TFEB, a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and controls lipid catabolism via PGC1α and PPARα. During starvation, TFEB links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a novel therapeutic strategy for lipid metabolism disorders. The adaptive response to food deprivation involves major transcriptional and metabolic changes and is conserved across evolution. One of the most prominent metabolic changes during starvation is an increase in lipid catabolism in the liver. Autophagy, a lysosome-dependent catabolic process, is activated by starvation, and the resulting breakdown products are used to generate new cellular components and energy. Recent studies revealed that autophagy plays a central role in lipid metabolism since it shuttles lipid droplets to the lysosome where they are hydrolyzed into free fatty acids (FFAs) and glycerol. Excessive lipid overload may inhibit autophagy, while enhancing liver autophagy in murine genetic models of obesity (Ob/Ob) ameliorates their metabolic phenotype. These observations indicate the close relationship between intracellular lipid metabolism and the lysosomal-autophagic pathway. TFEB is induced by starvation through an autoregulatory loop. Starvation time-course studies of HeLa cells, mouse embryonic fibroblasts (MEFs) and hepatocytes revealed a significant and progressive increase of TFEB mRNA and protein expression levels starting as soon as 4 hours after the elimination of nutrients from the culture medium. These observations led us to hypothesize that TFEB exerted a positive effect on its own transcription. The overexpression of the human TFEB cDNA in MEFs from heterozygous Tcfeb-β-gal transgenic mice resulted in a significant increase in the transcription of the Tcfeb-β-galactosidase fusion transcript, indicating that the endogenous TFEB gene is positively regulated by the exogenous TFEB. These results indicate that exogenous TFEB can induce endogenous Tcfeb expression and suggest the presence of a positive feedback loop. TFEB regulates genes involved in lipid metabolism via PGC1α and PPARα. To test whether TFEB is in the metabolic response to starvation, we sought to define the complete TFEB-dependent transcriptome in the liver, a primary site for the organismal starvation response. Microarray analysis indicated that as a result of TFEB overexpression 773 genes were upregulated and 611 genes were downregulated. The gene ontology category most significantly up-regulated by TFEB overexpression was the cellular lipid metabolic process. SeveralTFEB, a master regulator of lysosomal biogenesis and autophagy, is induced by starvation through an autoregulatory feedback loop and controls lipid catabolism via PGC1α and PPARα. During starvation, TFEB links the autophagic pathway to cellular energy metabolism. The conservation of this mechanism in Caenorhabditis elegans suggests a fundamental role for TFEB in the adaptive response to food deprivation. Viral delivery of TFEB to the liver prevented weight gain and metabolic syndrome in both diet-induced and genetic mouse models of obesity, suggesting a novel therapeutic strategy for lipid metabolism disorders. The adaptive response to food deprivation involves major transcriptional and metabolic changes and is conserved across evolution. One of the most prominent metabolic changes during starvation is an increase in lipid catabolism in the liver. Autophagy, a lysosome-dependent catabolic process, is activated by starvation, and the resulting breakdown products are used to generate new cellular components and energy. Recent studies revealed that autophagy plays a central role in lipid metabolism since it shuttles lipid droplets to the lysosome where they are hydrolyzed into free fatty acids (FFAs) and glycerol. Excessive lipid overload may inhibit autophagy, while enhancing liver autophagy in murine genetic models of obesity (Ob/Ob) ameliorates their metabolic phenotype. These observations indicate the close relationship between intracellular lipid metabolism and the lysosomal-autophagic pathway. TFEB is induced by starvation through an autoregulatory loop. Starvation time-course studies of HeLa cells, mouse embryonic fibroblasts (MEFs) and hepatocytes revealed a significant and progressive increase of TFEB mRNA and protein expression levels starting as soon as 4 hours after the elimination of nutrients from the culture medium. These observations led us to hypothesize that TFEB exerted a positive effect on its own transcription. The overexpression of the human TFEB cDNA in MEFs from heterozygous Tcfeb-β-gal transgenic mice resulted in a significant increase in the transcription of the Tcfeb-β-galactosidase fusion transcript, indicating that the endogenous TFEB gene is positively regulated by the exogenous TFEB. These results indicate that exogenous TFEB can induce endogenous Tcfeb expression and suggest the presence of a positive feedback loop. TFEB regulates genes involved in lipid metabolism via PGC1α and PPARα. To test whether TFEB is in the metabolic response to starvation, we sought to define the complete TFEB-dependent transcriptome in the liver, a primary site for the organismal starvation response. Microarray analysis indicated that as a result of TFEB overexpression 773 genes were upregulated and 611 genes were downregulated. The gene ontology category most significantly up-regulated by TFEB overexpression was the cellular lipid metabolic process. Several