The 14th Ile residue is essential for Leptin function in regulating energy homeostasis in rat

نویسندگان

  • Shuyang Xu
  • Xianmin Zhu
  • Hong Li
  • Youtian Hu
  • Jinping Zhou
  • Di He
  • Yun Feng
  • Lina Lu
  • Guizhen Du
  • Youjin Hu
  • Tiancheng Liu
  • Zhen Wang
  • Guohui Ding
  • Jiayu Chen
  • Shaorong Gao
  • Fang Wu
  • Zhigang Xue
  • Yixue Li
  • Guoping Fan
چکیده

LEPTIN (LEP) is a circulating hormone released primarily from white adipocytes and is crucial for regulating satiety and energy homeostasis in humans and animals. Using the CRISPR technology, we created a set of Lep mutant rats that carry either null mutations or a deletion of the 14(th) Ile (LEP(∆I14)) in the mature LEP protein. We examined the potential off-target sites (OTS) by whole-genome high-throughput sequencing and/or Sanger-sequencing analysis and found no OTS in mutant rats. Mature LEP(∆I14) is incessantly produced and released to blood at a much elevated level due to the feedback loop. Structure modeling of binding conformation between mutant LEP(∆I14) and LEPTIN receptor (LEPR) suggests that the conformation of LEP(∆I14) impairs its binding with LEPR, consistent with its inability to activate STAT3-binding element in the luciferase reporter assay. Phenotypic study demonstrated that Lep(∆I14) rats recapitulate phenotypes of Lep-null mutant rats including obesity, hyperinsulinemia, hepatic steatosis, nephropathy, and infertility. Compared to the existing ob/ob mouse models, this Lep(∆I14/∆I14) rat strain provides a robust tool for further dissecting the roles of LEP in the diabetes related kidney disease and reproduction problem, beyond its well established function in regulating energy homeostasis.

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عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2016