MSDC-0602 is a PPARγ-sparing thiazolidinedione derivative.1 It binds only weakly to PPARγ (IC50 = 18.25 ?M) and induces minimal activation of a Gal4-PPARγ reporter construct when used at a concentration of 50 ?M. MSDC-0602 binds to mitochondrial membranes and decreases the pyruvate-induced oxygen consumption rate in control mitochondria but not in liver-specific mitochondrial pyruvate carrier 2 knockout (LS-Mpc2-/-) mitochondria.2 It reduces body weight gain and adiposity, as well as increases intrascapular brown adipose tissue (BAT) mass in a mouse model of non-alcoholic steatohepatitis (NASH) induced by a high-trans-fat, -fructose, and -cholesterol diet when administered in the diet for 12 weeks, starting four weeks after the beginning of the diet.3 It also reverses hepatic fibrosis and stellate cell fibrinogenesis when administered for three weeks, starting 16 weeks after the beginning of the diet. MSDC-0602 decreases plasma glucose, triglyceride, and cholesterol levels in ob/ob mice and increases insulin sensitivity in the striatal muscle, adipose tissue, and liver of diet-induced obese mice.1
1.Chen, Z., Vigueira, P.A., Chambers, K.T., et al.Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor γ-sparing thiazolidinedioneJ. Biol. Chem.287(28)23537-23548(2012) 2.McCommis, K.S., Chen, Z., Fu, X., et al.Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cyclingCell Metab.22(4)682-694(2015) 3.McCommis, K.S., Hodges, W.T., Brunt, E.M., et al.Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitisHepatology65(5)1543-1556(2017)