title: The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
abstract: Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKDΔNkx2.1cre). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKDΔSim1cre) and proopiomelanocortin neurons (GLP-1RKDΔPOMCcre). Chow-fed GLP-1RKDΔNkx2.1cremice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKDΔSim1creand GLP-1RKDΔPOMCcremice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKDΔNkx2.1cremice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL mburmeister@sbpdiscovery.org.
authors.forename: Melissa A
authors.identifier: 0000-0001-8017-8666
authors.initials: MA
authors.lastname: Burmeister
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ayala
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.
authors.forename: Hannah
authors.initials: H
authors.lastname: Smouse
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.
authors.forename: Adriana
authors.initials: A
authors.lastname: Landivar-Rocha
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Brown
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: Department of Medicine, University of Pennsylvania, Pennsylvania, PA.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Darleen A
authors.initials: DA
authors.lastname: Sandoval
authors.affiliation: Department of Surgery, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.affiliation: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL.
authors.forename: Julio E
authors.initials: JE
authors.lastname: Ayala
mesh_terms: D000818:Animals; D001823:Body Composition; D059305:Diet, High-Fat; D004435:Eating / Q000187:drug effects / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D000077270:Exenatide; D055785:Gene Knockdown Techniques; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000235:genetics; D007031:Hypothalamus / Q000378:metabolism*; D054795:Incretins / Q000494:pharmacology; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D010455:Peptides; D014688:Venoms; D011333:Pro-Opiomelanocortin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005947:Glucose