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Published VersionCC BY V4.0, Open Access
Journal article
CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity
International Journal of Molecular Sciences, Vol.23(19), pp.1-16
2022
PMID: 36232744
Abstract
Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a "browning" of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.
Details
- Title
- CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity
- Authors
- Lannie O'Keefe - Victoria UniversityTeresa Vu - Monash UniversityAnna C. Simcocks - Victoria UniversityKayte A. Jenkin - Victoria UniversityMichael L. Mathai - Florey Institute of Neuroscience and Mental HealthDeanne H. Hryciw - Griffith UniversityDana S. Hutchinson (Corresponding Author) - Monash UniversityAndrew J. McAinch (Corresponding Author) - Australian Institute for Musculoskeletal Science
- Publication details
- International Journal of Molecular Sciences, Vol.23(19), pp.1-16
- Publisher
- MDPI AG
- Date published
- 2022
- DOI
- 10.3390/ijms231911447
- ISSN
- 1422-0067; 1661-6596
- PMID
- 36232744
- Copyright note
- © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://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 research 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
- 991186524602621
- Output Type
- Journal article
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