Fig. 2: Mechanisms of small intestinal nutrient sensing.

a Mechanisms of small intestinal lipid sensing. Small intestinal long-chain fatty acids are taken up (via CD36/FATP4 and/or simple diffusion) by enterocytes to form triglycerides and eventually packaged into chylomicrons released on the basolateral side. LCFA are also taken up by enteroendocrine cells to undergo ACSL3-dependent metabolism and activate PKCs to potentially stimulate CCK and/or GLP-1 release. Luminal LCFA may activate GPR40/120 to stimulate peptide release. The hydrolysis of chylomicrons by nearby enterocytes on the basolateral membrane may lead to increased LCFAs that can activate basolateral GPR40 to induce peptide release. In the setting of a high-fat diet or obesity, GPRs/ACSL3 expression, the release of GLP-1/CCK, and CCK signaling are reduced, leading to a disruption of fatty acid sensing. b Mechanisms of small intestinal carbohydrate sensing. Luminal glucose and fructose are transported into upper small intestinal enterocytes and/or enteroendocrine cells via SGLT1 and GLUT5, respectively. Through SGLT1, glucose directly and/or indirectly (via cellular metabolism) stimulates the release of gut peptides and regulates feeding and systemic glucose control in the upper small intestine. However, ileal glucose sensing may stimulate the release of GLP-1 independent of SGLT1. In response to high-fat feeding or obesity, small intestinal SGLT1 expression is reduced, leading to an impairment of glucose sensing, GLP-1 secretion, and glucose control. c Mechanisms of small intestinal protein sensing. Luminal small oligopeptides and amino acids are taken up by PepT1 and amino acid transporters, respectively, into the enterocyte and enteroendocrine cells. Small intestinal protein sensing stimulates the release of CCK and GLP-1 and regulates feeding and glucose homeostasis potentially via PepT1 dependent mechanisms. In addition, amino acids stimulate peptide release via the membrane-bound calcium-sensing receptor, the umami taste receptor, and G-protein-coupled receptor 6A. However, the downstream mechanism mediating the peptide release remains elusive. In parallel, amino acids are also transported to the basolateral side, and studies implicated that they may activate the calcium-sensing receptor to stimulate GLP-1 secretion.