GLP-1 physiology informs the pharmacotherapy of obesity

Highlights

• Brainstem-derived but not gut-derived GLP-1 contributed to the regulation of food intake.

• GLP-1 actions reduce food intake through a single G protein-coupled receptor (GPCR).

• GLP-1 receptors coupled to food intake are widely distributed in the central nervous system.

• GLP-1-based co-agonists and their combinations may transform the therapy of obesity.

Abstract

Background

Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity.

Scope of review

Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted.

Major conclusions

The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.