IGF-1 Acts through Kiss1-expressing Cells to Influence Metabolism and Reproduction

Abstract

ABSTRACTObjectiveKisspeptin, encoded by theKiss1gene, ties puberty and fertility to energy status; however, the metabolic factors that controlKiss1-expressing cells need to be clarified.MethodsTo evaluate the impact of IGF-1 on the metabolic and reproductive functions of kisspeptin producing cells, we created mice with IGF-1 receptor deletion driven by theKiss1promoter (IGF1RKiss1mice). Previous studies have shown IGF-1 and insulin can bind to each other’s receptor, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we also generated mice with simultaneous deletion of the IGF1R and insulin receptor (IR) inKiss1-expressing cells (IGF1R/IRKiss1mice).ResultsLoss of IGF1R inKiss1cells caused stunted body length. In addition, female IGF1RKiss1mice displayed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was linked to higher proopiomelanocortin (POMC) expression and heightened brown adipose tissue (BAT) thermogenesis. Male IGF1RKiss1mice had mild changes in metabolic functions. Moreover, IGF1RKiss1mice of both sexes experienced delayed puberty. Notably, male IGF1RKiss1mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R inKiss1-expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IRKiss1mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR inKiss1-expressing cells together regulate body composition and glucose homeostasis.ConclusionsOverall, our study shows that IGF1R and IR inKiss1have cooperative roles in body length, metabolism, and reproduction.