ESPE Yearbook of Paediatric Endocrinology

Brief Summary: IGF1R signaling in cells expressing Kiss1 gene affects energy balance, food intake, and physical activity in a sex-specific manner. Female IGF1R^Kiss1 mice showed lower body weight and food intake plus higher energy expenditure and physical activity. This phenotype was associated with higher proopiomelanocortin (POMC) expression. The additional deletion of insulin receptor (IR) in Kiss1-expressing cells reversed the lean phenotype seen in female IGF1R^Kiss1. In male mice, the loss of both IGF1R and IR signaling led to delayed puberty and reduced fertility. Overall, these results suggest cooperative roles of IGF1R and IR in metabolism and reproduction.

Kiss1-expressing neurons may link metabolic status to reproduction. Kisspeptin (encoded by Kiss1 gene) exerts its effects on the hypothalamic-pituitary-gonadal (HPG) axis by stimulating gonadotropin-releasing hormone (GnRH) neuron activity (1). Previous studies in rodents have shown an impact of nutrition on Kiss1 expression in the hypothalamus (2-4). IGF-1 and insulin act through related tyrosine kinase receptors and brain IGF-1 signaling has been shown to affect reproduction. Brain IGF1R knockout mice suffer from growth retardation and infertility, but deletion of IGF1R in GnRH neurons does not impact fertility. Based on these observations, the authors hypothesized that the central reproductive effects of IGF-1 may be mediated by IGF1R and IR signaling in Kiss1-expressing neurons.

To test these hypotheses, the authors characterized the metabolic and reproductive functions of mice lacking only IGF1R (IGF1R^Kiss1 mice) or both IGF1R and IR specifically in Kiss1-expressing cells (IGF1R/IR^Kiss1 mice).

Loss of IGF1R in Kiss1 cells in female mice caused lower body length and weight, lower food intake, higher energy expenditure and physical activity. This phenotype was linked to higher mRNA expression of proopiomelanocortin (POMC) in the hypothalamus. Male IGF1R^Kiss1 mice had only mild changes in metabolic profile. IGF1R/IR^Kiss1 female mice showed a reversed phenotype as compared to IGF1R^Kiss1 mice with higher fat mass, decreased hypothalamic mRNA expression of POMC and glucose intolerance, suggesting that IGF1R and IR signaling in Kiss1-expressing cells have divergent roles in regulating food intake and physical activity in female mice. This finding was only partially confirmed in IGF1R/IR^Kiss1 male mice.

Delayed puberty was found in both sexes as a result of single IGF1R deletion and combined IGF1R and IR deletions in Kiss1 cells. Male IGF1R^Kiss1 and IGF1R/IR^Kiss1 mice had impaired adulthood fertility in terms of reduced number of spermatids and spermatozoa in seminiferous tubules, and lower gonadotropin and testosterone levels.

This study elegantly uncovers another piece of the puzzle linking metabolism and reproduction, showing that IGF1R and IR have cooperative roles in regulating body size, metabolism and reproduction via Kiss1-expressing cells in a sex-specific manner.

References: 1. Kirilov M, Clarkson J, Liu X, Roa J, Campos P, Porteous R, Schütz G, Herbison AE. Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nat Commun. 2013;4:2492. doi: 10.1038/ncomms3492. PMID: 24051579.2. Luque RM, Kineman RD, Tena-Sempere M. Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line. Endocrinology. 2007 Oct;148(10):4601-11. doi: 10.1210/en.2007-0500. Epub 2007 Jun 26. PMID: 17595226.3. Castellano JM, Navarro VM, Fernández-Fernández R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005 Sep;146(9):3917-25. doi: 10.1210/en.2005-0337. Epub 2005 Jun 2. PMID: 15932928.4. Conde K, Kulyk D, Vanschaik A, Daisey S, Rojas C, Wiersielis K, Yasrebi A, Degroat TJ, Sun Y, Roepke TA. Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity. Biomolecules. 2022 Sep 25;12(10):1370. doi: 10.3390/biom12101370. PMID: 36291579; PMCID: PMC9599822.