• Areesha Moiz, Kristian B Filion, Michael A Tsoukas, Oriana Hy Yu, Tricia M Peters, and Mark J Eisenberg.
• Centre of Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada; Division of Experimental Medicine, McGill University, Montreal, Canada.
• Am. J. Med. 2025 Jan 30.

AbstractGlucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become central in managing obesity and type 2 diabetes, primarily through appetite suppression and metabolic regulation. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. Centrally, GLP-1 RAs modulate brain regions controlling appetite, influencing neurotransmitter and peptide release to regulate hunger and energy expenditure. Peripherally, GLP-1 RAs improve glycemic control by enhancing insulin secretion, reducing glucagon release, delaying gastric emptying, and regulating gut hormones. They also reduce triglycerides and low-density lipoprotein cholesterol, mitigate adipose tissue inflammation, and minimize ectopic fat deposition, promoting overall metabolic health. Emerging dual and triple co-agonists, targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide, and glucagon pathways, may enhance weight loss and metabolic flexibility. Understanding these mechanisms is crucial as the therapeutic landscape evolves, offering clinicians and researchers insights to optimize the efficacy of current and future obesity treatments.Copyright © 2025. Published by Elsevier Inc.

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