Brain Glucagon-Like Peptide 1 Signaling Controls the Onset of High-Fat Diet-Induced Insulin Resistance and Reduces Energy Expenditure

Jun 17, 2008Endocrinology

Brain signals of glucagon-like peptide 1 may control when high-fat diets cause insulin resistance and lower energy use

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Abstract

A 1-month blockage of brain GLP-1 signaling completely prevented hyperinsulinemia and insulin resistance in high-fat diet mice.

Blocking brain GLP-1 signaling may counteract the effects of a high-fat diet on glucose metabolism.
Increased food intake was observed without a corresponding increase in body weight.
Brain GLP-1 signaling is associated with reduced energy expenditure through decreased metabolic thermogenesis and ambulatory activity.
Exendin-9 treatment led to higher levels of thermogenesis, glucose utilization, oxygen consumption, carbon dioxide production, and muscle activity.

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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.

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Brain Glucagon-Like Peptide 1 Signaling Controls the Onset of High-Fat Diet-Induced Insulin Resistance and Reduces Energy Expenditure

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