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.

doi:10.1016/j.bbrc.2020.08.105

Cited by 5 publications

(6 citation statements)

References 15 publications

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“…Figure 4B implies a roughly 5-fold higher density of GLUT4 in smaller adipocytes than larger cells. These data are consistent with reduced insulin-stimulated GUT4 translocation reported in larger fat cells 47,48 , studies of hypertrophic adipocytes 49,50 and our data on glucose transport in 3T3-L1 adipocytes of different sizes 46 . This effect would be magni ed if the reported inverse relationship between adipocyte size and GLUT4 levels in human adipocytes 51 also operates in 3T3-L1 adipocytes.…”

Section: Hdbscan Analysissupporting

confidence: 91%

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

Koester

Geiser

Bowman

et al. 2022

Preprint

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The regulated delivery of the glucose transporter, GLUT4, to the surface of adipocytes and muscle is a key action of insulin. This is underpinned by the delivery and fusion of GLUT4-containing vesicles with the plasma membrane. Recent studies have revealed that a further action of insulin is to mediate the dispersal of GLUT4 molecules away from the site of GLUT4 vesicle fusion with the plasma membrane. Although shown in adipocytes, whether insulin-stimulated dispersal occurs in other cells and/or is exhibited by other proteins remains a matter of debate. Here we show that insulin-stimulates GLUT4 dispersal in the plasma membrane of adipocytes, induced pluripotent stem cell-derived cardiomyocytes and HeLa cells, suggesting that this phenomenon is specific to GLUT4 expressed in all cell types. By contrast, insulin-stimulated dispersal of TfR was not observed in HeLa cells, suggesting that the mechanism may be unique to GLUT4. Consistent with dispersal being an important physiological mechanism, we observed that insulin stimulated GLUT4 dispersal is reduced under conditions of insulin resistance. Adipocytes of different sizes have been shown to exhibit distinct metabolic properties: larger adipocytes exhibit reduced insulin-stimulated glucose transport than smaller cells. Here we show that both GLUT4 delivery to the plasma membrane and GLUT4 dispersal are reduced in larger adipocytes compared to their smaller counterparts, supporting the hypothesis that larger adipocytes are refractory to insulin challenge compared to their smaller counterparts, even within a supposedly homogeneous population of cells.

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Section: Hdbscan Analysissupporting

confidence: 91%

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

Koester

Geiser

Bowman

et al. 2022

Preprint

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“…In adipose tissue, MRTF-A/SRF pathway suppresses peroxisome proliferator-activated receptor γ (PPARγ) expression/activity and negatively regulates adipocyte differentiation including white ( 37 , 113 ), beige ( 16 , 114 ) and brown adipogenesis ( 115 ) ( Figure 2 ). Furthermore, activation of this pathway was found to reduce expression of insulin receptor substrate-1 (IRS1) and PPARγ in mature human adipocytes and in hypertrophic adipocytes from ob/ob mice, thus contributing to adipocyte dysfunction and insulin resistance ( 116 ). This pathway also promotes fibrosis, inflammation and insulin resistance in diet-induced obesity, since perivascular progenitor cells will preferentially differentiate into a fibroblast lineage as opposed to a normal adipocyte lineage ( 117 ).…”

Section: Overview Of Major Rock Signaling Pathways In Regulating Meta...mentioning

confidence: 99%

“…In addition to adipose tissue, MRTF-A/SRF pathway is involved in hepatic fibrosis ( 119 ) and diabetic nephropathy ( 120 ): MRTF-A knockout reduced macrophage infiltration, and ameliorated inflammation and fibrosis of liver tissues in mice with nonalcoholic steatohepatitis induced by high-fat diet (HFD) ( 119 ); through an epigenetic mechanism, MRTF-A deficiency also attenuated connective tissue growth factor in diabetic nephropathy ( 120 ). It should be noted some metabolic studies cited above were interested in the connection between RhoA/ROCK/F-actin and MRTF-A/SRF pathways ( 16 , 37 , 114 , 116 ), but some mainly focused on MRTF-A and its downstream effectors ( 113 , 115 , 117 ). Together, besides the well-established role for the RhoA/ROCK/F-actin/MRTF-A/SRF pathway in regulating vascular cell function, abovementioned studies support that the RhoA/ROCK/F-actin/MRTF-A/SRF pathway negatively regulates adipocyte differentiation, plays a negative role in maintaining adipose tissue health, and contributes to liver fibrosis and diabetic nephropathy.…”

Section: Overview Of Major Rock Signaling Pathways In Regulating Meta...mentioning

confidence: 99%

“…Future animal study with adipocyte specific ROCK2 knockout should help determine adipocyte autonomous function of ROCK2 in vivo . Mechanistically, downstream of RhoA/ROCK-mediated F-actin assembly, nuclear translocation of MRTF-A suppresses the expression of IRS1 and PPARγ in hypertrophic adipocytes, contributing to adipocyte dysfunction and insulin resistance ( 116 ). Moreover, RhoA/ROCK-mediated actomyosin contractility promotes nuclear translocation of the transcriptional co-activators YAP/TAZ which suppress expression of pro-apoptotic factor Bim and protect against white adipocyte cell death during obesity ( 177 ).…”

Section: Cellular Actions Of Rock Signaling Pathways In Adipose Tissuementioning

confidence: 99%

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Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Wei

Shi

2022

Front. Endocrinol.

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Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

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“…It has now been found that there is a relationship between adipocyte size and the system’s capacity to form new adipocytes. People with large subcutaneous adipocytes have little ability to differentiate mesenchymal cells into adipocytes, which is due to their impaired PPARγ activation [ 51 , 52 ]. Mature, healthy adipocytes release BMP4 during adipogenesis, which causes mesenchymal cells to differentiate into adipocytes.…”

Section: Adipogenesis and Pparγ Activitymentioning

confidence: 99%

PPARγ—A Factor Linking Metabolically Unhealthy Obesity with Placental Pathologies

Kwiatkowski

Kajdy

Stefańska

et al. 2021

IJMS

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Obesity is a known factor in the development of preeclampsia. This paper links adipose tissue pathologies with aberrant placental development and the resulting preeclampsia. PPARγ, a transcription factor from the ligand-activated nuclear hormone receptor family, appears to be one common aspect of both pathologies. It is the master regulator of adipogenesis in humans. At the same time, its aberrantly low activity has been observed in placental pathologies. Overweight and obesity are very serious health problems worldwide. They have negative effects on the overall mortality rate. Very importantly, they are also conducive to diseases linked to impaired placental development, including preeclampsia. More and more people in Europe are suffering from overweight (35.2%) and obesity (16%) (EUROSTAT 2021 data), some of them young women planning pregnancy. As a result, we will be increasingly encountering obese pregnant women with a considerable risk of placental development disorders, including preeclampsia. An appreciation of the mechanisms shared by these two conditions may assist in their prevention and treatment. Clearly, it should not be forgotten that health education concerning the need for a proper diet and physical activity is of utmost importance here.

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

Cited by 5 publications

References 15 publications

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

PPARγ—A Factor Linking Metabolically Unhealthy Obesity with Placental Pathologies

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