O’Keefe, Lannie, Simcocks, Anna C, Jenkin, Kayte, Monazzami, Amirabbas, Chandrasiri, Shavin, Mathai, Michael ORCID: https://orcid.org/0000-0001-8783-2122, Hryciw, Deanne H ORCID: https://orcid.org/0000-0003-1697-8890 and McAinch, Andrew ORCID: https://orcid.org/0000-0002-8762-4865 (2026) CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats. Obesity Research and Clinical Practice. ISSN 1871-403X

Abstract

Aims: Diet-induced obesity (DIO) results in alterations in skeletal muscle metabolism that affects oxidative capacity and adiponectin signaling. In obesity, agonism of the cannabinoid receptor 2 (CNR2) has been shown to reduce body weight and increase energy expenditure but the effect on skeletal muscle metabolism is unknown. We aimed to investigate the effects of a CNR2 inverse agonist, AM630 and a CNR2 agonist, AM1241, on skeletal muscle. Methods: Male Sprague Dawley rats (n = 30) were fed a high fat diet (HFD) (21% fat) for 9 weeks, then received daily intraperitoneal injections with vehicle (n = 10), AM630 (0.3 mg/kg, n = 10) or AM1241 (3 mg/kg, n = 10) for another six weeks. Skeletal muscle, citrate synthase (CS) activity, mRNA and protein expression of markers of the fatty acid oxidative pathways with and without acute ex vivo adiponectin (0.1 mg/ml) treatment were measured. Results: AM630 increased CS enzyme activity in the red gastrocnemius. In addition, in soleus AM630 increased the ratio of 4EBP1 phosphorylated to total protein, reduced AMPKα phosphorylated to total protein and reduced PDK4 mRNA. In soleus, AM1241 activated 4EBP1 and reduced PDK4 mRNA. While, in the EDL both AM630 and AM1241 reduced PGCl-α and AM1241 increased AdipoR1 mRNA. Interestingly, in the EDL, acute ex vivo adiponectin exposure reduced 4EBP1 phosphorylated to total protein in control animals, however increased PGCl-α in AM630 treated animals. Conclusions: Targeting CNR2 in obesity alters mitochondrial content in the skeletal muscle of rodents, yet the relationship appears to be complex and further exploration is required.

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