title: Jejunal leptin-PI3K signaling lowers glucose production.
abstract: 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.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Rasmussen
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Danna M
authors.initials: DM
authors.lastname: Breen
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Duca
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Clémence D
authors.initials: CD
authors.lastname: Côté
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Melika
authors.initials: M
authors.lastname: Zadeh-Tahmasebi
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Filippi
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: tony.lam@uhnres.utoronto.ca.
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D059305:Diet, High-Fat; D013505:Digestive System Surgical Procedures; D005947:Glucose / Q000096:biosynthesis*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects / Q000201:enzymology*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose