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Activation of a classic hunger circuit slows luteinizing hormone pulsatility.

Abstract

INTRODUCTION

The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation.

OBJECTIVE

We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation.

METHODS

We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons.

RESULTS

Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect.

CONCLUSIONS

These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31630145

Citation

Coutinho, Eulalia, et al. "Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility." Neuroendocrinology, 2019.
Coutinho E, Prescott M, Hessler S, et al. Activation of a classic hunger circuit slows luteinizing hormone pulsatility. Neuroendocrinology. 2019.
Coutinho, E., Prescott, M., Hessler, S., Marshall, C., Herbison, A., & Campbell, R. E. (2019). Activation of a classic hunger circuit slows luteinizing hormone pulsatility. Neuroendocrinology, doi:10.1159/000504225.
Coutinho E, et al. Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility. Neuroendocrinology. 2019 Oct 21; PubMed PMID: 31630145.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of a classic hunger circuit slows luteinizing hormone pulsatility. AU - Coutinho,Eulalia, AU - Prescott,Melanie, AU - Hessler,Sabine, AU - Marshall,Christopher, AU - Herbison,Allan, AU - Campbell,Rebecca E, Y1 - 2019/10/21/ PY - 2019/09/06/received PY - 2019/10/11/accepted PY - 2019/10/21/entrez PY - 2019/10/21/pubmed PY - 2019/10/21/medline JF - Neuroendocrinology JO - Neuroendocrinology N2 - INTRODUCTION: The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. OBJECTIVE: We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. METHODS: We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. RESULTS: Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. CONCLUSIONS: These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion. SN - 1423-0194 UR - https://www.unboundmedicine.com/medline/citation/31630145/Activation_of_a_classic_hunger_circuit_slows_luteinizing_hormone_pulsatility L2 - https://www.karger.com?DOI=10.1159/000504225 DB - PRIME DP - Unbound Medicine ER -