Incretin‐Based Therapies: A Testable Hypothesis Linking Incretin Signaling, Mitochondrial Redox, and OXPHOS Efficiency

ABSTRACT Objective Incretin‐based obesity therapies (IBTs), especially GLP‐1 receptor agonists (GLP‐1 RAs), effectively treat obesity and improve comorbidities. However, their impact on energy metabolism is unclear. A recent case of acute generalized muscle weakness in a patient with mitochondrial myopathy after tirzepatide exposure raises concerns about IBTs' potential to uncouple oxidative phosphorylation (OXPHOS). Given the widespread use of IBTs, this inquiry is crucial due to potential adverse effects. Methods A narrative literature review of evidence linking incretins and IBTs to mitochondrial physiology, bioenergetics, and OXPHOS was conducted. Results Early research on incretin physiology focused on insulin secretion in pancreatic β‐cells. However, GLP‐1 counteracts insulin signaling during excessive nutrient delivery by activating anti‐inflammatory pathways associated with fasting, suggesting it mitigates the adverse effects of overfeeding. Preclinical studies show that IBTs activate thermogenic genes and uncoupling proteins. Conclusions We have identified indirect evidence suggesting that IBTs may induce OXPHOS uncoupling. We propose a testable hypothesis that establishes a close relationship between the distinct effects of IBTs on weight loss and their direct reduction of oxidative stress. Should this hypothesis be validated, it would enhance our comprehension of the physiology underlying IBTs and the potential adverse effects on muscle.