CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats

Lannie O’Keefe; Anna C. Simcocks; Kayte A. Jenkin; Amirabbas Monazzami; Shavin Chandrasiri; Michael L. Mathai; Deanne H. Hryciw; Andrew J. McAinch

doi:10.1016/j.orcp.2026.09.005

Back

CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats

Journal article

Open access

Peer reviewed

CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats

Lannie O’Keefe, Anna C. Simcocks, Kayte A. Jenkin, Amirabbas Monazzami, Shavin Chandrasiri, Michael L. Mathai, Deanne H. Hryciw and Andrew J. McAinch

Obesity Research & Clinical Practice, Vol.Advanced access

26-Sep-2026

DOI: https://doi.org/10.1016/j.orcp.2026.09.005

PMID: 42800728

Files and links (1)

pdf

CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats1.85 MBDownload View

Published Version (Advanced Access) Open Access CC BY V4.0

Abstract

AM1241

AM630

Cannabinoid receptor 2 (CNR2)

Diet-induced obesity (DIO)

Endocannabinoid system (ECS)

Skeletal muscle

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.

Details

Title: CNR2 inverse-agonist AM630 increases citrate synthase activity in the skeletal muscle of diet induced obese rats
Authors: Lannie O’Keefe - Victoria University
Anna C. Simcocks - Victoria University
Kayte A. Jenkin - Victoria University
Amirabbas Monazzami - Victoria University
Shavin Chandrasiri - Victoria University
Michael L. Mathai - Florey Institute of Neuroscience and Mental Health
Deanne H. Hryciw - University of the Sunshine Coast
Andrew J. McAinch (Corresponding Author) - Australian Institute for Musculoskeletal Science
Publication details: Obesity Research & Clinical Practice, Vol.Advanced access
Publisher: Elsevier BV
DOI: 10.1016/j.orcp.2026.09.005
ISSN: 1878-0318
PMID: 42800728
Copyright note: © 2026 The Author(s). Published by Elsevier Ltd on behalf of Asia Oceania Association for the Study of Obesity. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ).
Data Availability: The data presented in this study are available on request from the corresponding author.
Grant note: This work was funded by the Allen Foundation grant number 2011.385 and A.C.S. was supported by the Australian Rotary Health Scholarship.
Organisation Unit: School of Health - Biomedicine
Language: English
Record Identifier: 991266096202621
Output Type: Journal article

Metrics

1 Record Views