The anorectic effect of GLP-1 in rats is nutrient dependent

PLoS One. 2012;7(12):e51870. doi: 10.1371/journal.pone.0051870. Epub 2012 Dec 17.

Abstract

GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd) cerebroventricularly (i3vt)-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1's anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / metabolism
  • Animals
  • Anorexia / etiology*
  • Anorexia / metabolism
  • Fasting / physiology*
  • Glucagon-Like Peptide 1 / adverse effects*
  • Glucokinase / physiology*
  • Glucose / metabolism*
  • Heterozygote
  • Incretins / adverse effects*
  • Male
  • Mice
  • Mice, Knockout
  • Protein Kinases / metabolism
  • Rats
  • Rats, Long-Evans
  • Ribonucleotides / metabolism

Substances

  • Incretins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Glucagon-Like Peptide 1
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Glucokinase
  • AICA ribonucleotide
  • Glucose