A miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning

Fischer, Carina; Seki, Takahiro; Lim, Sharon; Nakamura, Masaki; Andersson, Patrik; Yang, Yunlong; Honek, Jennifer; Wang, Yangang; Gao, Yanbin; Chen, Fang; Samani, Nilesh J.; Zhang, Jun; Miyake, Masato; Oyadomari, Seiichi; Yasue, Akihiro; Li, Xuri; Zhang, Yun; Liu, Yizhi; Cao, Yihai

doi:10.1038/s41467-017-02158-z

Cited by 53 publications

(55 citation statements)

References 47 publications

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“…The mir-17 family of miRNAs is important for FGF10/FGFR2b downstream signaling during lung bud morphogenesis ( Carraro et al, 2009 ) and miR-31 negatively regulates expression of Fgf10 during hair follicle growth and hair fiber formation ( Mardaryev et al, 2010 ). More recently, it has been suggested that the miR-327/FGF10/FGFR2 signaling axis may be a therapeutic target for treatment of obesity and metabolic diseases ( Fischer et al, 2017 ) and that the crosstalk between miR-145-5p and FGF10 expression regulates vascular smooth muscle cells proliferation and migration ( Shi et al, 2018 ).…”

Section: Modulation Of Fgf10 Expression and Activimentioning

confidence: 99%

Regulation of FGF10 Signaling in Development and Disease

Watson

Francavilla

2018

Front. Genet.

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Fibroblast Growth Factor 10 (FGF10) is a multifunctional mesenchymal-epithelial signaling growth factor, which is essential for multi-organ development and tissue homeostasis in adults. Furthermore, FGF10 deregulation has been associated with human genetic disorders and certain forms of cancer. Upon binding to FGF receptors with heparan sulfate as co-factor, FGF10 activates several intracellular signaling cascades, resulting in cell proliferation, differentiation, and invasion. FGF10 activity is modulated not only by heparan sulfate proteoglycans in the extracellular matrix, but also by hormones and other soluble factors. Despite more than 20 years of research on FGF10 functions, context-dependent regulation of FGF10 signaling specificity remains poorly understood. Emerging modes of FGF10 signaling regulation will be described, focusing on the role of FGF10 trafficking and sub-cellular localization, heparan sulfate proteoglycans, and miRNAs. Systems biology approaches based on quantitative proteomics will be considered for globally investigating FGF10 signaling specificity. Finally, current gaps in our understanding of FGF10 functions, such as the relative contribution of receptor isoforms to signaling activation, will be discussed in the context of genetic disorders and tumorigenesis.

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Section: Modulation Of Fgf10 Expression and Activimentioning

confidence: 99%

Regulation of FGF10 Signaling in Development and Disease

Watson

Francavilla

2018

Front. Genet.

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“…Induced WAT browning and activated BAT increase energy consumption and non-shivering thermogenesis, thus inhibit weight gain. 34 It explained why our Irs-1 −/− mice could be protected against high-fat diet-induced obesity.…”

Section: Discussionmentioning

confidence: 96%

“…One of strong inducer of WAT browning is cold exposure. 34,40 To verify the roles of miR-503, BMPR1a, and PI3K/AKT pathway in the browning of WAT, we treated WT mice with cold exposure. Cold exposure promoted the browning of sWAT with UCP1 expressed at a higher level, it also promoted BMPR1a expression but blocked miR-503 expression.…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate‐1 inhibits high‐fat diet‐induced obesity by browning of white adipose tissue through miR‐503

Man

Tan

et al. 2020

FASEB j.

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Genetic variation of insulin receptor substrate 1 (IRS‐1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS‐1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs‐1 (Irs‐1−/−) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis‐related genes with miRNA arrays and PCR arrays. Irs‐1−/− mice showed decreased miR‐503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR‐503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3‐kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs‐1−/− and cold‐induced models, sWAT exhibited BAT features, and showed tissue‐specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS‐1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR‐503‐BMPR1a pathway, which played important roles in high‐fat diet‐induced obesity.

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“…Caveolin‐related transcripts were shown to participate in lipid storage and increase in adipocytes with high‐fat diet , and high expression of Ehd1 has a genetic basis for susceptibility to obesity . Transcripts within the blood vessel remodeling pathway infer improved blood flow and increased beiging ( Fgf10 ) in adipose from MusMyD88 −/− females. Finally, the meta‐inflammation related gene Hmox1 (↓ in MusMyD88 −/− ) was shown to be a strong positive predictor of metabolic disease in humans .…”

Section: Discussionmentioning

confidence: 99%

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

Mahmassani

Reidy

McKenzie

et al. 2020

Obesity

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Objective Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88−/−) would prevent, whereas miR146a−/− (MyD88 inhibitor) would exacerbate, inactivity‐induced metabolic disturbances. Methods Cre‐control, MusMyD88−/−, and miR146a−/− mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (3H)2‐deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88−/− and Cre‐control SMC mice. Results The SMC induced adiposity, hyperinsulinemia, and muscle insulin‐stimulated glucose uptake, which was worsened in miR146a−/− mice. In females, MusMyD88−/− mice were protected. Female MusMyD88−/− mice during the SMC period (vs. Cre‐control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta‐inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation‐related gene 993011J21Rik2 were decreased in both muscle and fat. Conclusions Whole‐body miR146a−/− exacerbated inactivity‐induced fat gain and muscle insulin resistance, whereas MusMyD88−/− prevented insulin resistance in female mice.

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A miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning

Cited by 53 publications

References 47 publications

Regulation of FGF10 Signaling in Development and Disease

Regulation of FGF10 Signaling in Development and Disease

Insulin receptor substrate‐1 inhibits high‐fat diet‐induced obesity by browning of white adipose tissue through miR‐503

Absence of MyD88 from Skeletal Muscle Protects Female Mice from Inactivity‐Induced Adiposity and Insulin Resistance

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