Jejunal leptin-PI3K signaling lowers glucose production

Cell Metab. 2014 Jan 7;19(1):155-61. doi: 10.1016/j.cmet.2013.11.014. Epub 2013 Dec 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / metabolism
  • Diet, High-Fat
  • Digestive System Surgical Procedures
  • Glucose / biosynthesis*
  • Hypoglycemic Agents / pharmacology
  • Jejunum / drug effects
  • Jejunum / enzymology*
  • Leptin / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Net / drug effects
  • Nerve Net / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Leptin / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction* / drug effects


  • Hypoglycemic Agents
  • Leptin
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Phosphatidylinositol 3-Kinases
  • Glucose