Of the >7000 tested substances, one chemical compound, termed MSL (4-(4-fluorophenyl)sulfonyl-5-methylthio-2-phenyloxazole), (i) enhanced autophagic activity through Tfeb activation, (ii) expedited lipid clearance, probably through lipophagy, and (iii) reduced inflammasome activation through amelioration of mitochondrial dysfunction both in vitro and in vivo, leading to improved metabolic profile of mice with genetic or diet-induced obesity. Here, TFEB is linked to obesity due to melanocortin 4 receptor deficiency.