Improving incretin-mediated body weight loss via energy expenditure

Incretin-based therapies have transformed obesity and type 2 diabetes treatment. While current therapeutics safely reduce food intake and lower body weight, a compensatory drop-in basal metabolic rate represents a barrier to sustainable weight loss. Current efforts aim to incorporate energy expenditure (EE) stimulation with the anorectic actions currently available in the clinic. Glucagon receptor agonism, for instance, has demonstrated the benefit of a multipronged increase in EE; however, compensatory challenges persist. We detail peripheral mechanisms that can increase EE independent of activity and the key central mechanisms controlling them. Understanding the complex interplay between these mechanisms and their central modulation is critical for a coordinated engagement of EE pathways to complement and improve current weight loss treatments.