Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity

Abstract

The neuropeptide kisspeptin regulates reproduction by stimulating gonadotropin-releasing hormone (GnRH) neurons via the kisspeptin receptor KISS1R. In addition to GnRH neurons, KISS1R is expressed in other brain areas and peripheral tissues, which suggests that kisspeptin has additional functions beyond reproduction. Here, we studied the energetic and metabolic phenotype in mice lacking kisspeptin signaling (Kiss1r KO mice). Compared with WT littermates, adult Kiss1r KO females displayed dramatically higher BW, leptin levels, and adiposity, along with strikingly impaired glucose tolerance. Conversely, male Kiss1r KO mice had normal BW and glucose regulation. Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females; however, Kiss1r KO females displayed markedly reduced locomotor activity, respiratory rate, and energy expenditure, which were not due to impaired thyroid hormone secretion. The BW and metabolic phenotype in Kiss1r KO females was not solely reflective of absent gonadal estrogen, as chronically ovariectomized Kiss1r KO females developed obesity, hyperleptinemia, reduced metabolism, and glucose intolerance compared with ovariectomized WT females. Our findings demonstrate that in addition to reproduction, kisspeptin signaling influences BW, energy expenditure, and glucose homeostasis in a sexually dimorphic and partially sex steroid-independent manner; therefore, alterations in kisspeptin signaling might contribute, directly or indirectly, to some facets of human obesity, diabetes, or metabolic dysfunction. IntroductionThe neuropeptide kisspeptin (encoded by KISS1) and its receptor, KISS1R (formerly known as GPR54), are key regulators of reproduction. Humans and mice with mutations in these genes show impaired puberty, hypogonadism, and infertility (1-3). Kisspeptin activates the reproductive axis by directly stimulating, via KISS1R, gonadotropin-releasing hormone (GnRH) neurons (4). Although kisspeptin is expressed in discrete brain regions (5), it is also present in some peripheral tissues (6-8). Likewise, Kiss1r is also expressed in multiple non-GnRH brain areas and in several peripheral tissues (8-10), including metabolic tissues like fat, liver, and pancreas. This suggests that kisspeptin has additional uncharacterized roles outside of reproduction. Yet, thus far, virtually all research on kisspeptin signaling has focused on reproductive regulation. Changes in energy status or metabolic signals affect both reproduction and hypothalamic kisspeptin levels (11, 12), which suggests that kisspeptin neurons mediate metabolic effects on reproductive status. However, whether kisspeptin signaling also plays a reciprocal role in regulating energy and metabolic status is unclear. Young Kiss1 KO, Kiss1r KO, and WT mice display no genotype differences in BW (3); however, in that study, BW was only measured before full maturity, and other metabolic parameters were not assessed. Initial studies in male rats found no effects of central kisspeptin on

Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats

“…Surprisingly, despite their obesity, Kiss1r KO females ate less than WT females. The finding that Kiss1r KO mice have decreased food intake despite increased body weight (Tolson et al 2014) is not consistent with our data. In the current experiment, kisspeptin has been shown to affect food intake only in younger female rats, whereas adult female mice have been found to have decreased food intake.…”

“…The studies on the effects of kisspeptin on food intake and body weight are controversial. A recent study (Tolson et al 2014) has demonstrated that kisspeptin signaling has a potential to become an important and novel regulator of energy metabolism besides governing reproduction. In that study, adult female mice lacking kisspeptin signaling (Kiss1r KO) displayed dramatically higher body weight, leptin levels, and adiposity, along with strikingly impaired glucose tolerance.…”

“…Kisspeptin neurons are relatively well known to mediate metabolic effects on reproductive status (De Bond & Smith 2014, Roa & Tena-Sempere 2014. Adult female mice lacking kisspeptin signaling (kiss1r KO) displayed dramatically higher body weight (Tolson et al 2014), which also suggests that kisspeptin signaling also plays a reciprocal role in regulating energy and metabolic status. The modulatory effects of RFRP on kisspeptin are important in terms of not only reproductive functions but also nutritional aspects.…”

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

“…We previously reported that body weight at 18 -20 weeks old was still markedly higher in KO than control females even when both genotypes had been chronically without gonadal sex steroids (14). However, additional measures besides body weight were not previously assessed.…”

“…We recently reported that, in addition to stimulating the reproductive axis, the kisspeptin system is also an important player in body weight (BW), energy balance, and glucose regulation (14). We found that, compared with WT littermates, adult Kiss1r knockout (KO) females maintained on a standard chow diet displayed dramatically higher BWs, but this phenotype did not emerge not until early adulthood, beginning around 10 weeks of age.…”