2512-P: Metformin Restores Upper Small Intestinal Protein Sensing via a PepT1-GLP-1–Dependent Pathway to Reduce Food Intake

Introduction and Objective: Upper small intestinal (USI) nutrient sensing regulates feeding but is disrupted by high-fat (HF) feeding-induced hyperphagia. Metformin has recently been documented to enhance USI lipid sensing to reduce feeding by selectively increasing GIP secretion, rather than PYY or GLP-1, in HF rats. In parallel, USI protein sensing activates peptide transporter 1 (PepT1) to stimulate GLP-1 release and suppresses feeding, but both responses are blunted by HF feeding. Here, we tested whether metformin rescues the anorexic effect of USI protein sensing in HF-fed rats. Methods: We conducted fasting-refeeding experiments and measured plasma active GLP-1, total PYY, and total GIP 5 min after USI infusion of casein hydrolysate (8% w/v) in chow- and HF-fed male rats. Results: Casein failed to suppress feeding in HF rats and was associated with a blunted GLP-1 response, but not PYY or GIP (FI (kcal): HF-cas vs HF-sal: 51±2 vs 46 ±2, n=10; active GLP-1 (pg/ml): HF-cas vs Chow-cas: 0.8±0.1 vs 1.4±0.1, n=7, p<0.01). Importantly, USI metformin (50 mg/kg, per se does not affect FI or gut hormone levels) administered one day prior restored casein-induced hypophagia in HF rats (FI (kcal) HF-met-cas vs HF-sal-cas: 37±1 vs 55±4, n=10, p<0.001) and selectively increased active GLP-1 levels ((pg/ml): HF-met-cas vs HF-sal-cas: 2.8 ± 0.3 vs 0.8 ± 0.1; n=7; p<0.001), to a greater extent than in chow-fed rats (p<0.001). Mechanistically, lentiviral knockdown of PepT1 (shPepT1) in the USI (~42%, vs mismatch control (shMM); p < 0.05) abolished metformin-restored casein-induced hypophagia (FI (kcal): shPepT1-met-cas vs shMM-met-cas: 55±1 vs 42±1, n=10, p<0.001) and blunted active GLP-1 release ((pg/ml): shPepT1-met-cas vs shMM-met-cas: vs 1.3±0.2 vs 2.1±0.2, n=9, 8, p< 0.05). Conclusion: Therefore, metformin targets the USI to therapeutically enhance protein sensing to reduce food intake via a PepT1-GLP1-dependent mechanism. Disclosure Z. Yang: None. J. Lo Choy: None. G. Back: None. M.T. Wang: None. A. Garrido: None. K. Bruce: None. R.W. Li: None. D. Moslemian: None. R. Kuah: None. J. Beaudry: None. S. Zhang: None. T. Lam: None. Funding Canadian Institutes of Health Research (PJT-183901 to T.K.T.L.)