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CLSTN3ß enforces adipocyte multilocularity to facilitate lipid utilization.
Qian, Kevin; Tol, Marcus J; Wu, Jin; Uchiyama, Lauren F; Xiao, Xu; Cui, Liujuan; Bedard, Alexander H; Weston, Thomas A; Rajendran, Pradeep S; Vergnes, Laurent; Shimanaka, Yuta; Yin, Yesheng; Jami-Alahmadi, Yasaman; Cohn, Whitaker; Bajar, Bryce T; Lin, Chia-Ho; Jin, Benita; DeNardo, Laura A; Black, Douglas L; Whitelegge, Julian P; Wohlschlegel, James A; Reue, Karen; Shivkumar, Kalyanam; Chen, Feng-Jung; Young, Stephen G; Li, Peng; Tontonoz, Peter.
Affiliation
  • Qian K; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Tol MJ; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Wu J; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Uchiyama LF; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Xiao X; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Cui L; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Bedard AH; Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China.
  • Weston TA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Rajendran PS; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Vergnes L; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Shimanaka Y; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Yin Y; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Jami-Alahmadi Y; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Cohn W; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Bajar BT; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Lin CH; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Jin B; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • DeNardo LA; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Black DL; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
  • Whitelegge JP; Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Wohlschlegel JA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Reue K; Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles, Los Angeles, CA, USA.
  • Shivkumar K; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • Chen FJ; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • Young SG; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Li P; Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
  • Tontonoz P; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Nature ; 613(7942): 160-168, 2023 01.
Article in En | MEDLINE | ID: mdl-36477540
ABSTRACT
Multilocular adipocytes are a hallmark of thermogenic adipose tissue1,2, but the factors that enforce this cellular phenotype are largely unknown. Here, we show that an adipocyte-selective product of the Clstn3 locus (CLSTN3ß) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3ß is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER-LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3ß have abnormal LD morphology and altered substrate use in brown adipose tissue, and are more susceptible to cold-induced hypothermia despite having no defect in adrenergic signalling. Conversely, forced expression of CLSTN3ß is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3ß associates with cell death-inducing DFFA-like effector proteins and impairs their ability to transfer lipid between LDs, thereby restricting LD fusion and expansion. Functionally, increased LD surface area in CLSTN3ß-expressing adipocytes promotes engagement of the lipolytic machinery and facilitates fatty acid oxidation. In human fat, CLSTN3B is a selective marker of multilocular adipocytes. These findings define a molecular mechanism that regulates LD form and function to facilitate lipid utilization in thermogenic adipocytes.
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Full text: 1 Database: MEDLINE Main subject: Calcium-Binding Proteins / Adipocytes / Lipid Metabolism / Membrane Proteins Limits: Animals / Female / Humans Language: En Year: 2023 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Calcium-Binding Proteins / Adipocytes / Lipid Metabolism / Membrane Proteins Limits: Animals / Female / Humans Language: En Year: 2023 Type: Article