The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure

Adaptive thermogenesis in brown adipose tissue is regulated by PPARGC1A (PGC-1α), which could be affected by common polymorphism (rs8192678, Gly482Ser) that associates with metabolic disorders. We used CRISPR-Cas9 in immortalized human brown adipocyte cell line to edit the rs8192678 locus to evaluate the allele-dependent effects on cold response of brown adipocytes. In both 482Ser- and 482Gly-edited brown adipocytes, UCP1 expression increased after 6-hour cold exposure, but the increase was less pronounced in 482Gly cells, which also had lower mitochondrial activity. Furthermore, 482Gly PGC-1α had an almost two-fold longer half-life at 37°C, and four-fold longer half-life at 32°C, compared with the 482Ser variant. Despite the longer half-life, the 482Gly PGC-1α had lower activity, and was more prone to be retained in the cytoplasm after cold exposure. Our experimental data support gene x environment interactions between Gly482Ser and cold exposure in human brown adipocytes. These data support a novel molecular basis for the epidemiological observations that link the Gly482Ser polymorphism with obesity and related metabolic disorders.