Assessment of Sex Differences, Sex Steroid Dependency, and Developmental Onset of Impaired Metabolism and Energy Balance in Mice Lacking Kisspeptin Signaling

Presentation Number: OR15-1
Date of Presentation: March 6th, 2015

Kristen P Tolson*1, Christian J Garcia1, Iris S Delgado2, Jeremy Troy Smith3 and Alexander S Kauffman1
1University of California, San Diego, La Jolla, CA, 2University of California San Diego, La Jolla, CA, 3The University of Western Australia, Perth, Australia

Abstract

Kisspeptin is primarily known for the regulation of puberty and reproduction via its signaling through the receptor, Kiss1r (also known as GPR54), in GnRH neurons. However, both kisspeptin and Kiss1r are produced in multiple tissues and cell-types, and several recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We previously reported that Kiss1r KO mice display a sexually dimorphic obese phenotype, with adult KO females displaying obesity and impaired glucose homeostasis, as well as impaired metabolism, while KO males have normal body weight and glucose tolerance. However, KO males do exhibit decreased lean mass and increased fat mass, suggesting some effect of impaired kisspeptin signaling, but their metabolism and energy expenditure were not previously assessed. Here, we first determined whether KO males demonstrate alterations in metabolism or locomotor activity, as do KO females. We found that, compared to littermate controls, KO males have decreased metabolism and locomotor activity, though not as robust as in KO females. Next, we tested whether the reductions in energy expenditure and locomotor activity in both sexes are dependent on their chronic lack of gonadal sex steroids. We previously found that much of the obesity phenotype in Kiss1r KO females is not due to their lack of gonadal sex steroids during puberty or adulthood, but metabolic and locomotor measures were not similarly assessed. Here, we found that long-term gonadectomized (GDX) KO females still displayed marked decreases in metabolism and locomotor activity compared to GDX control females. Interestingly, in contrast, GDX KO males no longer differed in these measures from GDX control males, suggesting that the metabolic differences seen in gonad intact males reflect genotypic differences in gonadal sex steroids, whereas the metabolic phenotype in KO females is sex steroid-independent. Lastly, we determined that KO females already exhibit altered adiposity, metabolism, and locomotor activity, but not food intake or glucose tolerance, at young adult ages, weeks before the eventual emergence of increased body weight. Thus, the altered feeding and glucose regulation may be secondary to changes in metabolism and adiposity. Collectively, these data highlight sexually dimorphic effects of disrupted kisspeptin signaling on body weight, glucose homeostasis, and metabolism, and further confirm that multiple aspects of the metabolic phenotype in KO females are gonadal steroid-independent. Alterations in kisspeptin signaling could be a novel and important factor contributing to some facets of female obesity and metabolic dysfunction.

 

Nothing to Disclose: KPT, CJG, ISD, JTS, ASK