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

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

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amygdala / drug effects
  • Amygdala / metabolism
  • Amygdala / physiology
  • Appetite / drug effects
  • Appetite / physiology*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiology*
  • Case-Control Studies
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / physiology
  • Cross-Over Studies
  • Diabetes Mellitus, Type 2 / metabolism*
  • Exenatide
  • Feeding Behavior / drug effects
  • Feeding Behavior / physiology*
  • Female
  • Functional Neuroimaging
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Obesity / metabolism*
  • Peptide Fragments / pharmacology
  • Peptides / pharmacology
  • Photic Stimulation
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiology
  • Putamen / drug effects
  • Putamen / metabolism
  • Putamen / physiology
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / physiology*
  • Reward*
  • Venoms / pharmacology

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptide Fragments
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • exendin (9-39)
  • Exenatide

Associated data

  • ClinicalTrials.gov/NCT01281228