Age-related sex differences in metabolic alterations in mice lacking GABAB receptors in Kiss1 cells.

MASTROPIERRO R; BIZZOZZERO HIRIART, MARIANNE; BETTLER B; LUX LANTOS VAR; DI GIORGIO NP

Buenos Aires

Congreso; XXIV Jornadas Anuales de la Sociedad Argentina de Biología; 2022

Sociedad Argentina de Biología

AGE-RELATED SEX DIFFERENCES IN METABOLIC ALTERATIONS IN MICE LACKING GABAB RECEPTORS IN KISS1 CELLS Mastropierro R1, Bizzozzero Hiriart M1, Bettler B2, Lux-Lantos VA1. Di Giorgio NP1*.1Laboratory of Neuroendocrinology, IBYME-CONICET, Buenos Aires, Argentina. 2Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland.*contact e-mail: ndigiorgio@ibyme.conicet.gov.arKisspeptin, encoded by Kiss1 gene, and GABA are key factors in the regulation of reproduction but also of metabolism, as they are expressed in liver, pancreas, adipose tissue. We developed a unique mouse lacking GABAB receptors (GABABR) exclusively from Kiss1 cells/neurons (Kiss1-GABAB1KO or KO) to study the impact on reproduction/metabolism. In contrast to reproduction, we found clear alterations in metabolic parameters. 3-month-old (3M) KO females showed increased body weight (BW), non-fasted glycemia (NFG), insulin secretion and HOMA-beta-cell index and reduced insulin sensitivity. 3M KO 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 we determined whether these metabolic alterations persisted or worsened with age in 9-months-old (9M) KO and control mice. Interestingly, 9M KO males had higher BW and increased total white adipose tissue (WAT) mass and also WAT/BW. Although NFG and FG were similar between genotypes, KO males showed increased fasted serum insulin and pancreatic insulin content. Furthermore, HOMA-beta-cell and HOMA-IR indexes were increased in KO males. These alterations were not due to differences between genotypes in kisspeptin content in the medial basal hypothalamus. We did not find differences between genotypes either in serum kisspeptin, cholesterol (CH) and triglycerides (TRI) levels or in WAT, brown adipose tissue (BAT) and hepatic kisspeptin content. However, kisspeptin levels were decreased by 35% in the pancreas of the KO males, and this decrease could be leading to the increased serum and pancreas insulin levels observed at this age. In contrast, 9M KO females showed similar BW, NFG, FG, fasted insulin levels, HOMA indexes, serum CH and TRI levels compared to controls. Although serum kisspeptin levels and kisspeptin content in liver, pancreas and BAT were similar between genotypes, 9M KO females had increased WAT kisspeptin content that could be leading to the decrease in WAT mass, and normalization of BW, insulin secretion and insulin sensitivity. In sum, lack of GABABR specifically in Kiss1 cells has a clear sex difference in metabolic alterations that becomes apparent with age. Peripheral response to insulin and also pancreas function worsened in males by aging, possibly due to altered autocrine/paracrine regulation of the pancreatic islet. Interestingly, KO females showed a reversion in their phenotype with age. Our results highlight the impact of GABABR in the regulation of the peripheral pancreas kisspeptin system in males and WAT kisspeptin system in females, which will be further studied. Supported by CONICET, ANPCYT, ISN-CAEN.