GLP-1 receptor signaling activates hormone-releasing neurons in the brain but does not restore reproductive hormone levels in energy-deficient mice without ovaries
signaling may interact with ARC Kiss1 neurons but does not maintain LH levels during fasting or normal feeding.
GLP-1-producing fibers are found near ARC Kiss1 neurons, which also express mRNA for GLP-1 receptors.
Liraglutide, a GLP-1R agonist, increases action potential firing and depolarizes ARC Kiss1 cells in brain slices.
A 48-hour fast decreases brainstem preproglucagon mRNA in mice, coinciding with suppressed ARC Kiss1 expression and LH release.
Activation of GLP-1R signaling with liraglutide in fasted mice fails to prevent the inhibition of LH release.
Chronic infusion of a GLP-1R antagonist does not change ARC Kiss1 mRNA levels or plasma LH in fed mice.
Simplified
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 () 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 containmRNA. 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-fed mice did not alter ARCmRNA 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. Glp1r ad libitum Kiss1
Key numbers
60%
ARC Kiss1 Cells Activated
Percentage of ARC Kiss1 neurons that showed membrane depolarization with liraglutide treatment.
7–8 animals per group
LH Inhibition During Fasting
Animal count for assessing LH levels in saline-fasted and liraglutide-fasted groups.
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