Tolson Kristen P, Garcia Christian, Yen Stephanie, Simonds Stephanie, Stefanidis Aneta, Lawrence Alison, Smith Jeremy T, Kauffman Alexander S
J Clin Invest. 2014 Jul;124(7):3075-9. doi: 10.1172/JCI71075. Epub 2014 Jun 17.
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.
神经肽 kisspeptin 通过亲吻素受体 KISS1R 刺激促性腺激素释放激素（GnRH）神经元来调节生殖。除了 GnRH 神经元外，KISS1R 在其他脑区和外周组织中也有表达，这表明 kisspeptin 除了生殖功能外还有其他功能。在此，我们研究了缺乏 kisspeptin 信号传导的小鼠（Kiss1r 基因敲除小鼠）的能量和代谢表型。与野生型同窝小鼠相比，成年 Kiss1r 基因敲除雌性小鼠的体重、瘦素水平和肥胖程度显著更高，同时糖耐量明显受损。相反，雄性 Kiss1r 基因敲除小鼠的体重和血糖调节正常。令人惊讶的是，尽管 Kiss1r 基因敲除雌性小鼠肥胖，但它们的食量比野生型雌性小鼠少；然而，Kiss1r 基因敲除雌性小鼠的运动活性、呼吸频率和能量消耗明显降低，这并非由于甲状腺激素分泌受损所致。Kiss1r 基因敲除雌性小鼠的体重和代谢表型并非完全由性腺雌激素缺乏所致，因为与卵巢切除的野生型雌性小鼠相比，长期卵巢切除的 Kiss1r 基因敲除雌性小鼠出现了肥胖、高瘦素血症、代谢降低和糖耐量异常。我们的研究结果表明，除了生殖功能外，kisspeptin 信号传导以性别二态性和部分与性类固醇无关的方式影响体重、能量消耗和葡萄糖稳态；因此，kisspeptin 信号传导的改变可能直接或间接地导致人类肥胖、糖尿病或代谢功能障碍的某些方面。
