miRNAs in human subcutaneous adipose tissue: Effects of weight loss induced by hypocaloric diet and exercise

Kristensen, Malene M; Davidsen, Peter K.; Vigelsø, Andreas; Hansen, Christina; Jensen, Lars Juhl; Jessen, Niels; Bruun, Jens Meldgaard; Dela, Flemming; Helge, Jørn Wulff

doi:10.1002/oby.21765

Cited by 41 publications

(34 citation statements)

References 38 publications

(46 reference statements)

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“…Indeed, previously published work demonstrates that in a cohort of 66 men and women, ranging from lean to obese, miR-29a in visceral and subcutaneous WAT is negatively correlated with BMI 20 . A second human study found an increase in miR-29a in subcutaneous WAT from 19 obese individuals following diet and exercise-induced weight loss 29 .…”

Section: Figmentioning

confidence: 99%

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

O’Connor

Murphy

et al. 2020

Preprint

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MicroRNAs (miRNAs) are short, non-coding RNAs that associate with Argonaute (AGO) to regulate mRNA stability and translation. While individual miRNAs have been shown to play important roles in white and brown adipose tissue in normal physiology and disease 1,2,3 , a comprehensive analysis of miRNA activity in these tissues has not been performed. We used high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) to comprehensively characterize the network of high-confidence, in vivo mRNA:miRNA interactions across white and brown fat, revealing over 100,000 unique miRNA binding sites. Targets for each miRNA were ranked to generate a catalog of miRNA binding activity, and the miR-29 family emerged as a top regulator of adipose tissue gene expression. Among the top targets of miR-29 was leptin, an adipocyte-derived hormone that acts on the brain to regulate food intake and energy expenditure 4 . Two independent miR-29 binding sites in the leptin 3'-UTR were validated using luciferase assays, and miR-29 gain and loss-of-function modulated leptin mRNA and protein secretion in primary adipocytes. In mice, miR-29 abundance inversely correlated with leptin levels in two independent models of obesity. This work represents the only experimentally generated miRNA targetome in adipose tissue and identifies the first known post-transcriptional regulator of leptin. Future work aimed at manipulating miR-29:leptin binding may provide a therapeutic opportunity to treat obesity and its sequelae.Much of the work on adipocyte development and function over the last several decades has focused on transcriptional regulators. These include PPARG2, which is necessary and sufficient for the development and maintenance of white and brown adipocytes 5 , and PRDM16, which regulates brown and beige adipocyte identity 6,7 . More recently, it has become clear that post-transcriptional regulators also play 3 a key role in influencing adipocyte phenotype. Studies with adipose-specific dicer KO mice demonstrate that microRNAs (miRNAs) are essential in regulating adipogenesis, insulin sensitivity and non-shivering thermogenesis 8,9 . Several individual miRNAs have been shown to contribute to these phenotypic effects.miR-133 represses BAT function by directly targeting Prdm16 and inhibiting expression of thermogenic genes 2 . miR-196a induces browning of WAT by targeting Hoxc8 1 , and miR-26 protects mice from dietinduced obesity by blocking adipogenesis 10 . These studies, and most others in adipose tissue, rely on computational predictions and low-throughput validation to identify miRNA targets. Although highthroughput crosslinking techniques to map the miRNA targetome have been applied to liver, brain, heart and other tissues 11,12,13 , thus far, no comprehensive targetome has been described for adipose tissue.To profile the complete network of in vivo, adipose-specific miRNA binding activity across both brown and white fat, we used AGO HITS-CLIP on interscapular brown adipose tissue (iBAT) and epididymal white a...

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Section: Figmentioning

confidence: 99%

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

O’Connor

Murphy

et al. 2020

Preprint

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“…Recent years, the number of microRNA profiling studies has increased rapidly. MicroRNAs profiles in several different tissues were investigated after CR, EX or HF, including adipose tissue, skeletal muscle, heart, especially circulating microRNAs [13][14][15][16]. There are only few microRNAs profiling studies in liver under these lifestyle modification conditions.…”

Section: Introductionmentioning

confidence: 99%

Differential microRNAs expression profiles in liver from three different lifestyle modification mice models

Gong

Zhang

Han³

et al. 2020

Preprint

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Background MicroRNAs play an important role in many fundamental biological and pathological processes. Defining the microRNAs profile underlying the processes by beneficial and detrimental lifestyles, including caloric restriction(CR), exercise and high-fat diet(HF), is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We used the microarray to detect microRNAs expression in livers from CR, EX and HF mice models. After predicted potential target genes of differentially expressed microRNAs with four algorithms, we applied GO and KEGG to analyze the function of predicted microRNA targets. Results We describe the overall microRNAs expression pattern, and identified 84 differentially expressed microRNAs changed by one or two or even all the three lifestyle modifications. The common and different enriched categories of gene function and main biochemical and signal transduction pathways were presented. Conclusions We provided for the first time a comprehensive and thorough comparison of microRNAs expression profiles in liver among these lifestyle modifications.With this knowledge, our findings provide us with an overall vision of microRNAs in the molecular impact of lifestyle on health as well as useful clues for future and thorough research of the role of microRNAs.

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“…Interestingly, these three miRNAs were shown to be expressed in AT. Let‐7f has been reported to be highly expressed in ovine AT , while miR‐296 was highly expressed in both ovine visceral AT (VAT) and subcutaneous AT (SAT) , and miR‐20b‐5p was significantly elevated in human SAT , suggesting the potential regulatory mechanisms that these miRNAs could play in AT regulation. Accordingly, in this study, we analyzed the expression levels of miR‐20b, miR‐296, and Let‐7f in human VAT and SAT in relation to obesity and T2D and dissected their gene interaction network using bioinformatic prediction analysis, with a focus on TGs that are related to the pathogenesis of both obesity and T2D.…”

Section: Introductionmentioning

confidence: 99%

miR‐20b, miR‐296, and Let‐7f Expression in Human Adipose Tissue is Related to Obesity and Type 2 Diabetes

Gentile

Lhamyani

Coín‐Aragüez

et al. 2018

Obesity

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Objective: This study aimed to analyze the potential association of different microRNA (miRNA) molecules with both type 2 diabetes (T2D) and obesity and determine their target genes. Methods: Quantitative PCR was used to analyze the miR-20b, miR-296, and Let-7f levels in human visceral and subcutaneous adipose tissues (ATs) in relation to obesity and T2D, miRTarBase 4.0 was used for validation of target genes, and the Protein Analysis Through Evolutionary Relationships (PANTHER) Classification System and the Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to annotate the biological processes of the predicted targets. Results: In AT, miR-20b, miR-296, and Let-7f levels were significantly different between normoglycemic subjects and those with T2D. In visceral adipose tissue, miRNA levels were higher in normoglycemic/obesity samples than in T2D/obesity samples. miR-20b, miR-296, and Let-7f target genes that showed significant differences in both ATs in relation to obesity and T2D were CDKN1A, CX3CL1, HIF1A, PPP2R1B, STAT3, and VEGFA. These genes are known to be principally involved in the vascular endothelial growth factor (VEGF) and WNT pathways. Conclusions: This study provides experimental evidence of the possible correlation between AT miR-20b, miR-296, and Let-7f with obesity and T2D, which might involve vascular endothelial growth factor and WNTdependent pathways that are regulated by six different genes, suggesting a novel signaling pathway that could be important for understanding the mechanisms underlying the AT dysfunction associated with obesity and T2D.

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miRNAs in human subcutaneous adipose tissue: Effects of weight loss induced by hypocaloric diet and exercise

Abstract: Weight loss influenced several miRNAs, some of which were negatively correlated with predicted targets. These dysregulated miRNAs may affect adipocytokine signaling and forkhead box protein O signaling.

Cited by 41 publications

References 38 publications

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

Differential microRNAs expression profiles in liver from three different lifestyle modification mice models

miR‐20b, miR‐296, and Let‐7f Expression in Human Adipose Tissue is Related to Obesity and Type 2 Diabetes

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