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

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A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ. / Hansson, Björn; Schumacher, Sara; Fryklund, Claes; Morén, Björn; Björkqvist, Maria; Swärd, Karl; Stenkula, Karin G.

I: Biochemical and Biophysical Research Communications, Vol. 533, Nr. 1, 26.11.2020, s. 64-69.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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T1 - A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ

AU - Hansson, Björn

AU - Schumacher, Sara

AU - Fryklund, Claes

AU - Morén, Björn

AU - Björkqvist, Maria

AU - Swärd, Karl

AU - Stenkula, Karin G.

PY - 2020/11/26

Y1 - 2020/11/26

N2 - 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.

AB - 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.

KW - Adipocytes

KW - Glucose transport

KW - Insulin

KW - Insulin signaling

KW - MRTF-A

KW - Obesity

KW - PPARγ

UR - http://www.scopus.com/inward/record.url?scp=85090598631&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2020.08.105

DO - 10.1016/j.bbrc.2020.08.105

M3 - Article

C2 - 32921413

AN - SCOPUS:85090598631

VL - 533

SP - 64

EP - 69

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 1090-2104

IS - 1

ER -