title: The anorectic effect of GLP-1 in rats is nutrient dependent.
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.
authors.affiliation: Division of Endocrinology and Metabolism, University of Cincinnati, Cincinnati, OH, USA. darleen.sandoval@uc.edu
authors.forename: Darleen
authors.initials: D
authors.lastname: Sandoval
authors.forename: Jason G
authors.initials: JG
authors.lastname: Barrera
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Stefater
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sisley
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: David D
authors.initials: DD
authors.lastname: D'Alessio
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000209:etiology* / Q000378:metabolism; D005215:Fasting / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects*; D005941:Glucokinase / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006579:Heterozygote; D054795:Incretins / Q000009:adverse effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D054795:Incretins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D052216:Glucagon-Like Peptide 1; D011494:Protein Kinases; D005941:Glucokinase; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide; D005947:Glucose