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AIMS/HYPOTHESIS: PPARGC1A encodes peroxisome proliferator-activated receptor γ coactivator 1-α (±Ê³Ò°ä-1α), a central regulator of energy metabolism and mitochondrial function. A common polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been associated with obesity and related metabolic disorders, but no published functional studies have investigated direct allele-specific effects in adipocyte biology. We examined whether rs8192678 is a causal variant and reveal its biological function in human white adipose cells.METHODS: We used CRISPR-Cas9 genome editing to perform an allelic switch (C-to-T or T-to-C) at rs8192678 in an isogenic human pre-adipocyte white adipose tissue (hWAs) cell line. Allele-edited single-cell clones were expanded and screened to obtain homozygous T/T (Ser482Ser), C/C (Gly482Gly) and heterozygous C/T (Gly482Ser) isogenic cell populations, followed by functional studies of the allele-dependent effects on white adipocyte differentiation and mitochondrial function.RESULTS: After differentiation, the C/C adipocytes were visibly less BODIPY-positive than T/T and C/T adipocytes, and had significantly lower triacylglycerol content. The C allele presented a dose-dependent lowering effect on lipogenesis, as well as lower expression of genes critical for adipogenesis, lipid catabolism, lipogenesis and lipolysis. Moreover, C/C adipocytes had decreased oxygen consumption rate (OCR) at basal and maximal respiration, and lower ATP-linked OCR. We determined that these effects were a consequence of a C-allele-driven dysregulation of ±Ê³Ò°ä-1α protein content, turnover rate and transcriptional coactivator activity.CONCLUSIONS/INTERPRETATION: Our data show allele-specific causal effects of the rs8192678 variant on adipogenic differentiation. The C allele confers lower levels of PPARGC1A mRNA and ±Ê³Ò°ä-1α protein, as well as disrupted dynamics of ±Ê³Ò°ä-1α turnover and activity, with downstream effects on cellular differentiation and mitochondrial function. Our study provides the first experimentally deduced insights on the effects of rs8192678 on adipocyte phenotype.