부산대학교 도서관

Human genetic variation in PPARGC1B has been associated with adiposity, but the genetic variants that affect PPARGC1B expression have not been experimentally determined. Here, guided by previous observational data, we used clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) to scarlessly edit the alleles of the candidate causal genetic variant rs10071329 in a human brown adipocyte cell line. Switching the rs10071329 genotype from A/A to G/G enhanced PPARGC1B expression throughout the adipogenic differentiation, identifying rs10071329 as a cis-expression quantitative trait loci (eQTL). The higher PPARGC1B expression in G/G cells coincided with greater accumulation of triglycerides and higher expression of mitochondriaencoded genes, butwithout significant effects on adipogenic marker expression. Furthermore, G/G cells had improved basal- and norepinephrine-stimulated mitochondrial respiration, possibly relating to enhancedmitochondrial gene expression. The G/G cells also exhibited increased norepinephrine-stimulated glycerol release, indicating improved lipolysis. Altogether, our results showed that rs10071329 is a cis-eQTL, with the G/G genotype conferring enhanced PPARGC1B expression, with consequent improved mitochondrial function and response to norepinephrine in brown adipocytes. This genetic variant, and as yet undetermined eQTLs, atPPARGC1Bcould prove useful in genotype-based precisionmedicine for obesity treatment. [ABSTRACT FROM AUTHOR]