exendin-(9-39) and Glucose-Intolerance

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.

Topics: Adiposity; Analysis of Variance; Animals; Dietary Fats; Energy Metabolism; Feeding Behavior; Fluorescent Antibody Technique; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperphagia; In Situ Hybridization; Injections, Intraventricular; Islets of Langerhans; Male; Motor Activity; Obesity; Peptide Fragments; Proglucagon; Rats; Rats, Long-Evans; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; Tissue Culture Techniques

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.

Topics: Animals; Blood Glucose; Body Temperature Regulation; Brain Stem; Carbon Dioxide; Diabetes Mellitus, Type 2; Dietary Fats; Energy Metabolism; Glucagon-Like Peptide 1; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Motor Activity; Muscle, Skeletal; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxygen Consumption; Peptide Fragments; Physical Endurance; Proglucagon; RNA, Messenger; Signal Transduction; Uncoupling Protein 2