Hormonal Gut-Brain Signaling for the Treatment of Obesity

Abstract

The brain, particularly the hypothalamus and brainstem, monitors and integrates circulating metabolic signals, including gut hormones. Gut-brain communication is also mediated by the vagus nerve, which transmits various gut-derived signals. Recent advances in our understanding of molecular gut-brain communication promote the development of next-generation anti-obesity medications that can safely achieve substantial and lasting weight loss comparable to metabolic surgery. Herein, we comprehensively review the current knowledge about the central regulation of energy homeostasis, gut hormones involved in the regulation of food intake, and clinical data on how these hormones have been applied to the development of anti-obesity drugs. Insight into and understanding of the gut-brain axis may provide new therapeutic perspectives for the treatment of obesity and diabetes.

Keywords: anti-obesity agents; brainstem; energy metabolism; gut hormones; hypothalamus.

Figure 1

Gut–brain regulation of food intake. Various peripheral hormones, including gut hormones, regulate food intake by acting on integrated neural circuits in the hypothalamus and brainstem. The hypothalamic melanocortin system is a central hub for the regulation of homeostatic food intake, including appetite-inducing neurons that co-express neuropeptide Y (NPY) and agouti-related peptides (AgRP), and anorexic neurons that express pro-opiomelanocortin (POMC). Gut–brain communication is mediated through vagus nerve afferents that project to the nucleus tractus solitarius in the hindbrain, or via the circulation reaching the median eminence of the hypothalamus and area postrema of the brainstem. ARC, arcuate nucleus; CCK, cholecystokinin; FGF21, fibroblast growth factor 21; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; MC4R, melanocortin 4 receptor; OXM, oxyntomodulin; PVN, paraventricular nucleus; PYY, peptide tyrosine tyrosine.

Figure 2

Metabolic action of GLP-1 and GIP on different tissues. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) share a function as incretins and have different pancreatic and extrapancreatic functions. GIP acts directly on the endocrine pancreas, brain and white adipose tissues, while GLP-1 acts directly on the endocrine pancreas, brain, and gastrointestinal tract. Up arrow (↑) symbol indicates increase, whereas down (↓) arrow symbol indicates decrease in the effect mentioned.