GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans

  1. Michaela Diamant1,
  1. 1Diabetes Center / Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
  3. 3Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, United States of America
  4. 4Department of Internal Medicine / Endocrine Section / Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
  5. 5Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
  1. Corresponding author: L van Bloemendaal, E-mail: l.vanbloemendaal{at}vumc.nl

Abstract

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.

Footnotes

  • Deceased.

  • Received May 28, 2014.
  • Accepted July 22, 2014.

This Article

  1. Diabetes
  1. Supplementary Data
  2. All Versions of this Article:
    1. db14-0849v1
    2. 63/12/4186 most recent