Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Huang, Mi LU ; Prasad, Rashmi B LU ; Coral, Daniel E LU orcid ; Hjort, Line LU ; Minja, Daniel T R ; Mulder, Hindrik LU orcid ; Franks, Paul W LU and Kalamajski, Sebastian LU (2024) In Diabetes
Abstract

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.... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Diabetes
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85188716739
  • pmid:38190589
ISSN
1939-327X
DOI
10.2337/db23-0531
language
English
LU publication?
yes
additional info
© 2024 by the American Diabetes Association.
id
cf3f0c88-98ee-46e8-8c42-c498afd2e049
date added to LUP
2024-02-22 11:57:24
date last changed
2024-04-22 13:19:58
@article{cf3f0c88-98ee-46e8-8c42-c498afd2e049,
  abstract     = {{<p>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.</p>}},
  author       = {{Huang, Mi and Prasad, Rashmi B and Coral, Daniel E and Hjort, Line and Minja, Daniel T R and Mulder, Hindrik and Franks, Paul W and Kalamajski, Sebastian}},
  issn         = {{1939-327X}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Human Genetic Variation at rs10071329 Correlates with Adiposity-related Traits, Modulates PPARGC1B Expression, and Alters Brown Adipocyte Function}},
  url          = {{http://dx.doi.org/10.2337/db23-0531}},
  doi          = {{10.2337/db23-0531}},
  year         = {{2024}},
}