Acute deletion of PLIN5 in brown adipocytes causes mitochondrial dysfunction and cold intolerance

Cold exposure of mice is associated with adaptive molecular and organellar changes in brown adipose tissue (BAT) that promote thermogenesis to defend body temperature. We previously reported that the lipid droplet protein Perilipin 5 (PLIN5) robustly increases in BAT during acute exposure of mice to cold. We demonstrated that chronic induction of BAT PLIN5 within the physiological range in mice housed at room temperature mimics the effects of cold exposure in terms of increased thermogenic gene expression in BAT, increased BAT mitochondria cristae packing, and increased uncoupled mitochondrial respiration. Additionally, BAT PLIN5 overexpression led to healthy remodeling of inguinal white adipose tissue with improved systemic glucose tolerance and reduced diet-induced hepatic steatosis. Conversely, PLIN5 constitutive deletion in brown adipose tissue resulted in decreased BAT thermogenic gene expression and in BAT mitochondrial dysfunction but did not lead to cold intolerance or changes in glucose tolerance. We hypothesized that preserved cold tolerance despite chronic deficiency of PLIN5 in BAT was the result of compensatory white adipose tissue (WAT) beiging, as suggested by the observed increase in thermogenic gene expression in inguinal WAT (iWAT). To test this hypothesis, we developed a mouse model of doxycycline-inducible, acute deficiency of PLIN5 in BAT of adult mice (BiKOPLIN5 mice). After 7 days of doxycycline treatment and housing at 6 °C, PLIN5 was significantly reduced in the BAT of BiKOPLIN5 mice compared with littermate control mice but was unchanged in the iWAT of these experimental groups. Under these conditions, thermogenic gene expression was reduced significantly in the BAT of BiKOPLIN5 mice compared to Control mice, as were mitochondrial cristae density and uncoupled BAT mitochondrial respiration. These effects of acute PLIN5 deficiency in BAT were associated with cold intolerance, which was consistent with the observed failure in iWAT of thermogenic gene expression to increase beyond that of Controls. These findings clarify the essential role of BAT PLIN5 in the physiological adaptive responses of mice to cold ambient temperature.