Gabra5 Plays a Sexually Dimorphic Role in POMC Neuron Activity and Glucose Balance

Authors

Zhou Pei
Yang He
Jonathan C Bean
Yongjie Yang
Hailan Liu
Meng Yu
Kaifan Yu
Ilirjana Hyseni
Xing Cai
Hesong Liu
Na Qu
Longlong Tu
Kristine M Conde
Mengjie Wang
Yongxiang Li
Na Yin
Nan Zhang
Junying Han
Camille Hs Potts
Nikolas A Scarcelli
Zili Yan
Pingwen Xu
Qi Wu
Yanlin He
Yong Xu
Chunmei Wang

Publication Date

1-1-2022

Journal

Frontiers in Endocrinology

DOI

10.3389/fendo.2022.889122

PMID

36120438

PMCID

PMC9471380

PubMedCentral® Posted Date

8-31-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Body Weight, Female, Glucose, Male, Mice, Mice, Transgenic, Neurons, Pro-Opiomelanocortin, Receptors, GABA-A, glucose tolerance, sex differences, POMC neurons, GABAA receptor, GABAergic input

Abstract

Pro-opiomelanocortin (POMC) neurons are important for the regulation of body weight and glucose balance. The inhibitory tone to POMC neurons is mediated primarily by the GABA receptors. However, the detailed mechanisms and functions of GABA receptors are not well understood. The α5 subunit of GABAA receptor, Gabra5, is reported to regulate feeding, and we found that Gabra5 is highly expressed in POMC neurons. To explore the function of Gabra5 in POMC neurons, we knocked down Gabra5 specifically from mature hypothalamic POMC neurons using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 strategy. This POMC-specific knock-down of Gabra5 did not affect body weight or food intake in either male or female mice. Interestingly, the loss of Gabra5 caused significant increases in the firing frequency and resting membrane potential, and a decrease in the amplitude of the miniature inhibitory postsynaptic current (mIPSC) in male POMC neurons. However, the loss of Gabra5 only modestly decreased the frequency of mIPSC in female POMC neurons. Consistently, POMC-specific knock-down of Gabra5 significantly improved glucose tolerance in male mice but not in female mice. These results revealed a sexually dimorphic role of Gabra5 in POMC neuron activity and glucose balance, independent of body weight control.