Multidrug resistance protein 4 (Mrp4) regulates nutrient and energy metabolism by altering the adipose tissue physiology

Abstract

Multidrug resistance protein 4 (Mrp4; encoded by Abcc4) belongs to the ATP‐binding cassette efflux transporter superfamily and transports several xenobiotics and endogenous molecules, such as prostaglandins and cyclic nucleotides. Mrp4 is highly expressed in the kidney and bladder, with minimal expression detected in the liver. We recently determined that the lack of Mrp4 increases adipose tissue and body weights in mice. Interestingly, the expression of Mrp4 and its role in adipose tissue physiology, nutrient metabolism and the pathogenesis of metabolic diseases are unknown. The current study was aimed at characterizing these specific roles of Mrp4 employing wildtype (WT) and knockout (Mrp4−/−) mice. Our studies determined that Mrp4 is expressed in high levels in adipose tissue and that the lack Mrp4 resulted in adipocyte hypertrophy. Along with increases in body and adipose tissue weights, lack of Mrp4 in mice also resulted in increased blood glucose and leptin levels, and impaired glucose tolerance. Additionally, Mrp4−/− mice have increased levels of adipose tissue phospho‐cAMP response element binding protein (p‐Creb), which is known to regulate adipocyte glucose and lipid metabolism. In contrast to altered glucose metabolism, Mrp4−/− mice did not show any significant changes in plasma triglycerides, free fatty acids or total cholesterol levels compared to WT mice. Indirect calorimetry measurements under basal conditions showed that Mrp4−/− mice have decreased volumetric oxygen consumption (VO2), respiratory exchange ratio (RER), energy expenditure (EE), ambulatory activity (AA) and wheel counts compared to WT mice. Decreased indirect calorimetry parameters and impaired glucose metabolism in Mrp4−/− mice can be attributed to increased adipose tissue weights, which complements the observed obese and diabetic phenotype in these mice. Together, our data indicate that Mrp4 regulates nutrient and energy metabolism by altering the adipose tissue physiology. In conclusion, the absence of Mrp4 function in mice results in the development of obesity and diabetes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.