Suppression of GATA-3 increases adipogenesis, reduces inflammation and improves insulin sensitivity in 3T3L-1 preadipocytes

Al-Mansoori, Layla; Al-Jaber, Hend; Madani, Aisha; Mazloum, Nayef; Agouni, Abdelali; Ramanjaneya, Manjunath; Abou‐Samra, Abdul Badi; Elrayess, Mohamed A.

doi:10.1016/j.cellsig.2020.109735

Cited by 21 publications

(14 citation statements)

References 47 publications

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“…We previously showed that GATA-3 inhibition causes reduction in GATA-3 expression in 3T3L-1 mouse preadipocytes after 48 h of treatment [ 27 ]. GATA3 inhibition was validated in primary human preadipocytes isolated from five BFP biopsies.…”

Section: Resultsmentioning

confidence: 99%

“…Analyzing adipocyte sizing profiles, DNA content, and fat histology indicated an increase in the number of new small adipocytes and a shrinkage or/and disappearance of existing mature adipocytes [ 26 ]. Our results indicated that such inhibition indeed improved adipocytes differentiation, modulated the cytokine profile, and improved insulin sensitivity in insulin resistant cells [ 27 ]. In this study, we investigated the role of targeting GATA3 expression in vitro and in vivo on modulating adipogenesis, oxidative stress, inflammation, and insulin signaling.…”

Section: Introductionmentioning

confidence: 92%

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In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

Al-Jaber

Mohamed²,

Govindharajan³

et al. 2022

IJMS

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Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

Al-Jaber

Mohamed²,

Govindharajan³

et al. 2022

IJMS

Self Cite

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“…The AP-1 family of TFs is prominently represented at loci opening chromatin, reflecting its ability to recruit chromatin remodeling enzymes to specific genomic loci 26 . A number of the binding site motifs correspond to TFs known to be involved in adipogenesis, including the CEBP 27 , RUNX 28 , TEAD 29 , GATA 30 , EBF 31, 32 , NF1 33 families of TFs, the ATF4 34 TF and the CTCF 35, 36 DNA-binding protein. These patterns of over-representation of TF binding sites provide us with a reference in normal differentiation against which to compare chemical-induced changes.…”

Section: Resultsmentioning

confidence: 99%

Molecular genomic studies of the obesogenic effects of tributyltin during adipogenic differentiation implicate a primary role for cytoskeletal damage

Thompson

Greally

2022

Preprint

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Environmental obesogens are being studied for their potential role in the increasing prevalence of obesity globally. A major focus in this field of research has been on the mechanism by which these agents act. In this study we focused on the obesogenic organotin tributyltin (TBT), which is believed to act by binding to the PPAR𝛾 nuclear receptor in a heterodimer with RXR to alter gene regulation. To test whether this was the dominant mechanism for TBT activity, we performed time-course studies of transcription and chromatin accessibility in mesenchymal stem cells differentiating to adipocytes. We found limited evidence for PPAR𝛾 effects by TBT, but a strong response by Ras-related GTPases and evidence for the loss of TEAD transcription factor activity during differentiation. These observations combine to implicate a known property of organotins, to cause cytoskeletal cytoskeletal damage as the primary event in an updated model for TBT effects, leading to the loss of YAP co-regulator activity and the consequent failure of TEAD repression of adipogenesis.

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“…GATA3 is a transcription factor with a multi-faceted role in hematopoiesis [35], while related genetic and epigenetic aberrations are strongly associated with AML development, prognosis and response to therapy [36,37]. Regarding T2D, GATA3 is considered an anti-adipogenic factor and a potential molecular therapeutic target for insulin resistance, through restoration of adipogenesis and amelioration of inflammation [38,39].…”

Section: Discussionmentioning

confidence: 99%

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

Kyriakou

Papageorgis

Christodoulou

2021

IJMS

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Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

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Suppression of GATA-3 increases adipogenesis, reduces inflammation and improves insulin sensitivity in 3T3L-1 preadipocytes

Cited by 21 publications

References 47 publications

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

Molecular genomic studies of the obesogenic effects of tributyltin during adipogenic differentiation implicate a primary role for cytoskeletal damage

Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

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