Oral Presentation The International Congress of Neuroendocrinology 2014

A novel role for kisspeptin signaling in obesity and glucose homeostasis: analysis of developmental onset and sex steroid-independence (#49)

Kristen P Tolson 1 , Christian Garcia 1 , Jeremy T Smith 2 , Alexander S Kauffman 1
  1. University of California, San Diego, La Jolla, CA, United States
  2. University of Western Australia, Perth, Australia

Kisspeptin regulates reproduction by stimulating GnRH neurons via the receptor, Kiss1r. In mammals, Kiss1r is also expressed in non-GnRH brain areas and peripheral tissues, suggesting additional functions beyond reproduction, but this has not been closely examined. We studied the energetic and metabolic phenotype of mice lacking kisspeptin signaling (Kiss1r KO mice). Compared to WT littermates, KO females displayed dramatically higher body weights in adulthood, along with higher leptin, increased adiposity, higher basal glucose, and markedly impaired glucose tolerance. Conversely, male KOs had normal body weights and glucose regulation. Despite their obesity, adult KO females ate less than WT females. However, adult KO females displayed significantly reduced locomotor activity and energy expenditure. Next, comparing KO and WT females that were ovariectomized (OVX) before or just after normal puberty age (2 wks and 5 wks old, respectively), we determined that over half of the excess body weight and adiposity of KO females is due to gonadal sex steroid-independent mechanisms, indicating that the obesity phenotype is not solely due to the KO’s lack of sex steroids during puberty or adulthood. This was supported by findings from female hypogonadal (hpg) mice, which lack GnRH and gonadal sex steroids. As expected, adult hpg females had a similarly mild weight gain phenotype as OVX WT females (~14% higher than gonad-intact controls), but did not have the additional obesity observed in Kiss1r KO females (~30%). We are currently completing additional studies in younger cohorts of Kiss1r KOs of various ages to determine the developmental onset of the various individual components of the metabolic, obesity, and glucose phenotypes. Our findings demonstrate that, aside from regulating reproduction, kisspeptin signaling in mammals may serve novel functions of influencing adult body weight, energy expenditure, and glucose homeostasis in females in a partly sex steroid-independent manner.