Acute loss of PLIN5 in brown adipocytes reveals its indispensable role in maintaining mitochondrial function and cold tolerance.

Cold exposure induces adaptive molecular and mitochondrial remodeling in brown adipose tissue (BAT) of mice to sustain thermogenesis. We previously showed that the lipid droplet protein Perilipin 5 (PLIN5) is strongly induced in BAT by cold exposure and promotes thermogenic gene expression, mitochondrial remodeling, and uncoupled respiration. However, constitutive BAT-specific PLIN5 deletion impaired mitochondrial function without causing cold intolerance, suggesting physiological compensation, likely via induction of thermogenic genes in white adipose tissue (WAT). To test this possibility, we generated mice with doxycycline-inducible BAT-specific PLIN5 deletion. Acute PLIN5 deletion in adult mice during cold exposure reduced BAT thermogenic gene expression, mitochondrial cristae density, and uncoupled mitochondrial respiration, which resulted in cold intolerance. Unlike constitutive PLIN5 knockout mice, mice acutely rendered deficient of PLIN5 in BAT failed to mount a compensatory thermogenic response in inguinal WAT. Together, these findings demonstrate that PLIN5 is required for mitochondrial homeostasis in brown adipocytes and for adaptive thermogenesis during cold exposure. Notably, by cell fractionation and protease protection assay, we observed that PLIN5 enriches on the outer mitochondrial membrane in BAT during cold exposure. We also observed that the absence of PLIN5 in BAT is not associated with reduced contacts between lipid droplets and mitochondria, thereby suggesting that the role of PLIN5 in adaptive thermogenesis may depend on its translocation to the mitochondrial outer membrane for a purpose unrelated to the formation of contacts between lipid droplets and mitochondria.