GLP-1 and the Neurobiology of Eating Control: Recent Advances

Abstract

Obesity is now considered a chronic relapsing progressive disease, associated with increased all-cause mortality that scales with body weight, affecting more than 1 billion people worldwide. Excess body fat is strongly associated with excess energy intake, and most successful anti-obesity medications (AOMs) counter this positive energy balance through the suppression of eating to drive weight loss. Historically, AOMs have been characterized by modest weight loss and side effects which are compliance-limiting, and in some cases life-threatening. However, the field of obesity pharmacotherapy has now entered a new era of AOMs based on analogues of the gut hormone and neuropeptide glucagon-like peptide-1 (GLP-1). The latest versions of these drugs elicit unprecedented levels of weight loss in clinical trials, which are now starting to be substantiated in real-world usage. Notably, these drugs reduce weight primarily by reducing energy intake, via activation of the GLP-1 receptor on multiple sites of action primarily in the central nervous system, although the most relevant sites of action, and the neural circuits recruited remain contentious. Here we provide a targeted synthesis of recent developments in the field of GLP-1 neurobiology, highlighting studies which have advanced our understanding of how GLP-1 signaling modulates eating, and identify open questions and future challenges we believe still need to be addressed to aid the prevention and/or treatment of obesity.

Keywords: GLP-1; eating; feeding; glucagon-like peptide-1; liraglutide; obesity; semaglutide.

Figure 1.

Gut-brain pathways and sites of action of endogenous and exogenous GLP-1 signaling. A, Schematic overview of the neuronal and hormonal/pharmacological pathways by which endogenous GLP-1 and GLP-1-based AOMs convey anorectic signals to the brain. Under physiological conditions, proximal L-cells in the upper small intestine release GLP-1 in response to ingested nutrients, signaling via paracrine and endocrine routes (blue) to act on GLP-1 receptors on chemosensory vagal afferent in intestinal villi and the hepatic portal vein (HPV), and on gut-innervating mechanosensory vagal afferents. Under supraphysiological conditions, for example, after exceptionally large and/or nutrient-dense meals, GLP-1 from L-cells may also reach sufficiently high systemic concentrations to act directly on the brain, via neuronal GLP-1 receptors in circumventricular organs such as the area postrema. Undigested nutrients reaching the ileum can trigger GLP-1 release from distal L-cells to trigger the multisynaptic gut-brain circuit (orange) comprising the ileal brake. Peripherally administered GLP-1-based AOMs reach steady-state systemic concentrations orders of magnitude higher than endogenous GLP-1, reaching and acting primarily on circumventricular organs in the CNS (magenta). AOMs also presumably bind all peripheral sites of action of endogenous GLP-1, but these pathways may be dispensable for AOM effects on eating and body weight. B, Recent mechanistic studies, primarily conducted in rodents, have identified a number of sites of direct action putatively mediating the effects of GLP-1-based AOMs on eating and body weight, including the area postrema and nucleus tractus solitarius (47‐49), locus coeruleus (50), hypothalamic arcuate (51, 52) and dorsomedial nuclei (53), and the lateral septal nucleus (54). (Created in BioRender. Brierley, D. (2024) BioRender.com/d09h242).