title: GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance.
abstract: Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitary-gonadal axis, as they regulate the basal pulsatile release of gonadotropin releasing hormone (GnRH). ARC Kiss1 action is dependent on energy status, and unmasking metabolic factors responsible for modulating ARC Kiss1 neurons is of great importance. One possible factor is glucagon-like peptide 1 (GLP-1), an anorexigenic neuropeptide produced by brainstem preproglucagon neurons. Because GLP fiber projections and the GLP-1 receptor (GLP-1R) are abundant in the ARC, we hypothesized that GLP-1R signaling could modulate ARC Kiss1 action. Using ovariectomized mice, we found that GLP-producing fibers come in close apposition with ARC Kiss1 neurons; these neurons also containGlp1rmRNA. Electrophysiological recordings revealed that liraglutide (a long-acting GLP-1R agonist) increased action potential firing and caused a direct membrane depolarization of ARC Kiss1 cells in brain slices. We determined that brainstem preproglucagon mRNA is decreased after a 48-h fast in mice, a negative energy state in which ARC Kiss1 expression and downstream GnRH/luteinizing hormone (LH) release are potently suppressed. However, activation of GLP-1R signaling in fasted mice with liraglutide was not sufficient to prevent LH inhibition. Furthermore, chronic central infusions of the GLP-1R antagonist, exendin(9-39), inad libitum-fed mice did not alter ARCKiss1mRNA or plasma LH. As a whole, these data identify a novel interaction of the GLP-1 system with ARC Kiss1 neurons but indicate that CNS GLP-1R signaling alone is not critical for the maintenance of LH during fasting or normal feeding.
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Arian F
authors.initials: AF
authors.lastname: Baquero
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Camdin M
authors.identifier: 0000-0001-6541-7868
authors.initials: CM
authors.lastname: Bennett
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Sarah R
authors.identifier: 0000-0002-2115-7803
authors.initials: SR
authors.lastname: Lindsley
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Melissa A
authors.identifier: 0000-0002-2570-777X
authors.initials: MA
authors.lastname: Kirigiti
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Baylin
authors.identifier: 0000-0001-6541-7868
authors.initials: B
authors.lastname: Bennett
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University , Portland, OR, 97239.
authors.forename: Martha A
authors.identifier: 0000-0002-3023-3150
authors.initials: MA
authors.lastname: Bosch
authors.affiliation: Novo Nordisk Research Center , Seattle, WA 98109.
authors.forename: Aaron J
authors.identifier: 0000-0002-9586-6610
authors.initials: AJ
authors.lastname: Mercer
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, 97239; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.
authors.forename: Oline K
authors.identifier: 0000-0003-1841-4386
authors.initials: OK
authors.lastname: Rønnekleiv
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University , Beaverton, OR 97006.
authors.forename: Cadence
authors.initials: C
authors.lastname: True
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Novo Nordisk Research Center, Seattle, WA 98109.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, 97239; Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.
authors.forename: M Susan
authors.identifier: 0000-0002-3057-7009
authors.initials: MS
authors.lastname: Smith
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004343:Drug Implants; D004435:Eating / Q000502:physiology; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000008:administration & dosage; D005215:Fasting / Q000378:metabolism*; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004763:Glucagon-Like Peptides / Q000378:metabolism; D059648:Kisspeptins / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors / Q000097:blood*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D004343:Drug Implants; D004967:Estrogens; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D012333:RNA, Messenger; D004958:Estradiol; D004763:Glucagon-Like Peptides; D007986:Luteinizing Hormone; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: GLP-1; LH; fasting; hypothalamus; kisspeptin; liraglutide