Liver-Specific Kisspeptin Deletion Impairs Energy Metabolism in Mice

Kisspeptin, a neuroendocrine protein critical for the control of pubertal development and fertility has been shown to be modulated by nutritional signals. While the secretion of kisspeptin from specific hypothalamic nuclei is well-known to regulate GnRH-mediated pubertal maturation and reproduction, it remains unclear what role peripheral kisspeptin, specifically of hepatic origin, plays in regulating metabolism and glucose homeostasis. To define the role of kisspeptin in the liver, we developed a novel Kiss1(f/f) mouse line and targeted liver-specific Kiss1 ablation by injecting a AAV8-TBG-iCre virus via the tail vein (LKiss1KO). Control mice included Kiss1(f/f) male and female mice injected with AAV-GFP (LKiss1WT). We previously showed that deletion of hepatic kisspeptin did not affect body weight, but resulted in decreased insulin secretion and glucose intolerance in both sexes. To clarify the effects of liver-specific Kiss1 knockout on insulin action and glucose homeostasis in vivo, we conducted hyperinsulinemic-euglycemic clamp studies three weeks after tail injections. We noted a sexual dimorphism in the glucose infusion rate (GIR), female mice have a higher GIR to maintain euglycemia associated with an elevated glucose consumption rate, suggesting that female mice are more insulin sensitive than male mice. However, the deletion of liver kisspeptin had no effect on the glucose production rate in either sex. Indirect calorimetry assessment was conducted 4 weeks post-injection. Both male and female LKiss1KO mice showed significantly higher oxygen consumption, carbon dioxide production, and increased energy expenditure as compared to the LKiss1WT groups. However, there were no differences in either the respiratory exchange ratio or total ambulatory activity among treatments. These findings clearly define a pivotal role for hepatic Kiss1 in the modulation of insulin secretion to maintain glucose homeostasis without modulating glucose production as well as in maintaining energy homeostasis in both male or female mice.