The accumulation of dysfunctional proteins and organelles is a defining feature of metabolic disease in nearly every tissue. A key pathway addressing this challenge is the autophagy-lysosome system which serves to identify, sequester, and degrade cellular components. Here, I first report on harnessing TFEB, a transcription factor master regulator of genes involved in autophagy-lysosome biogenesis, lipid metabolism, and mitochondrial metabolism to drive this pathway in adipocytes. We found that TFEB overexpression protects mice from diet induced obesity and adverse metabolic sequelae including insulin resistance and hepatic steatosis. TFEB modestly induces expression of autophagy and lysosomal genes, but this targeting seemed insufficient to explain the observed metabolic phenotypes. Instead, we found that TFEB robustly induced expression of mitochondrial and lipid metabolic genes, resulting in enhanced thermogenesis. We identified the transcriptional coactivator PGC-1[alpha] as a key target of TFEB in adipocytes and demonstrated that TFEB-induced effects were largely PGC-1[alpha] dependent. These studies position TFEB as a potent regulator of adipocyte physiology with implications for targeting this pathway therapeutically.Second, I functionally characterized genetic variants in the Lysosomal Acid Lipase (LIPA) genetic risk locus for coronary artery disease. LIPA is the sole lysosomal cholesterol esterase crucial for lipid metabolism in the atherosclerotic plaque, and rare loss-of-function variants lead to severe cholesterol accumulation and early death. As a whole, we found the risk variants were associated with a gain-of-function in human monocyte enzyme activity and expression attributable to intronic variants in the locus. We also identified a single exonic variant in the risk locus resulting in the amino acid substitution T16P which could plausibly disrupt enzyme trafficking amounting to a net loss of function. Studied in isolation, however, the exonic variant did not functionally impair enzyme expression, secretion, stability, or trafficking to the lysosome. These results establish the LIPA risk locus for coronary artery disease as resulting from a gain-of-function and set the stage for future studies mechanistically exploring mechanisms of pathogenesis.