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, Pénicaud 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