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

Kristy M. Heppner, Arian F. Baquero, Camdin M. Bennett, Sarah R. Lindsley, Melissa A. Kirigiti, Baylin Bennett, Martha A. Bosch, Aaron J. Mercer, Oline Ronnekleiv, Cadence True, Kevin Grove, M (Susan) Smith

Research output: Contribution to journalArticle

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Abstract

Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitarygonadal 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 contain Glp1r mRNA. 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), in ad libitum–fed mice did not alter ARC Kiss1 mRNA 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.

Original languageEnglish (US)
Article numbere0198
JournaleNeuro
Volume4
Issue number1
DOIs
StatePublished - Jan 5 2017

Fingerprint

Kisspeptins
Arcuate Nucleus of Hypothalamus
Luteinizing Hormone
Brain
Neurons
Proglucagon
Glucagon-Like Peptide 1
Gonadotropin-Releasing Hormone
Messenger RNA
Brain Stem
Glucagon-Like Peptide-1 Receptor
Neuropeptides
Action Potentials
Fasting

Keywords

  • Fasting
  • GLP-1
  • Hypothalamus
  • Kisspeptin
  • LH
  • Liraglutide

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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. / Heppner, Kristy M.; Baquero, Arian F.; Bennett, Camdin M.; Lindsley, Sarah R.; Kirigiti, Melissa A.; Bennett, Baylin; Bosch, Martha A.; Mercer, Aaron J.; Ronnekleiv, Oline; True, Cadence; Grove, Kevin; Smith, M (Susan).

In: eNeuro, Vol. 4, No. 1, e0198, 05.01.2017.

Research output: Contribution to journalArticle

Heppner, Kristy M. ; Baquero, Arian F. ; Bennett, Camdin M. ; Lindsley, Sarah R. ; Kirigiti, Melissa A. ; Bennett, Baylin ; Bosch, Martha A. ; Mercer, Aaron J. ; Ronnekleiv, Oline ; True, Cadence ; Grove, Kevin ; Smith, M (Susan). / 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. In: eNeuro. 2017 ; Vol. 4, No. 1.
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abstract = "Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitarygonadal 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 contain Glp1r mRNA. 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), in ad libitum–fed mice did not alter ARC Kiss1 mRNA 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.",
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AU - Baquero, Arian F.

AU - Bennett, Camdin M.

AU - Lindsley, Sarah R.

AU - Kirigiti, Melissa A.

AU - Bennett, Baylin

AU - Bosch, Martha A.

AU - Mercer, Aaron J.

AU - Ronnekleiv, Oline

AU - True, Cadence

AU - Grove, Kevin

AU - Smith, M (Susan)

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N2 - Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitarygonadal 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 contain Glp1r mRNA. 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), in ad libitum–fed mice did not alter ARC Kiss1 mRNA 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.

AB - Kisspeptin (Kiss1) neurons in the hypothalamic arcuate nucleus (ARC) are key components of the hypothalamic-pituitarygonadal 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 contain Glp1r mRNA. 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), in ad libitum–fed mice did not alter ARC Kiss1 mRNA 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.

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