SUMMARY Obesity is highly related to excess nutrient intake, and particularly consumption of a high-fat diet. The prevalence of severe obesity (BMI e 35 kg/m2) is increasing more rapidly than general obesity trends, and is estimated to affect 6% of the population. This degree of obesity is a particularly significant health problem due to higher rates of metabolic co-morbidities. Gastric bypass surgery is the only effective means to achieve a meaningful and sustained weight loss and improve co-morbidities in people with a BMI e 35 kg/m2; however, this approach is not feasible to reverse global obesity rates. Work from our lab and others have described beneficial metabolic effects of gastric bypass that occur immediately after surgery and appear to be weight-loss independent. As a result, much attention has been placed on the gastrointestinal tract as a non-surgical therapeutic target for obesity and metabolic diseases. The intestines express numerous taste receptors that can sense the nutrient content of a meal and communicate this information to the body via hormonal and neuronal signals to control food intake, absorption, and metabolism. It has been shown that a high-fat diet can attenuate the ability of intestinal lipid to initiate neuroendocrine pathways that promote satiety and reduce hepatic glucose production. Intestinal chemosensing is increasingly cited as a potential therapeutic target for obesity and metabolic diseases. Yet, much of the information related to nutrient sensing pathways has been derived from animal and in vitro studies, and it remains unknown whether foregut nutrient sensing mechanisms regulate food absorption and metabolism in humans. Given the prevalence of obesity and its significant health effects, the translation of intestinal chemosensing mechanisms in humans is extremely relevant. Our preliminary studies in humans suggest that the presence of a small amount of lipid in the duodenum, insufficient to increase circulating plasma free fatty acid and triglyceride levels, can decrease splanchnic glucose uptake and increase glucose oxidation and can also decrease hepatic glucose production. The overall hypothesis of this proposal is that lipid nutrient sensing in the foregut regulates glucose absorption and metabolism and these mechanisms might be defective in obesity. In this proposal, we will assess the effect of intestinal lipid infusions on splanchnic glucose absorption, oxidation, and metabolism in lean and obese humans. We will also examine the impact of obesity on the expression of molecular mediators of lipid nutrient sensing in duodenal biopsies obtained during upper endoscopy from obese and lean humans. The results of our studies will significantly advance the understanding of foregut nutrient sensing in humans and also determine if nutrient sensing is defective in obesity. Future studies will determine if foregut nutrient sensing contributes to the effectiveness of gastric bypass surgery to induce weight loss and improve nutrient metabolism. Foregut nutrient sensing may provide a therapeutic target for treatment of obesity alone or in conjunction with less invasive (but less effective) bariatric surgeries such as adjustable gastric banding.