Exploring GABA and kisspeptin roles in reproductive and metabolic regulation: Insights from Kiss1 -GABAB1KO female mice

Abstract

γ-Aminobutyric acid (GABA) and kisspeptin play essential roles in reproduction and metabolism, being expressed in the central nervous system and peripheral organs (ovaries, testes, pancreas, liver, and white adipose tissue [WAT]). While previous research has shed light on their functions, the interaction between GABA and kisspeptin in regulating these processes remains poorly explored. In a recent study, in which we evaluated the action of GABA through GABAB receptors (GABABRs) in Kiss1-expressing cells, we focused on male mice lacking GABABR specifically in Kiss1 cells (Kiss1-GABAB1KO), revealing normal reproductive functions but impaired glucose homeostasis that worsened with age. Here, we explored reproduction and metabolism in Kiss1-GABAB1KO females. Kiss1-GABAB1KO females had increased Kiss1/Tac2 expression in the arcuate nucleus (ARC), while displaying normal estrous cycles and fertility. Metabolically, they showed increased expression of key ARC metabolic genes (Npy/Agrp, Pomc, Lepr), increased WAT weight and leptin secretion, and body weight (BW) gain, not linked to food intake (FI) changes. They exhibited normal glucose levels but heightened insulin secretion and peripheral insulin resistance, potentially due to increased WAT mass. Kisspeptin was specifically increased in KO WAT. Interestingly, BW in older KO females was not different from WTs, yet maintained elevated WAT kisspeptin content, similar to younger females. Our results highlight the effect of GABA, through GABABRs, in the regulation of the WAT kisspeptin system and ARC gene expression in female mice, underscoring that the effect of deletion of GABABRs in Kiss1 cells found in this and our previous study is sex, age, and tissue specific.