Role of leptin receptor-induced STAT3 signaling in modulation of intestinal and hepatic inflammation in mice

Leptin‐deficient ob/ob mice are resistant to dextran sulfate sodium (DSS)‐induced colitis and Concanavalin A (Con A)‐induced hepatitis. However, the signal transduction pathways involved have not been identified. The present study investigated the effect of leptin‐induced STAT3 signaling in the DSS and Con A models. Mice carrying a leptin receptor (LEPR) gene mutant for Y1138 (s/s mice), with abrogated leptin‐induced STAT3 signaling, were compared with wild‐type (WT) and LEPR‐deficient db/db mice. Administration of DSS to s/s mice resulted in a clinical score and colon shortening of intermediate severity compared with disease induced in WT and db/db mice—the latter group having the lowest disease severity. A comparable degree of inflammatory infiltrate and epithelial damage was observed in the colon of WT and s/s mice, and these parameters were reduced in db/db mice. Levels of IFN‐γ, IL‐6, IL‐10, and TNF‐α were comparable in the colon of s/s and db/db mice, and a similar trend was observed for CXCL2. s/s and WT mice developed severe liver disease in response to Con A, whereas db/db mice were protected. However, Con A‐induced serum IL‐6 and TNF‐α levels in s/s mice mimicked levels observed in db/db rather than WT mice. In conclusion, lack of leptin‐induced STAT3 signaling is associated with reduced cytokine production following DSS and Con A administration, but it appears to sensitize mice to the effects of proinflammatory mediators.