A miR‐29a‐driven negative feedback loop regulates peripheral glucocorticoid receptor signaling

Glantschnig, Christina; Koenen, Mascha; Gil‐Lozano, Manuel; Karbiener, Michael; Pickrahn, Ines; Williams-Dautovich, Jasmine; Patel, Rucha; Cummins, Carolyn L.; Giroud, Maude; Hartleben, Götz; Vogl, Elena Sophie; Blüher, Matthias; Tuckermann, Jan; Uhlenhaut, N. Henriette; Herzig, Stephan; Scheideler, Marcel

doi:10.1096/fj.201801385rr

Cited by 34 publications

(23 citation statements)

References 87 publications

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“…The analysis of improved bone mineral density and trabecular morphology in miR-29aTg mice explained the requirement of considerable energy expenditure for preserving osteoblast function and microstructure integrity, which prevented HFD-induced bone mass loss. Expanding studies have revealed that miR-29a signaling regulates lipid metabolism in the muscles of diabetic mice [38] and delays fatty liver development in HFD-fed mice [39], as well as inhibits adipocyte formation of human adipose mesenchymal stem cells [40]. We uncovered mild marrow adiposis together with moderate visceral adipose deposit in miR-29aTg mice.…”

Section: Discussionmentioning

confidence: 82%

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

Lian

Chen

et al. 2021

IJMS

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Skeletal tissue involves systemic adipose tissue metabolism and energy expenditure. MicroRNA signaling controls high-fat diet (HFD)-induced bone and fat homeostasis dysregulation remains uncertain. This study revealed that transgenic overexpression of miR-29a under control of osteocalcin promoter in osteoblasts (miR-29aTg) attenuated HFD-mediated body overweight, hyperglycemia, and hypercholesterolemia. HFD-fed miR-29aTg mice showed less bone mass loss, fatty marrow, and visceral fat mass together with increased subscapular brown fat mass than HFD-fed wild-type mice. HFD-induced O2 underconsumption, respiratory quotient repression, and heat underproduction were attenuated in miR-29aTg mice. In vitro, miR-29a overexpression repressed transcriptomic landscapes of the adipocytokine signaling pathway, fatty acid metabolism, and lipid transport, etc., of bone marrow mesenchymal progenitor cells. Forced miR-29a expression promoted osteogenic differentiation but inhibited adipocyte formation. miR-29a signaling promoted brown/beige adipocyte markers Ucp-1, Pgc-1α, P2rx5, and Pat2 expression and inhibited white adipocyte markers Tcf21 and Hoxc9 expression. The microRNA also reduced peroxisome formation and leptin expression during adipocyte formation and downregulated HFD-induced leptin expression in bone tissue. Taken together, miR-29a controlled leptin signaling and brown/beige adipocyte formation of osteogenic progenitor cells to preserve bone anabolism, which reversed HFD-induced energy underutilization and visceral fat overproduction. This study sheds light on a new molecular mechanism by which bone integrity counteracts HFD-induced whole-body fat overproduction.

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Section: Discussionmentioning

confidence: 82%

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

Lian

Chen

et al. 2021

IJMS

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“…If miR-29a serves as a physiologically relevant regulator of leptin in humans, our findings suggest that miR-29a should be reduced in obese patients. 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: 94%

“…1k). miR-29 has been described previously as a regulator of the glucocorticoid receptor in adipocytes 20 , but has otherwise not been well studied in fat cells. Of the three miR-29 family members, miR-29a is 60-70 fold more abundant in adipose tissue than miR-29b and miR-29c (Supplementary Fig.…”

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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“…Similarly, transfection of miR-331-3p mimic promotes CS sensitivity in several transformed cell lines by inhibiting JKN phosphorylation ( Lucafo et al, 2020 ). Other pro-CSR miRNAs are miR-21, miR-29a and miR-222; conversely, miR-15b, miR-16, and miR-128b promote CS sensitivity in cancer cells ( Kotani et al, 2009 ; Rainer et al, 2009 ; Wang et al, 2011 ; Glantschnig et al, 2019 ; Xu et al, 2019 ). Evidence for both pro- and anti-CSR effects of miR-221 and miR-124 has been reported ( Kotani et al, 2009 ; Lv et al, 2012 ; Kim et al, 2015 ; Liang et al, 2017 ; Xu et al, 2019 ).…”

Section: Mirnas and Their Role In Vkh Etiology And Treatmentmentioning

confidence: 99%

miRNA Landscape in Pathogenesis and Treatment of Vogt–Koyanagi–Harada Disease

Vega-Tapia

Bustamante

Valenzuela

et al. 2021

Front. Cell Dev. Biol.

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miRNAs, one of the members of the noncoding RNA family, are regulators of gene expression in inflammatory and autoimmune diseases. Changes in miRNA pool expression have been associated with differentiation of CD4+ T cells toward an inflammatory phenotype and with loss of self-tolerance in autoimmune diseases. Vogt–Koyanagi–Harada (VKH) disease is a chronic multisystemic pathology, affecting the uvea, inner ear, central nervous system, and skin. Several lines of evidence support an autoimmune etiology for VKH, with loss of tolerance against retinal pigmented epithelium-related self-antigens. This deleterious reaction is characterized by exacerbated inflammation, due to an aberrant TH1 and TH17 polarization and secretion of their proinflammatory hallmark cytokines interleukin 6 (IL-6), IL-17, interferon γ, and tumor necrosis factor α, and an impaired CD4+ CD25high FoxP3+ regulatory T cell function. To restrain inflammation, VKH is pharmacologically treated with corticosteroids and immunosuppressive drugs as first and second line of therapy, respectively. Changes in the expression of miRNAs related to immunoregulatory pathways have been associated with VKH development, whereas some genetic variants of miRNAs have been found to be risk modifiers of VKH. Furthermore, the drugs commonly used in VKH treatment have great influence on miRNA expression, including those miRNAs associated to VKH disease. This relationship between response to therapy and miRNA regulation suggests that these small noncoding molecules might be therapeutic targets for the development of more effective and specific pharmacological therapy for VKH. In this review, we discuss the latest evidence regarding regulation and alteration of miRNA associated with VKH disease and its treatment.

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A miR‐29a‐driven negative feedback loop regulates peripheral glucocorticoid receptor signaling

Cited by 34 publications

References 87 publications

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

MicroRNA-29a in Osteoblasts Represses High-Fat Diet-Mediated Osteoporosis and Body Adiposis through Targeting Leptin

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

miRNA Landscape in Pathogenesis and Treatment of Vogt–Koyanagi–Harada Disease

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