Lipid sensing and brain hormone receptors in food intake and glucose regulation.

The body possesses critical nutrient sensors that rapidly coordinate feeding behaviour and systemic metabolism through hormones and neural pathways. In this Review, we highlight the mechanisms by which lipid sensing triggers the release of small intestinal-derived cholecystokinin, peptide YY, glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, as well as kidney-derived growth differentiation factor 15, to regulate satiety and glucose homeostasis through the brain. We discuss how dysregulation of lipid sensing pathways contributes to obesity and type 2 diabetes mellitus, and how interventions including bariatric surgery, modulation of the gut microbiota and pharmacological agonists restore polyhormonal secretion and action on metabolism. We propose that lipid sensing in the small intestine and the kidney orchestrates an endocrine and neural axis that governs energy balance, providing a lipid-sensing-dependent framework for the development of next-generation therapies in obesity and metabolic disease to remotely and concurrently target multiple brain hormone receptors to lower food intake and body weight.