Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice

Abstract

Kisspeptin regulates reproduction via signaling through the receptor, Kiss1r, in GnRH neurons. However, both kisspeptin and Kiss1r are produced in several peripheral tissues, and recent studies have highlighted a role for kisspeptin signaling in metabolism and glucose homeostasis. We recently reported that Kiss1r KO mice display a sexually-dimorphic metabolic phenotype, with KO females displaying obesity, impaired metabolism, and glucose intolerance at 4 -5 months of age. However, it remains unclear when this metabolic phenotype first emerges in development, or which aspects of the pleiotropic phenotype underlie the metabolic defects and which are secondary to the obesity. Here, we studied Kiss1r KO females at different ages, including several weeks before the emergence of body weight differences and later when obesity is present. We determined that at young adult ages (6 weeks old), KO females already exhibit altered adiposity, leptin levels, metabolism, and energy expenditure, despite having normal body weights at this time. In contrast, food intake, water intake, and glucose tolerance are normal at young ages, and only show impairments at older adult ages, suggesting that these impairments may be secondary to earlier alterations in metabolism and adiposity. We also demonstrate that, in addition to body weight, all other facets of the adult metabolic phenotype persist even when gonadal sex steroids are similar between genotypes. Collectively, these data highlight the developmental emergence of a metabolic phenotype induced by disrupted kisspeptin signaling, and reveal that multiple-but not all-aspects of this phenotype are already disrupted prior to detectable changes in body weight.

Conditional knockout of kisspeptin signaling in brown adipose tissue increases metabolic rate and body temperature and lowers body weight

“…[15][16][17] Here we further demonstrate that global Kiss1r KOs have lower body temperature and decreased BAT thermogenic gene expression, correlating with their lower metabolic rates. However, recent evidence from our group and others demonstrate that kisspeptin signaling is also important for non-reproductive processes, including metabolism and energy balance.…”

“…15,16 In addition to becoming obese, adult Kiss1r KO females also had increased adiposity, higher leptin levels, and substantially impaired glucose tolerance, both on standard chow and high-fat diets. Specifically, compared with WT littermates, global Kiss1r knockout (KO) female micelacking kisspeptin signaling in all tissues-displayed dramatically higher BWs beginning in early adulthood, weighing as much as 30% more than control females.…”

“…Specifically, compared with WT littermates, global Kiss1r knockout (KO) female micelacking kisspeptin signaling in all tissues-displayed dramatically higher BWs beginning in early adulthood, weighing as much as 30% more than control females. 15,16 Importantly, the BW and metabolic phenotype in Kiss1r KO females were not solely reflective of absent gonadal sex steroids, in particular ovarian estradiol (E 2 ), as longterm ovariectomized Kiss1r KO females still developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance versus similarly ovariectomized WT females (ovaries removed before puberty to permanently eliminate ovarian-derived E 2 in both genotypes) . 15,16 This obesity phenotype was sexually dimorphic, as Kiss1r KO males had normal BW and glucose regulation out to 6 months of age.…”

“…15,16 In addition to becoming obese, adult Kiss1r KO females also had increased adiposity, higher leptin levels, and substantially impaired glucose tolerance, both on standard chow and high-fat diets. 15,16 The findings above in Kiss1r KOs demonstrated that globally absent kisspeptin signaling can be an important factor in BW, adiposity, glucose tolerance, and metabolism, particularly in females. Despite their obesity, adult Kiss1r KO females did not have increased food intake, but they did display significantly reduced metabolic parameters, including lower respiratory rates and energy expenditure, suggesting that their obesity reflects, at least in part, lower daily energy expenditure.…”

Maternal plasma kisspeptin‐10 level in preeclamptic pregnant women and its relation in changing their reproductive hormones

“…Interestingly, studies with mice without a KP receptor (Kiss1r KO mice) showed that adult Kiss1r KO females remained on a standard chow diet revealed a marked increase in body weight compared to wild littermates . Following studies have shown that impaired kisspeptin signaling results in lower metabolism and energy expenditure, resulting in increased Kiss1r KO female mice adiposity . However, it is still unclear if increased levels of kisspeptin increase human energy expenditure.…”