7A, B). mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth element and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues corpulence tissue browning, as does codeletion of PGC-1. Conversely, inducible expression of PGC-1 in white corpulence tissue is sufficient to induce beige fat gene expression in festn. These data thus unveil a novel FLCNmTORTFE3PGC-1 pathwayseparate from the canonical TSCmTORS6K pathwaythat regulates browning of corpulence tissue. White adipose tissue (WAT) stores energy, while brown corpulence tissue (BAT) dissipates energy via thermogenesis. The activation of mitochondrial biogenesis and a browning program in WAT has gained traction recently as a possible approach to combat obesity and diabetes (Harms and Seale 2013). Understanding the mechanisms underlying corpulence tissue browning is therefore of great interest. Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a critical multiprotein signaling hub nucleated around the protein raptor and conserved from yeast to humans that integrates intracellular and extracellular cues to regulate cellular growth and metabolism (Zoncu et al. 2011; Dibble and Manning 2013; Goberdhan et al. 2016). Numerous signals affect mTORC1 function, including amino acids levels, oxygen tension, and the presence of growth factors. At the same time, mTORC1 outputs vary widely from increasing protein synthesis and mRNA synthesis to regulation of lipid synthesis and autophagy. How separate inputs to mTORC1 can segregate to separate outputs (i. e., how functional specificity is achieved) remains an enigmatic aspect of mTOR signaling. The role of mTOR in adipocyte browning is unclear. Loss of raptor in fat and portions of the brain leads to browning of WAT (Polak et al. 2008), while activation of mTOR in the same tissue distribution via deletion of tuberous sclerosis complex-1 (TSC1) leads to whitening of BAT (Xiang et al. 2015), suggesting that mTOR suppresses corpulence browning in vivo. On the other hand, recent work shows that loss of raptor in fat or pharmacological inhibition GRL0617 of mTOR blocks cold-induced browning of WAT (Liu et al. 2016; Tran et al. 2016), demonstrating that mTOR can also promote adipose browning in GRL0617 festn. A mechanistic reconciliation of these observations is lacking. Germline heterozygous mutations in folliculin (FLCN) cause Birt-Hogg-Dub (BHD) syndrome, a hamartomatous GRL0617 disease marked by renal cell tumors with loss of heterozygosity and impressive increases in mitochondrial content (Schmidt 2013). In mice, genetic deletion of FLCN in renal cells induces mitochondrial biogenesis via the transcriptional coactivator PGC-1, although how this GRL0617 occurs is not known (Hasumi et al. 2012). Biochemically, FLCN was recognized recently as a GTP-activating protein (GAP) intended for RagC/D, which, in its GDP-bound state, activates mTORC1, implicating FLCN as a positive regulator of the mTOR pathway (Petit et al. 2013; Tsun et al. 2013). On the other hand, tumors with FLCN deletions typically uncover elevated mTOR activity (Baba et al. 2008), as is also noticed following deletion of FLCN in murine hearts (Hasumi et al. 2014), suggesting that, under chronic conditions, counterregulatory signals maintain or even increase mTOR activity in the absence of FLCN. How deletion of FLCN drives PGC-1 and GRL0617 mitochondrial biogenesis and whether the process involves mTOR activation or suppression are not known. The transcription element TFE3 is a member of the MiTF gene family that contains four highly homologous transcription factors: MiTF, TFE3, TFEB, and TFEC. MiTF and TFEC have specialized roles in melanocytes and monocytes, respectively (Rehli et al. 1999; Haq et al. 2013; Shoag et al. 2013), while TFE3 and TFEB are more widely expressed, including in corpulence tissue. TFEB regulates a broad program of lysosomal biogenesis in numerous cell DLEU7 types (Sardiello et al. 2009; Settembre et al. 2011). The role of TFE3 is less well understood. Conventional TFE3 knockout animals do not show any obvious phenotype (Steingrimsson et al. 2002). In pluripotent stem cells, TFE3 favors the maintenance of a pluripotent state, which, interestingly, is.