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Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function

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posted on 2024-01-08, 20:49 authored by Mi Huang, Rashmi B. Prasad, Daniel E. Coral, Line Hjort, Daniel T. R. Minja, Hindrik Mulder, Paul W. Franks, Sebastian Kalamajski

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 CRISPR/Cas9 to scarlessly edit the alleles of the candidate causal genetic variant rs10071329 in a human brown adipocyte cell line (hBAs). Switching the rs10071329 genotype from A/A to G/G enhanced PPARGC1B expression throughout the adipogenic differentiation, identifying rs10071329 as a cis-eQTL. The higher PPARGC1B expression in G/G cells coincided with greater accumulation of triglycerides, and higher expression of mitochondria-encoded genes, but without significant effects on adipogenic marker expression. Furthermore, G/G cells had improved basal- and norepinephrine-stimulated mitochondrial respiration, possibly relating to enhanced mitochondrial 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, at PPARGC1B could prove useful in genotype-based precision medicine for obesity treatment.

Funding

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal in January 2023. M.H. was supported by a doctoral fellowship from the China Scholarship Council (201708420158 to M.H.). The research was supported by grants from the European Commission (ERC-2015-CoG -681742 NASCENT to P.W.F.), Swedish Research Council (Distinguished Young Researcher Reward in Medicine), Swedish Strategy Research Foundation (LUDC-IRC to P.W.F.), The Swedish Research Council (to H.M.), The Bo and Kerstin Hjelt Foundation (to S.K.), The Swedish Research Council (2021-02623, to R.B.P.), The Danish Council for Strategic Research (the study and core analyses of the FOETALforNCD cohort, grant number 1309-00003B to L.H.). L.H. is supported the BRIDGE - Translational Excellence Programme, funded by the Novo Nordisk Foundation (NNF20SA0064340).

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