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

ABSTRACT Objective Kisspeptin, encoded by the Kiss1 gene, ties puberty and fertility to energy status; however, the metabolic factors that control Kiss1 -expressing cells need to be clarified. Methods To 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 the Kiss1 promoter (IGF1R Kiss1 mice). 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) in Kiss1 -expressing cells (IGF1R/IR Kiss1 mice). Results Loss of IGF1R in Kiss1 cells caused stunted body length. In addition, female IGF1R Kiss1 mice 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 IGF1R Kiss1 mice had mild changes in metabolic functions. Moreover, IGF1R Kiss1 mice of both sexes experienced delayed puberty. Notably, male IGF1R Kiss1 mice had impaired adulthood fertility accompanied by lower gonadotropin and testosterone levels. Thus, IGF1R in Kiss1 -expressing cells impacts metabolism and reproduction in a sex-specific manner. IGF1R/IR Kiss1 mice had higher fat mass and glucose intolerance, suggesting IGF1R and IR in Kiss1 -expressing cells together regulate body composition and glucose homeostasis. Conclusions Overall, our study shows that IGF1R and IR in Kiss1 have cooperative roles in body length, metabolism, and reproduction.