1: Endocrinology. 2008 Oct;149(10):4768-77. Epub 2008 Jun 12. Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure. Knauf C, Cani PD, Ait-Belgnaoui A, Benani A, Dray C, Cabou C, Colom A, Uldry M, Rastrelli S, Sabatier E, Godet N, Waget A, PĂ©nicaud L, Valet P, Burcelin R. Institut de Medecine Moleculaire de Rangueil, Toulouse III University, Centre Hospitalier Universitaire Rangueil, BP84225, 31432 Toulouse Cedex 4, France. Glucagon-like peptide-1 (GLP-1) is a peptide released by the intestine and the brain. We previously demonstrated that brain GLP-1 increases glucose-dependent hyperinsulinemia and insulin resistance. These two features are major characteristics of the onset of type 2 diabetes. Therefore, we investigated whether blocking brain GLP-1 signaling would prevent high-fat diet (HFD)-induced diabetes in the mouse. Our data show that a 1-month chronic blockage of brain GLP-1 signaling by exendin-9 (Ex9), totally prevented hyperinsulinemia and insulin resistance in HFD mice. Furthermore, food intake was dramatically increased, but body weight gain was unchanged, showing that brain GLP-1 controlled energy expenditure. Thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, muscle glycolytic respiratory index, UCP2 expression in muscle, and basal ambulatory activity were all increased by the exendin-9 treatment. Thus, we have demonstrated that in response to a HFD, brain GLP-1 signaling induces hyperinsulinemia and insulin resistance and decreases energy expenditure by reducing metabolic thermogenesis and ambulatory activity. PMID: 18556349 [PubMed - in process] Related Links Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage. [J Clin Invest. 2005] PMID:16322793 Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice. [J Mol Endocrinol. 2008] PMID:18234911 Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. [Gastroenterology. 2004] PMID:15300587 Brain glucagon-like peptide-1 regulates arterial blood flow, heart rate, and insulin sensitivity. [Diabetes. 2008] PMID:18633100 Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. [Diabetes. 2001] PMID:11679431