EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes

Fryklund, Claes; Morén, Björn; Shah, Shrenika; Grossi, Mario; Degerman, Eva; Matthaeus, Claudia; Stenkula, Karin G.

doi:10.3389/fphys.2021.740666

Cited by 5 publications

(11 citation statements)

References 46 publications

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“…Thus, we have provided more evidence that LPL hypermethylation can predispose to metabolic diseases like T2D. Similarly, EHD2, the EH domain-containing 2, is a known obesity-associated gene implicated in GLUT4 endocytosis and in the maintenance of intracellular lipid metabolism in adipocytes [46,47]. Its methylation has only been found as altered in epididymal adipocytes of mice with obesity [48].…”

Section: Discussionmentioning

confidence: 83%

DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

et al. 2022

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Background Obesity is accompanied by excess adipose fat storage, which may lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Currently, the tendency to develop T2D in obesity cannot be explained by genetic variation alone—epigenetic mechanisms, such as DNA methylation, might be involved. Here, we aimed to identify changes in DNA methylation and gene expression in visceral adipose tissue (VAT) that might underlie T2D susceptibility in patients with obesity. Methods We investigated DNA methylation and gene expression in VAT biopsies from 19 women with obesity, without (OND = 9) or with T2D (OD = 10). Differences in genome-scale methylation (differentially methylated CpGs [DMCs], false discovery rate < 0.05; and differentially methylated regions [DMRs], p value < 0.05) and gene expression (DEGs, p value <0.05) between groups were assessed. We searched for overlap between altered methylation and expression and the impact of altered DNA methylation on gene expression, using bootstrap Pearson correlation. The relationship of altered DNA methylation to T2D-related traits was also tested. Results We identified 11 120 DMCs and 96 DMRs distributed across all chromosomes, with the greatest density of epigenomic alterations at the MHC locus. These alterations were found in newly and previously T2D-related genes. Several of these findings were supported by validation and extended multi-ethnic analyses. Of 252 DEGs in the OD group, 68 genes contained DMCs (n = 88), of which 24 demonstrated a significant relationship between gene expression and methylation (p values <0.05). Of these, 16, including ATP11A, LPL and EHD2 also showed a significant correlation with fasting glucose and HbA1c levels. Conclusions Our results revealed novel candidate genes related to T2D pathogenesis in obesity. These genes show perturbations in DNA methylation and expression profiles in patients with obesity and diabetes. Methylation profiles were able to discriminate OND from OD individuals; DNA methylation is thus a potential biomarker.

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Section: Discussionmentioning

confidence: 83%

DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

et al. 2022

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“…In recent studies, we and others have confirmed a role for EHD2 in lipid handling using a global EHD2 knockout (EHD2 KO) C57Bl6/N mouse model, which displayed altered lipid metabolism ( Matthaeus et al. , 2020 ; Fryklund et al. , 2021 ), impaired lipolysis, and diminished insulin-mediated inhibition of lipolysis in primary adipocytes ( Fryklund et al.…”

Section: Introductionmentioning

confidence: 90%

“…, 2020 ; Fryklund et al. , 2021 ), impaired lipolysis, and diminished insulin-mediated inhibition of lipolysis in primary adipocytes ( Fryklund et al. , 2021 ).…”

Section: Introductionmentioning

confidence: 99%

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events

Neuhaus,

Fryklund,

Taylor

et al. 2023

MBoC

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Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.

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“…In addition, the overexpression of EHD2 in human adipocytes increases lipid signaling and inhibits the activity of the transcription factor PPARγ 61 . Meanwhile, Fryklund et al 62 revealed that the deficiency of EHD2 inhibits the expansion of adipose tissue and impairs lipolysis in primary inguinal adipocytes. They also highlighted the variations in lipid metabolism controlled by EHD2 in different adipose tissue depots.…”

Section: The Role Of Ehd2 In Lipid Uptake and Metabolismmentioning

confidence: 99%

EH domain‐containing protein 2 (EHD2): Overview, biological function, and therapeutic potential

Zhu,

Zhang,

Xia

et al. 2024

Cell Biochemistry & Function

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EH domain‐containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear‐cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N‐terminal of EHD2 is attached to the cell membrane, while its C‐terminal binds to the actin‐binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.

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EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes

Cited by 5 publications

References 46 publications

DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events

EH domain‐containing protein 2 (EHD2): Overview, biological function, and therapeutic potential

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