Adipocyte‐specific overexpression of retinol‐binding protein 4 causes hepatic steatosis in mice

There is considerable evidence that both retinoids and retinol‐binding protein 4 (RBP4) contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human RBP4 (hRBP4) specifically in adipocytes. When fed a chow diet, these mice show an elevation in adipose total RBP4 (mouse RBP4 + hRBP4) protein levels. However, no significant differences in plasma RBP4 or retinol levels or in hepatic or adipose retinoid (retinol, retinyl ester, and all‐trans‐retinoic acid) levels were observed. Strikingly, male adipocyte‐specific hRBP4 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3‐4 months of age compared to matched littermate controls. When mice were fed a high‐fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance), worsened. Because adipocyte‐specific hRBP4 mice have increased tumor necrosis factor‐α and leptin expression and crown‐like structures in adipose tissue, our data are consistent with the notion that adipose tissue is experiencing RBP4‐induced inflammation that stimulates increased lipolysis within adipocytes. Our data further establish that elevated hepatic triglyceride levels result from increased hepatic uptake of adipose‐derived circulating free fatty acids. We obtained no evidence that elevated hepatic triglyceride levels arise from increased hepatic de novo lipogenesis, decreased hepatic free fatty acid oxidation, or decreased very‐low‐density lipoprotein secretion. Conclusion: Our investigations establish that RBP4 expressed in adipocytes induces hepatic steatosis arising from primary effects occurring in adipose tissue. (Hepatology 2016;64:1534‐1546)