MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition

Hilton, Catriona; Neville, Matt J.; Wittemans, Laura B. L.; Todorčević, Marijana; Pinnick, Katherine E.; Pulit, Sara L.; Luan, Jian’an; Kulyté, Agné; Dahlman, Ingrid; Wareham, Nick; Lotta, Luca A.; Arner, Peter; Lindgren, Cecilia M.; Langenberg, Claudia; Karpe, Fredrik

doi:10.1016/j.ebiom.2019.05.047

Cited by 23 publications

(17 citation statements)

References 47 publications

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“…It is generally believed that DNA methylation is associated with gene silencing, however, recent findings suggest that DNA methylation is functionally complex and may regulate mechanisms beyond gene silencing ( Bird, 2002 ; Pheiffer et al, 2016 ). Other epigenetic mechanisms such as histone modifications ( Castellano-Castillo et al, 2019 ) and microRNAs ( Klöting et al, 2009 ; Hilton et al, 2019 ) may also contribute to differences in obesity and adipose distribution and should be studied to fully understand the mechanisms that underlie ethnic differences in metabolic risk.…”

Section: Discussionmentioning

confidence: 99%

Ethnic and Adipose Depot Specific Associations Between DNA Methylation and Metabolic Risk

et al. 2020

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Background Metabolic risk varies according to body mass index (BMI), body fat distribution and ethnicity. In recent years, epigenetics, which reflect gene-environment interactions have attracted considerable interest as mechanisms that may mediate differences in metabolic risk. The aim of this study was to investigate DNA methylation differences in abdominal and gluteal subcutaneous adipose tissues of normal-weight and obese black and white South African women. Methods Body composition was assessed using dual-energy x-ray absorptiometry and computerized tomography, and insulin sensitivity was measured using a frequently sampled intravenous glucose tolerance test in 54 normal-weight (BMI 18–25 kg/m 2 ) and obese (BMI ≥ 30 kg/m 2 ) women. Global and insulin receptor ( INSR ) DNA methylation was quantified in abdominal (ASAT) and gluteal (GSAT) subcutaneous adipose depots, using the Imprint methylation enzyme-linked immunosorbent assay and pyrosequencing. INSR gene expression was measured using quantitative real-time PCR. Results Global DNA methylation in GSAT varied according to BMI and ethnicity, with higher levels observed in normal-weight white compared to normal-weight black ( p = 0.030) and obese white ( p = 0.012) women. Pyrosequencing of 14 CpG sites within the INSR promoter also showed BMI, adipose depot and ethnic differences, although inter-individual variability prevented attainment of statistical significance. Both global and INSR methylation were correlated with body fat distribution, insulin resistance and systemic inflammation, which were dependent on ethnicity and the adipose depot. Adipose depot and ethnic differences in INSR gene expression were observed. Conclusion We show small, but significant global and INSR promoter DNA methylation differences in GSAT and ASAT of normal-weight and obese black and white South African women. DNA methylation in ASAT was associated with centralization of body fat in white women, whereas in black women DNA methylation in GSAT was associated with insulin resistance and systemic inflammation. Our findings suggest that GSAT rather than ASAT may be a determinant of metabolic risk in black women and provide novel evidence that altered DNA methylation within adipose depots may contribute to ethnic differences in body fat distribution and cardiometabolic risk.

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Section: Discussionmentioning

confidence: 99%

Ethnic and Adipose Depot Specific Associations Between DNA Methylation and Metabolic Risk

et al. 2020

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“…Furthermore, Divoux et al demonstrated higher MiR-196a expression in the gluteal AT depot leading to decreased fat development in this depot, whilst higher MiR-196a expression in the abdominal depot seems beneficial and associated with decreased fat mass [ 127 ]. Finally, using functional studies and transcriptomic profiling of MiR-196a knockdown pre-adipocytes, Hilton et al showed that MiR-196a regulates pre-adipocyte proliferation and extracellular matrix pathways, highlighting that this miRNA is involved in the regulation of human body fat distribution [ 128 ]. This study also documented that a single nucleotide polymorphism (rs11614913) in pre-MiR-196a-2 influences the expression of MiR-196a in abdominal scAT and is associated with the waist-to-hip ratio [ 128 ].…”

Section: Micro Rnas Regulating Brite Atmentioning

confidence: 99%

“…Finally, using functional studies and transcriptomic profiling of MiR-196a knockdown pre-adipocytes, Hilton et al showed that MiR-196a regulates pre-adipocyte proliferation and extracellular matrix pathways, highlighting that this miRNA is involved in the regulation of human body fat distribution [ 128 ]. This study also documented that a single nucleotide polymorphism (rs11614913) in pre-MiR-196a-2 influences the expression of MiR-196a in abdominal scAT and is associated with the waist-to-hip ratio [ 128 ].…”

