Jejunal Leptin-PI3K Signaling Lowers Glucose Production

The fat-derived hormone leptin binds to its hypothalamic receptors to regulate glucose homeostasis. Leptin is also synthesized in the stomach and subsequently binds to its receptors expressed in the intestine, although the functional relevance of such activation remains largely unknown. We report here that intrajejunal leptin administration activates jejunal leptin receptors and signals through a phosphatidylinositol 3-kinase (PI3K)-dependent and signal transducer and activator of transcription 3 (STAT3)-independent signaling pathway to lower glucose production in healthy rodents. Jejunal leptin action is sufficient to lower glucose production in uncontrolled diabetic and high-fat-fed rodents and contributes to the early antidiabetic effect of duodenal-jejunal bypass surgery. These data unveil a glucoregulatory site of leptin action and suggest that enhancing leptin-PI3K signaling in the jejunum lowers plasma glucose concentrations in diabetes. [Display omitted] •Intrajejunal leptin infusion activates leptin receptors to lower glucose production•Jejunal PI3K and a neuronal network are required for leptin action•Jejunal leptin action lowers glucose production in high-fat-fed or diabetic rats•Jejunal leptin action is required for the antidiabetic effect of bariatric surgery Leptin has recently been found to be synthesized in the stomach and to act on the intestine. Rasmussen et al. show that jejunal leptin signaling is sufficient to lower glucose production in uncontrolled diabetic and high-fat-fed rodents and contributes to the rapid antidiabetic effect of bariatric surgery during refeeding.