Role of Jak3 in Kupffer‐cell mediated hepatic steatosis during obesity

Background Janus kinase 3 (Jak3), a non‐receptor protein kinase, plays an essential role in hematopoietic cell‐growth and differentiation of intestinal epithelial mucosa. Previously, we have shown that loss of Jak3 exacerbates symptoms of obesity associated metabolic syndrome in a murine model of diet‐induced obesity through compromised intestinal barrier functions and induction of chronic low‐grade inflammation (CLGI). Though, recent studies suggest a strong linkage between CLGI and hepatic steatosis, the genetic regulation of intestinal dysbiosis and their role in hepatic steatosis is not known. In this report, we investigated the tissue‐specific role of Jak3 in maintaining hepatic homeostasis during obesity associated metabolic syndrome. Methods In order to test our hypothesis, we used a global Jak3 KO ( Jak3 −/− ) mice model and compared its effect with either the intestinal epithelial specific Jak3 KO (Int Jak3 KO) mice or immune cell specific Jak3 KO (Imm Jak3 KO) mice in a model of diet‐induced obesity. The organs were collected at the end of the study period under aseptic conditions and analyzed using a combination of flowcytometric, confocal microscopy, and western analysis techniques. Results Our results show increased susceptibility to obesity associated metabolic syndrome in high‐fat diet treated Jak3 −/− mice compared to their co‐housed littermates. Jak3 −/− mice showed increased predisposition to CLGI, hepatic steatosis, increased liver to body weight ratio, and hyperglycemia compared to their co‐housed littermate controls. To determine the tissue specific role of Jak3, a high‐degree of association between CLGI and hepatic inflammation in Imm Jak3 KO mice, indicated a prominent role of hematopoietic Jak3 in maintaining Kupffer‐cell mediated hepatic steatosis. A differential flowcytometric assay showed an increased influx of monocytes, but reduced differentiation of residential Kupffer cells in imm Jak3 KO mice compared to its floxed control during diet‐induced obesity. Further, the same group of mice also showed an increased hepatic expression of TLR‐2 and TLR‐4 and a higher IL‐6, IL‐17 and Tnf‐α as compared to the control mice. Together, these results showed that a lack of Jak3 expression in immune cells leads to CLGI and a compromise in the activation of Kupffer cells coupled with increased extravasation of the circulating monocytes into the liver. This could lead to hepatic steatosis in obesity. In addition, we also found an increased Th 17 effector function and simultaneous suppression of T reg cell proliferation in the absence of immune cell Jak3, when compared to its control mice, on treatment with HFD. Conclusion Collectively, these results indicate that Jak3 plays a major role in regulating the macrophage based hepatic homeostasis. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .