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A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ

Hansson, Björn LU ; Schumacher, Sara ; Fryklund, Claes LU ; Morén, Björn LU orcid ; Björkqvist, Maria LU orcid ; Swärd, Karl LU and Stenkula, Karin G. LU (2020) In Biochemical and Biophysical Research Communications 533(1). p.64-69
Abstract

Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function. Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob... (More)

Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function. Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob mice. Overexpression of MRTF-A, but not MRTF-B, markedly suppressed PPARγ expression. Further, MRTF-A expression resulted in decreased IRS-1 level, shifted phosphorylation of Akt (pS473/pT308), IRS-1 (pS302) and AS160 (pT642), and lowered insulin-stimulated glucose uptake. Hypertrophic adipocytes from Ob/Ob mice displayed an increased proportion of polymerized actin, and increased nuclear translocation of MRTF-A compared with control (Ob/+). Similar with human adipocytes overexpressing MRTF-A, adipocytes isolated from Ob/Ob mice had reduced expression of IRS-1 and PPARγ, as well as impaired insulin response. Together, these data demonstrate that MRTF-A negatively influences insulin sensitivity and the expression of key targets in fully mature human adipocytes. This suggests that MRTF-A is poised to exert a transcriptional response in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adipocytes, Glucose transport, Insulin, Insulin signaling, MRTF-A, Obesity, PPARγ
in
Biochemical and Biophysical Research Communications
volume
533
issue
1
pages
6 pages
publisher
Elsevier
external identifiers
  • scopus:85090598631
  • pmid:32921413
ISSN
0006-291X
DOI
10.1016/j.bbrc.2020.08.105
language
English
LU publication?
yes
id
0867f7b4-b39f-450e-93ff-18c022c18af7
date added to LUP
2020-10-26 10:16:23
date last changed
2024-06-12 22:34:00
@article{0867f7b4-b39f-450e-93ff-18c022c18af7,
  abstract     = {{<p>Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding. Therefore, we hypothesized that the actin-driven myocardin-related transcription factor (MRTF-A) contributes to impaired mature adipocyte function. Primary human adipocytes were subjected to adenoviral overexpression of MRTF-A or MRTF-B, followed by Western blot analysis and tracer glucose uptake assay. Further, we assessed cell size distribution, insulin response, MRTF-A localization, actin organization and degree of polymerization in adipocytes isolated from Ob/Ob mice. Overexpression of MRTF-A, but not MRTF-B, markedly suppressed PPARγ expression. Further, MRTF-A expression resulted in decreased IRS-1 level, shifted phosphorylation of Akt (pS473/pT308), IRS-1 (pS302) and AS160 (pT642), and lowered insulin-stimulated glucose uptake. Hypertrophic adipocytes from Ob/Ob mice displayed an increased proportion of polymerized actin, and increased nuclear translocation of MRTF-A compared with control (Ob/+). Similar with human adipocytes overexpressing MRTF-A, adipocytes isolated from Ob/Ob mice had reduced expression of IRS-1 and PPARγ, as well as impaired insulin response. Together, these data demonstrate that MRTF-A negatively influences insulin sensitivity and the expression of key targets in fully mature human adipocytes. This suggests that MRTF-A is poised to exert a transcriptional response in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance.</p>}},
  author       = {{Hansson, Björn and Schumacher, Sara and Fryklund, Claes and Morén, Björn and Björkqvist, Maria and Swärd, Karl and Stenkula, Karin G.}},
  issn         = {{0006-291X}},
  keywords     = {{Adipocytes; Glucose transport; Insulin; Insulin signaling; MRTF-A; Obesity; PPARγ}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{1}},
  pages        = {{64--69}},
  publisher    = {{Elsevier}},
  series       = {{Biochemical and Biophysical Research Communications}},
  title        = {{A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ}},
  url          = {{http://dx.doi.org/10.1016/j.bbrc.2020.08.105}},
  doi          = {{10.1016/j.bbrc.2020.08.105}},
  volume       = {{533}},
  year         = {{2020}},
}