Section: Micro Rnas Regulating Brite Atmentioning

confidence: 99%

Regulatory microRNAs in Brown, Brite and White Adipose Tissue

Gharanei

Shabir

Brown

et al. 2020

Cells

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MicroRNAs (miRNAs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA, inducing translational repression and messenger RNA degradation. This regulation of gene expression by miRNAs in adipose tissue (AT) can impact on the regulation of metabolism and energy homeostasis, particularly considering the different types of adipocytes which exist in mammals, i.e., white adipocytes (white AT; WAT), brown adipocytes (brown AT; BAT), and inducible brown adipocytes in WAT (beige or brite or brown-in-white adipocytes). Indeed, an increasing number of miRNAs has been identified to regulate key signaling pathways of adipogenesis in BAT, brite AT, and WAT by acting on transcription factors that promote or inhibit adipocyte differentiation. For example, MiR-328, MiR-378, MiR-30b/c, MiR-455, MiR-32, and MiR-193b-365 activate brown adipogenesis, whereas MiR-34a, MiR-133, MiR-155, and MiR-27b are brown adipogenesis inhibitors. Given that WAT mainly stores energy as lipids, whilst BAT mainly dissipates energy as heat, clarifying the effects of miRNAs in different types of AT has recently attracted significant research interest, aiming to also develop novel miRNA-based therapies against obesity, diabetes, and other obesity-related diseases. Therefore, this review presents an up-to-date comprehensive overview of the role of key regulatory miRNAs in BAT, brite AT, and WAT.

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“…This is in line with observations by Pinnick et al who found at cellular and miRNA level intrinsic differences between abdominal and gluteal adipose tissue. This result in an opposing metabolic disease risk, which is reduced forthe gluteal region -the site affected in lipedema 59,60 . Let-7c has been associated with regulation of macrophage polarization 61 .…”

Section: Discussionmentioning

confidence: 99%

SVF-derived extracellular vesicles carry characteristic miRNAs in lipedema

Priglinger

Strohmeier

Weigl

et al. 2020

Sci Rep

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Lipedema is a chronic, progressive disease of adipose tissue with lack of consistent diagnostic criteria. The aim of this study was a thorough comparative characterization of extracellular microRNAs (miRNAs) from the stromal vascular fraction (SVF) of healthy and lipedema adipose tissue. For this, we analyzed 187 extracellular miRNAs in concentrated conditioned medium (cCM) and specifically in small extracellular vesicles (sEVs) enriched thereof by size exclusion chromatography. No significant difference in median particle size and concentration was observed between sEV fractions in healthy and lipedema. We found the majority of miRNAs located predominantly in cCM compared to sEV enriched fraction. Surprisingly, hierarchical clustering of the most variant miRNAs showed that only sEVmiRNA profiles-but not cCMmiRNAs-were impacted by lipedema. Seven sEVmiRNAs (miR-16-5p, miR-29a-3p, miR-24-3p, miR-454-p, miR-144-5p, miR-130a-3p, let-7c-5p) were differently regulated in lipedema and healthy individuals, whereas only one cCMmiRNA (miR-188-5p) was significantly downregulated in lipedema. Comparing SVF from healthy and lipedema patients, we identified sEVs as the lipedema relevant miRNA fraction. This study contributes to identify the potential role of SVF secreted miRNAs in lipedema. Lipedema is a chronic, progressive disease characterized by bilateral, symmetrical, disproportional deposition of adipose tissue in the extremities and buttocks 1. Patients suffer from pain, reduced joint mobility, hematoma, edema and psychological impacts 2. It was first described in 1940 as a connective tissue disorder, characterized by fluid being collected in the interstitium instead of entering into lymphatics 3. This excess fluid in the interstitium potentially leads to growth of adipose tissue and hypoxia, which in turn might enhance angiogenesis of pathologic vessels 4,5. The area of lymphatic vessels and the number of blood vessels were found increased in non-obese lipedema patients compared to controls 6. Examination of adipose tissue from lipedema patients demonstrated hypertrophic adipocytes, crown-like structures and increased number of macrophages 6-8. Besides functioning as an energy storage, white adipose tissue (WAT) responds differentially to physiological and pathological metabolic changes by secreting a large diversity of proteins, hormones, lipids, non-coding ribonucleic acids (RNAs)-including microRNAs (miRNAs)-and extracellular vesicles (EVs) 9,10. Small EVs (sEVs) are a fraction of 70-150 nm sized, membrane-enclosed particles, which contain cell-type specific proteins, enzymes, growth factors, cytokines, lipids, as well as coding and non-coding RNAs. It has been repeatedly reported, that WAT-derived vesicular miRNAs are involved in metabolic regulations 11,12 and adipose tissue is considered a significant source of circulating sEV-miRNAs 11. By acting in an autocrine, paracrine as well as systemic manner, these factors can contribute to metabolic abnormalities, modulation of osteogenic differentiation, inhibition of...

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MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition

Cited by 23 publications

References 47 publications

Ethnic and Adipose Depot Specific Associations Between DNA Methylation and Metabolic Risk

Ethnic and Adipose Depot Specific Associations Between DNA Methylation and Metabolic Risk

Regulatory microRNAs in Brown, Brite and White Adipose Tissue

SVF-derived extracellular vesicles carry characteristic miRNAs in lipedema

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