SUN-261 Deletion of Hepatic Kisspeptin Results in Abnormal Glucose Metabolism in Female Mice

Kisspeptin is a hypothalamic protein critical for neuroendocrine control of pubertal development and fertility and is modulated by nutritional signals. Kisspeptin has been localized to specific neurons located in the arcuate and anteroventral periventricular (AVPV) nuclei of the hypothalamus and is secreted to control GnRH mediated pubertal maturation and reproduction. Kisspeptin has also been localized to peripheral tissues including the liver, fat, gonads, intestine and placenta, although its role in these tissues is unclear. The objective of current study is to define the role of hepatic kisspeptin as a metabolic sensor. A floxed Kiss1 mouse has been developed, and ablation of liver-specific Kiss1 was achieved in two to three month old Kiss1(f/f) male and female mice given a single tail vein injection of thyroid hormone-binding globulin (TBG) promoter-driven Cre recombinase adeno-associated virus (AAV-CRE). A control group of Kiss1(f/f) male and female mice received an injection of AAV-GFP, expressing green fluorescent protein. Two weeks after injection, a glucose tolerance test (GTT) was performed followed by an insulin tolerance test. To determine whether changes had occurred in the reproductive axis, estrous cyclicity was assessed by daily vaginal smears and estrous cycle phases determined by vaginal cytology. Mice were euthanized four weeks post-injection and tissues were collected for RNA extraction and gene expression analysis via qRT-PCR. As expected, qRT-PCR data showed absence of Kiss1 expression in the liver of AAV-CRE mice compared to AAV-GFP mice with no changes in kisspeptin gene expression were noted in the ovary, testes, spleen, pancreas, arcuate or AVPV. Estrous cyclicity was also not affected by viral ablation of hepatic Kiss1. Elevated fasting glucose and glucose intolerance in the GTT were found in AAV-CRE compared to AAV-GFP females (P < 0.05). No differences in AAV-CRE and AAV-GFP male mice were found, indicating the importance of Kiss1 in glucose homeostasis in females. The insulin tolerance test was not statistically different between groups or treatments. Further research is required to elucidate the mechanism by which hepatic kisspeptin alters glucose metabolism in mice in a sexually-dimorphic fashion.