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CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

Author

Listed:
  • Kevin Qian

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Marcus J. Tol

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Jin Wu

    (Fudan University)

  • Lauren F. Uchiyama

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Xu Xiao

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Liujuan Cui

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Alexander H. Bedard

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Thomas A. Weston

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Pradeep S. Rajendran

    (University of California, Los Angeles
    Massachusetts General Hospital)

  • Laurent Vergnes

    (University of California, Los Angeles)

  • Yuta Shimanaka

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

  • Yesheng Yin

    (Fudan University)

  • Yasaman Jami-Alahmadi

    (University of California, Los Angeles)

  • Whitaker Cohn

    (University of California, Los Angeles)

  • Bryce T. Bajar

    (University of California, Los Angeles)

  • Chia-Ho Lin

    (University of California, Los Angeles)

  • Benita Jin

    (University of California, Los Angeles)

  • Laura A. DeNardo

    (University of California, Los Angeles)

  • Douglas L. Black

    (University of California, Los Angeles)

  • Julian P. Whitelegge

    (University of California, Los Angeles)

  • James A. Wohlschlegel

    (University of California, Los Angeles)

  • Karen Reue

    (University of California, Los Angeles)

  • Kalyanam Shivkumar

    (University of California, Los Angeles)

  • Feng-Jung Chen

    (Fudan University)

  • Stephen G. Young

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Peng Li

    (Fudan University
    Tsinghua University)

  • Peter Tontonoz

    (University of California, Los Angeles
    University of California, Los Angeles
    University of California, Los Angeles)

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 (CLSTN3β) present in only placental mammals facilitates the efficient use of stored triglyceride by limiting lipid droplet (LD) expansion. CLSTN3β is an integral endoplasmic reticulum (ER) membrane protein that localizes to ER–LD contact sites through a conserved hairpin-like domain. Mice lacking CLSTN3β 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 CLSTN3β is sufficient to enforce a multilocular LD phenotype in cultured cells and adipose tissue. CLSTN3β 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 CLSTN3β-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.

Suggested Citation

  • Kevin Qian & Marcus J. Tol & Jin Wu & Lauren F. Uchiyama & Xu Xiao & Liujuan Cui & Alexander H. Bedard & Thomas A. Weston & Pradeep S. Rajendran & Laurent Vergnes & Yuta Shimanaka & Yesheng Yin & Yasa, 2023. "CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization," Nature, Nature, vol. 613(7942), pages 160-168, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7942:d:10.1038_s41586-022-05507-1
    DOI: 10.1038/s41586-022-05507-1
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    Cited by:

    1. Chuanhai Zhang & Mengchen Ye & Kamran Melikov & Dengbao Yang & Goncalo Dias do Vale & Jeffrey McDonald & Kaitlyn Eckert & Mei-Jung Lin & Xing Zeng, 2024. "CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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