المؤلفون: Wada, Shogo, Neinast, Michael, Jang, Cholsoon, Ibrahim, Yasir H, Lee, Gina, Babu, Apoorva, Li, Jian, Hoshino, Atsushi, Rowe, Glenn C, Rhee, James, Martina, José A, Puertollano, Rosa, Blenis, John, Morley, Michael, Baur, Joseph A, Seale, Patrick, Arany, Zoltan

المصدر: Genes & Development. 30(22)

مصطلحات موضوعية: Brain Disorders, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Respiration, Cytoplasm, Gene Deletion, Male, Mice, Mitochondria, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors, Tumor Suppressor Proteins, adipose tissue, beige fat, mitochondria, FLCN, mTOR, TFE3, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Developmental Biology

الوصف: Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor 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 adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8zt139qzTest

المؤلفون: Martina, José A.¹ (AUTHOR), Puertollano, Rosa¹ (AUTHOR) puertolr@mail.nih.gov

المصدر: Molecular Cell. Aug2022, Vol. 82 Issue 15, p2732-2734. 3p.

مصطلحات موضوعية: *IMMUNE response, *WEAPONS, *MITOCHONDRIA

مستخلص: Zhang et al. (2022) report that itaconate, a mitochondrial metabolite produced by macrophages upon inflammatory stimuli, activates the master regulator of lysosomal biogenesis TFEB to facilitate clearance of invading bacteria and efficient immune response. [ABSTRACT FROM AUTHOR]

المؤلفون: Shogo Wada¹, Neinast, Michael¹, Jang, Cholsoon^1,2, Ibrahim, Yasir H.³, Lee, Gina³, Babu, Apoorva¹, Jian Li¹, Atsushi Hoshino¹, Rowe, Glenn C.⁴, Rhee, James⁵, Martina, José A.⁶, Puertollano, Rosa⁶, Blenis, John³, Morley, Michael¹, Baur, Joseph A.¹, Seale, Patrick¹, Arany, Zoltan¹ zarany@mail.med.upenn.edu

المصدر: Genes & Development. 11/15/2016, Vol. 30 Issue 22, p8-8. 1p.

مصطلحات موضوعية: *TUMOR suppressor proteins, *ESTRONE, *MTOR protein, *ADIPOSE tissues, *GENETIC mutation

مستخلص: Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor 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 adipose tissue browning, as does codeletion of PGC-1ß. Conversely, inducible expression of PGC-1ß in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1ß pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue. [ABSTRACT FROM AUTHOR]