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.Our investigations establish that RBP4 expressed in adipocytes induces hepatic steatosis arising from primary effects occurring in adipose tissue. (Hepatology 2016;64:1534-1546).