Liraglutide Modulates Appetite and Body Weight Through Glucagon-Like Peptide 1 Receptor-Expressing Glutamatergic Neurons

Diabetes. 2018 Aug;67(8):1538-1548. doi: 10.2337/db17-1385. Epub 2018 May 18.

Abstract

Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in vGAT-expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in vGlut2-expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite Depressants / therapeutic use*
  • Diet, High-Fat / adverse effects
  • Energy Intake / drug effects
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • Genes, Reporter / drug effects
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / chemistry
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Green Fluorescent Proteins / chemistry
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hypoglycemic Agents / therapeutic use*
  • Hypothalamus / drug effects*
  • Hypothalamus / metabolism
  • Hypothalamus / pathology
  • Liraglutide / therapeutic use*
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Nerve Net / drug effects
  • Nerve Net / metabolism
  • Nerve Tissue Proteins / agonists
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Obesity / pathology
  • Random Allocation
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Vesicular Glutamate Transport Protein 2 / chemistry
  • Vesicular Glutamate Transport Protein 2 / genetics
  • Vesicular Glutamate Transport Protein 2 / metabolism
  • Vesicular Inhibitory Amino Acid Transport Proteins / chemistry
  • Vesicular Inhibitory Amino Acid Transport Proteins / genetics
  • Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
  • Weight Loss / drug effects

Substances

  • Appetite Depressants
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Nerve Tissue Proteins
  • Recombinant Fusion Proteins
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Liraglutide