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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.

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