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. 2025 Feb 7;15(2):253.
doi: 10.3390/life15020253.

A Hypothesis That Glucagon-like Peptide-1 Receptor Agonists Exert Immediate and Multifaceted Effects by Activating Adenosine Monophosphate-Activate Protein Kinase (AMPK)

C Mary Schooling  1   2 , Guoyi Yang  1 , Ghada A Soliman  2 , Gabriel M Leung  1
Affiliations

A Hypothesis That Glucagon-like Peptide-1 Receptor Agonists Exert Immediate and Multifaceted Effects by Activating Adenosine Monophosphate-Activate Protein Kinase (AMPK)

C Mary Schooling et al. Life (Basel). .

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce bodyweight and blood glucose. Extensive evidence from randomized controlled trials has indicated that GLP-1RAs have benefits well beyond weight loss and glucose control, extending from reductions in cardiovascular mortality to reductions in prostate cancer risk. Notably, some benefits of GLP-1RAs for the cardiovascular-kidney-metabolic (CKM) system arise before weight loss occurs for reasons that are not entirely clear but are key to patient care and drug development. Here, we hypothesize that GLP-1RAs act by inducing calorie restriction and by activating adenosine monophosphate-activated protein kinase (AMPK), which not only provides an explanation for the unique effectiveness of GLP-1RAs but also indicates a common mechanism shared by effective CKM therapies, including salicylates, metformin, statins, healthy diet, and physical activity. Whether AMPK activation is obligatory for effective CKM therapies should be considered. As such, we propose a mechanism of action for GLP-1RAs and explain how it provides an overarching framework for identifying means of preventing and treating cardiovascular, kidney, metabolic and related diseases, as well as informing the complementary question as to the components of a healthy lifestyle.

Keywords: AMPK; calorie restriction; non-communicable diseases; semaglutide; unifying theory.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hypothesized relations of GLP1-RAs with calorie restriction and AMPK (dotted arrows) and their established relations with cardiovascular–kidney–metabolic health and related diseases, and their major risk factors, along with other effective means of preventing or treating cardiovascular–kidney–metabolic and other diseases likely also operating via AMPK (solid arrows). Abbreviations: GLP-1RA: glucagon-like peptide-1 receptor agonist and AMPK: adenosine monophosphate-activated protein kinase.
See this image and copyright information in PMC

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