CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization

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, Yasaman Jami-Alahmadi, Whitaker Cohn, Bryce T. Bajar, Chia-Ho Lin, Benita Jin, Laura A. DeNardo, Douglas L. Black, Julian P. Whitelegge, James A. Wohlschlegel, Karen Reue, Kalyanam Shivkumar, Feng-Jung Chen, Stephen G. Young, Peng Li and Peter Tontonoz ()
Additional contact information
Kevin Qian: University of California, Los Angeles
Marcus J. Tol: University of California, Los Angeles
Jin Wu: Fudan University
Lauren F. Uchiyama: University of California, Los Angeles
Xu Xiao: University of California, Los Angeles
Liujuan Cui: University of California, Los Angeles
Alexander H. Bedard: University of California, Los Angeles
Thomas A. Weston: University of California, Los Angeles
Pradeep S. Rajendran: University of California, Los Angeles
Laurent Vergnes: University of California, Los Angeles
Yuta Shimanaka: 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
Peng Li: Fudan University
Peter Tontonoz: University of California, Los Angeles

Nature, 2023, vol. 613, issue 7942, 160-168

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05507-1

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