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PreprintCC BYbioRxiv

A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation

  • Yong Chen1,2
  • Li Chen3
  • Zezhou Zhao1,2,4
  • Tian Lu1,2
  • Youchen Guan1,2
  • Zinger Yang Loureiro1
  • Shingo Kajimura1,2
4 affiliations
  1. 1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  2. 2Howard Hughes Medical Institute, Chevy Chase, VA, USA
  3. 3Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  4. 4Harvard/MIT MD-PhD Program, Biological and Biomedical Sciences Program, Boston, MA, USA; Harvard/MIT Program in Health, Sciences, and Technology, Cambridge, MA, USA
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Abstract

Temperature is a fundamental determinant of mammalian metabolism. The canonical cold-adaptation pathway involves cold sensing by peripheral sensory neurons, which activate sympathetic outflow, {beta}-adrenergic signaling, and lipolysis in adipose tissue. In contrast, we report here a cell-intrinsic mechanism by which physiologically relevant cooling temperatures (27-31 oC) enhance lipolysis in subcutaneous adipose tissue. Mechanistically, cooling drives liquid-liquid phase separation (LLPS) of perilipin 1 (PLIN1), the dominant lipid droplet coat protein, promoting its condensation and the local recruitment of PKA to the droplet surface. This spatial reorganization selectively amplified PKA-mediated perilipin 1 phosphorylation, CGI-58 release, and ATGL-dependent lipolysis. The process depends on the intrinsically disordered region (IDR) of perilipin1, where four aromatic residues, conserved in endotherms but not in ectotherms, are required for cooling-induced LLPS and lipolysis in vivo. Notably, targeted delivery of an LLPS-competent perilipin 1 variant to the inguinal adipose tissue of mice enhanced local lipolysis and reduced depot mass. Together, these findings uncover a cell-intrinsic thermosensitive mechanism that can tune lipolytic responsiveness, offering a possible strategy for targeted depot-selective fat reduction.

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Cite

BibTeXRIS
BibTeX
@misc{chen2026cellautonomous,
  title = {{A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation}},
  author = {Yong Chen and Li Chen and Zezhou Zhao and Tian Lu and Youchen Guan and Zinger Yang Loureiro and Shingo Kajimura},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.22.760470},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.22.760470v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation
AU  - Yong Chen
AU  - Li Chen
AU  - Zezhou Zhao
AU  - Tian Lu
AU  - Youchen Guan
AU  - Zinger Yang Loureiro
AU  - Shingo Kajimura
PY  - 2026
DA  - 2026/10/22
PB  - bioRxiv
DO  - 10.64898/2026.10.22.760470
UR  - https://www.biorxiv.org/content/10.64898/2026.10.22.760470v1
AB  - Temperature is a fundamental determinant of mammalian metabolism. The canonical cold-adaptation pathway involves cold sensing by peripheral sensory neurons, which activate sympathetic outflow, {beta}-adrenergic signaling, and lipolysis in adipose tissue. In contrast, we report here a cell-intrinsic mechanism by which physiologically relevant cooling temperatures (27-31 oC) enhance lipolysis in subcutaneous adipose tissue. Mechanistically, cooling drives liquid-liquid phase separation (LLPS) of perilipin 1 (PLIN1), the dominant lipid droplet coat protein, promoting its condensation and the local recruitment of PKA to the droplet surface. This spatial reorganization selectively amplified PKA-mediated perilipin 1 phosphorylation, CGI-58 release, and ATGL-dependent lipolysis. The process depends on the intrinsically disordered region (IDR) of perilipin1, where four aromatic residues, conserved in endotherms but not in ectotherms, are required for cooling-induced LLPS and lipolysis in vivo. Notably, targeted delivery of an LLPS-competent perilipin 1 variant to the inguinal adipose tissue of mice enhanced local lipolysis and reduced depot mass. Together, these findings uncover a cell-intrinsic thermosensitive mechanism that can tune lipolytic responsiveness, offering a possible strategy for targeted depot-selective fat reduction.
SN  - 2692-8205
ER  -