Gut-derived hormones, such as glucagon-like peptide-1 (GLP-1), have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety leading to decreases in food intake and bodyweight. We hypothesized that food intake reduction following GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients, normoglycemic obese and lean individuals (n=48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin9-39, on brain responses to food pictures, during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese vs. lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide vs. placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.
- Received May 28, 2014.
- Accepted July 22, 2014.
- © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.