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Diabetes. 2014 Dec;63(12):4186-96. doi: 10.2337/db14-0849. Epub 2014 Jul 28.

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

Author information

  • 1Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands l.vanbloemendaal@vumc.nl.
  • 2Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands.
  • 3Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands.
  • 4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
  • 5Endocrine Section, Department of Internal Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
  • 6Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.

Abstract

Gut-derived hormones, such as 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 body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and 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 exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus 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 exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01281228.

© 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.

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