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 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.

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

“…33 The gut hormones, GLP-1, PYY and glucagon have key roles in glucose homeostasis. Additionally, in rodent studies, GLP-1 has been shown to alter hypothalamic kisspeptin expression and neuronal activity, 42,43 and in mice glucagon stimulates hepatic kisspeptin production to alter GSIS. 13 In our study, there was no difference in circulating GLP-1, PYY or glucagon levels following intravenous glucose during kisspeptin administration compared to vehicle ( Figure S1C-E).…”

Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway

“…GLP-1R agonist also results in a direct membrane depolarization of ARC KP cells. However, central infusions of the GLP-1R antagonist, exendin (9–39), did not exert any effect on expression of ARC Kiss1mRNA or plasma LH in the normal fed mice ( 128 ).…”

“…Heppner et al ( 128 ) reported that KP neurons in the hypothalamic ARC receive synaptic input from glucagon-like peptide 1 (GLP-1), which is an anorexigenic neuropeptide. Moreover, KP neurons also express Glp1r mRNA.…”

Feeding and glucagon‐like peptide‐1 receptor activation stabilise β‐catenin in specific hypothalamic nuclei in male rats

“…They are not neuropeptide Y/agouti‐related peptide or parvalbumin positive, although they may include a population of GABAergic interneurones . Interestingly, kisspeptin neurones in this nucleus were recently shown to express GLP1R mRNA and directly respond to GLP1 . Although these neurones are unlikely to be directly involved in metabolic regulation, they are known to be highly influenced by information about nutrient availability .…”

“…34 Interestingly, kisspeptin neurones in this nucleus were recently shown to express GLP1R mRNA and directly respond to GLP1. 35 Although these neurones are unlikely to be directly involved in metabolic regulation, they are known to be highly influenced by information about nutrient availability. 36,37 Similarly, the neurochemical identity of GLP1R-expressing neurones in the PVN and DMH remains to be determined 32 .…”