Lack of GABABR in Kiss1 cells alters metabolism that worsens with age in male mice.

DI GIORGIO NP; BIZZOZZERO HIRIART M; REPETTO E; BONAVENTURA MM; MASTROPIERRO R; CONVERTI A; RIAÑO GOMEZ JM; BETTLER B; LIBERTUN C; LUX-LANTOS VA

Glasgow, Escocia

Congreso; Kisspeptin 4th World Conference 2022-International Congress of Neuroendocrinology; 2022

Introduction/Aim: Kisspeptin and GABA are expressed in various peripheral organs/tissues critical to metabolic control (liver/pancreas/adipose). Moreover, kisspeptin neurons coexpress GABAB receptors (GABABR) and GABA controls the expression and secretion of kisspeptin. However, our understanding of how these two factors interact to regulate metabolism is still incomplete. We have developed a unique mouse lacking GABABR exclusively from kisspeptin cells/neurons (Kiss1-GABAB1KO) to evaluate the impact on metabolism/reproduction. 3-month-old Kiss1-GABAB1KO females showed increased body weight (BW), non-fasted glycemia (NFG), insulin secretion and HOMA-beta-cell index. 3-month-old Kiss1-GABAB1KO males showed normal BW and NFG, higher fasted glycemia (FG), serum insulin and HOMA-IR index, altered response to glucose overload and lower insulin sensitivity compared to control males. Here determined whether these metabolic alterations persisted or worsened with age. Methods/Results:We evaluated metabolic parameters in 9-months-old Kiss1-GABAB1KO and control mice.Interestingly, Kiss1-GABAB1KO males had higher BW and increased in total white adipose tissue (WAT) and also in WAT/BW. Although NFG and FG were similar between genotypes, Kiss1-GABAB1KO males showed increased fasted serum insulin and pancreatic insulin content. Furthermore, HOMA-beta-cell and HOMA-IR indexes were increased in Kiss1-GABAB1KO males. We also evaluated serum cholesterol and triglycerides but they were similar between genotypes. We did not find differences between genotypes either in serum kisspeptin levels or hepatic kisspeptin content. However, kisspeptin levels were decreased by 35% in the pancreas of the Kiss1-GABAB1KO males, and this decrease could be leading to the increased pancreas insulin observed at this age. In contrast, 9-months-old Kiss1-GABAB1KO females showed similar BW, NFG, FG, fasted insulin levels, HOMA indexes, serum cholesterol and triglycerides levels compared to controls. We need to further investigate kisspeptin levels in the main metabolic tissues in females to determine one possible cause of this striking phenotype reversion with age.Conclusions: In sum, lack of GABABR specifically in Kiss1 cells has a clear impact on BW, WAT, glucose homeostasis, pancreatic kisspeptin, insulin levels and insulin resistance in male mice, reinforcing the proposed kisspeptin involvement in metabolic regulation. Not only the peripheral response to insulin worsened, in line with the increased BW, but also pancreas function was affected by aging in males. These metabolic alterations may be due to altered autocrine/paracrine regulation of the pancreatic islet, which will be further studied. Our results highlight the impact of GABA through GABABR in the regulation of the peripheral pancreas kisspeptin system in contrast to the liver kisspeptin system that was not affected, suggesting tissue specific regulation.