Insulin Receptor Substrate Proteins
Adipogenesis
Endocannabinoids
Lipogenesis
Phosphorylation
Cannabinoids
Adipose Tissue
Cultured Cells
Triglycerides

Keywords

  • Adipogenesis
  • Cannabinoid receptor
  • Endocannabinoid
  • Liver
  • Skeletal muscle

Cite this

Lipina, Christopher ; Walsh, Sarah K. ; Mitchell, Sharon E. ; Speakman, John R. ; Wainwright, Cherry L. ; Hundal, Harinder. / GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues. In: FASEB Journal. 2019 ; Vol. 33, No. 1. pp. 1299-1312.
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abstract = "Emerging evidence indicates that G-protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L-a-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 enhancedinsulin signalingin cultured skeletalmuscle cells, adipocytes, andhepatocytes;this response was negated by receptor antagonists and GPR55 gene silencingin L6myotubes. 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.",
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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 (Lead / Corresponding author).

In: FASEB Journal, Vol. 33, No. 1, 01.2019, p. 1299-1312.

Research output: Contribution to journalArticle

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T1 - GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues

AU - Lipina, Christopher

AU - Walsh, Sarah K.

AU - Mitchell, Sharon E.

AU - Speakman, John R.

AU - Wainwright, Cherry L.

AU - Hundal, Harinder

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