A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ
(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
- Hansson, Björn LU ; Schumacher, Sara ; Fryklund, Claes LU ; Morén, Björn LU ; Björkqvist, Maria LU ; Swärd, Karl LU and Stenkula, Karin G. LU
- organization
-
- Glucose Transport and Protein Trafficking (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Biomarkers in Brain Disease (research group)
- Department of Experimental Medical Science
- Cellular Biomechanics (research group)
- publishing date
- 2020-11-26
- 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
-
- pmid:32921413
- scopus:85090598631
- 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}}, }