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bioRxiv · 10.64898/2026.10.22.760470

A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation

Chen, Y.·Chen, L.·Zhao, Z.·Lu, T.·Guan, Y.·Loureiro, Z. Y.·Kajimura, S.
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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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Chen, Y., Chen, L., Zhao, Z., Lu, T., Guan, Y., Loureiro, Z. Y., Kajimura, S.. 2026-10-27. A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation. https://doi.org/10.64898/2026.10.22.760470

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