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Engineered allele substitution at PPARGC1A rs8192678 alters human white adipocyte differentiation, lipogenesis, and PGC‑1α content and turnover – published online 12/05/2023

Huang graphical abstract

Mi Huang, Melina Claussnitzer, Alham Saadat, Daniel E. Coral, Sebastian Kalamajski, Paul W. Franks

Genetic association studies have correlated hundreds of loci with metabolic disorders, but the functional basis of these loci is rarely explored. A well-known common genetic polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been reproducibly associated with obesity and type 2 diabetes in various ancestries, highlighting the need to examine its allele-specific effects and pinpoint its clinical relevance. In this issue, Mi Huang et al (https://doi.org/10.1007/s00125-023-05915-6) report the use of a state-of-the-art CRISPR/Cas9 technique to generate isogenic adipose cell lines with different rs8192678 genotypes. They show that the rs8192678 T allele causally enhances adipogenic differentiation and mitochondrial function in an allele dosage-dependent manner. They also demonstrate that the T allele is associated with higher levels of the PPARGC1A-encoded peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) protein and of the adipogenesis master regulator peroxisome proliferator-activated receptor γ (PPARγ). These findings provide experimental insights into adipocyte-specific mechanisms underlying epidemiological correlations between rs8192678 and metabolic disorders. The authors conclude that this may prove useful for the development of genotype-based precision medicine for obesity.

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