1638-P: Metformin Enhances Upper Small Intestinal Lipid Sensing to Regulate Food Intake Independent of GDF15 Release

Metformin, a first-line therapy for obesity-associated diabetes, lowers feeding and weight by increasing plasma growth differentiation factor 15 (GDF15) levels, but whether GDF15-independent mechanisms are involved is unknown. The upper small intestine (USI) detects lipids and triggers a gut-brain axis to lower food intake in chow but not high fat (HF)-fed conditions, while metformin enhances USI glucose sensing to lower glucose levels in HF rats. Here, we assessed whether metformin enhances lipid sensing in the USI of HF rats to lower food intake. We performed refeeding studies and measured plasma GDF15 levels after infusing 10% Intralipid into the USI of male rats. Infusion of Intralipid vs. saline into the USI suppressed food intake (lipid: 31±1 vs. sal: 43±2 kcal; p<0.01; n=18, 15) and increased plasma GDF15 levels (lipid: 113±9 vs. sal: 70±6 pg/ml; p<0.01; n=4, 5) up to 6h after refeeding in chow rats. In HF rats, both the effects of USI Intralipid vs. saline on feeding (lipid: 42±3 vs. sal: 41±1 kcal; n=10, 11) and plasma GDF15 levels (lipid: 68±6 vs. sal: 73±5 pg/ml; n=5, 3) were consistently abolished. Interestingly, metformin (50 mg/kg) administered to the USI of HF rats 1d prior to the refeeding studies enhanced USI Intralipid vs. saline infusion to suppress food intake (met-lipid: 35±2 vs. met-sal: 45±3 kcal; p<0.01; n=24,17), but notably did not increase plasma GDF15 levels (met-lipid: 69±3 vs. met-sal: 76±13 pg/ml; p>0.05; n=6, 5). Thus, for the first time we found that metformin enhances lipid sensing in the USI to lower food intake independent of GDF15 release. We propose that metformin lowers feeding in GDF15-dependent and -independent pathways.