miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit

Chen, Yong; Siegel, Franziska; Kipschull, Stefanie; Haas, Bodo; Fröhlich, Holger; Meister, Gunter; Pfeifer, Alexander

doi:10.1038/ncomms2742

Cited by 240 publications

(205 citation statements)

References 58 publications

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“…Previous studies reported that TGF-β-mediated Smad4 expression induces miR-155 promoter activity and enriches miR-155 expression to contribute to cell migration and invasion (38), and found that NF-κB, STAT5, or CCAAT/enhancer binding protein beta (C/EBPβ) could bind to miR-155 promoter region and induce miR-155 expression in colon cancer, cutaneous T-cell lymphoma, or fat cells (20,39,40). miR-155 has been considered an "oncomicroRNA" by targeting several tumor suppressors, including SOCS1, FOXO3a, RhoA, C/EBPβ, PP2A/C, and von Hippel-Lindau tumor suppressor (VHL), and it has been found to promote the EMT, invasion, metastasis, growth, and angiogenesis of cancer cells (20,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3′UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

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Section: Discussionmentioning

confidence: 99%

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Chiu

Chang

Kuo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The brown transcriptional program could be corroborated by miR-378 that increases cAMP production via targeted degradation of phosphodiesterase 1B (Pde1b) (12) or by miR-30b that promotes degradation of Rip140, a transcriptional corepressor (13). Conversely, decreased levels of miR-133, miR-27a, miR-106b/93, and miR-155 have shown to enhance brown adipogenesis by preventing targeted degradation of transcription factors of Prdm16 (14), Ppar␥ (15), Ppar␣ (16), and C/ebp␤ (17), respectively (see Fig. 1E).…”

mentioning

confidence: 99%

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

Kim

Okla

Erickson

et al. 2016

Journal of Biological Chemistry

105

120

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Emerging evidence suggests that n-3 polyunsaturated fatty acids (PUFA) promote brown adipose tissue thermogenesis. However, the underlying mechanisms remain elusive. Here, we hypothesize that n-3 PUFA promotes brown adipogenesis by modulating miRNAs. To test this hypothesis, murine brown preadipocytes were induced to differentiate the fatty acids of palmitic, oleate, or eicosapentaenoic acid (EPA). The increases of brown-specific signature genes and oxygen consumption rate by EPA were concurrent with up-regulation of miR-30b and 378 but not by oleate or palmitic acid. Next, we hypothesize that free fatty acid receptor 4 (Ffar4), a functional receptor for n-3 PUFA, modulates miR-30b and 378. Treatment of Ffar4 agonist (GW9508) recapitulated the thermogenic activation of EPA by increasing oxygen consumption rate, brown-specific marker genes, and miR-30b and 378, which were abrogated in Ffar4-silenced cells. Intriguingly, addition of the miR-30b mimic was unable to restore EPA-induced Ucp1 expression in Ffar4-depleted cells, implicating that Ffar4 signaling activity is required for up-regulating the brown adipogenic program. Moreover, blockage of miR-30b or 378 by locked nucleic acid inhibitors significantly attenuated Ffar4 as well as brown-specific signature gene expression, suggesting the signaling interplay between Ffar4 and miR-30b/378. The association between miR-30b/378 and brown thermogenesis was also confirmed in fish oil-fed C57/BL6 mice. Interestingly, the Ffar4 agonism-mediated signaling axis of Ffar4-miR-30b/378-Ucp1 was linked with an elevation of cAMP in brown adipocytes, similar to cold-exposed or fish oil-fed brown fat. Taken together, our work identifies a novel function of Ffar4 in modulating brown adipogenesis partly through a mechanism involving cAMP activation and upregulation of miR-30b and miR-378.There are two specific types of fat with opposite functions, brown adipose tissue (BAT) 3 and white adipose tissue (WAT).WAT stores energy in the form of triglyceride, whereas BAT dissipates energy in the form of heat via uncoupling protein 1 (UCP1) (1). Recent advances in our understanding of BAT biology in humans have provided a new insight into weight loss strategies by boosting BAT thermogenesis. Despite the surge of research for identifying cellular and molecular regulators of brown fat development (2, 3), the role of dietary constituents, particularly dietary fatty acids (FA), in thermogenic activation is poorly understood. Depending on the degree of desaturation and the n-6/n-3 ratio, FA differentially control adiposity, insulin sensitivity, immune response (4), and probably energy expenditure (5-7). Lately, it has been suggested that n-3 polyunsaturated FA (PUFA) stimulate beige/brown adipogenesis in primary murine adipogenic precursor cells (5) as well as C57BL/6 mice (6, 7). The latter animal study suggests that n-3 PUFA are associated with sympathetic activation and increased ␤3-adrenergic receptor (Adrb3) signaling (7). However, the underlying mechanistic details of how dietary n-3 PUFA...

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“…In our opinion it will be important in the future to study factors which inhibit BAT activity with the same attention given to those that promote its activity. Our work, in fact, is one of a few 46,47 that focuses on an endogenous player that impairs BAT formation and activity. Only such an extended approach will allow us to draw a more comprehensive picture of the molecular mechanisms that regulate BAT activity to design new interventions that would take advantage of its potential to ameliorate metabolic diseases.…”

mentioning

confidence: 99%

The dual role of BMP4 in adipogenesis and metabolism

Modica

Wolfrum

2017

Adipocyte

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BMP4 has a well-established role in triggering commitment of mesenchymal stem cells into the osteogenic and adipogenic linage. We recently described an additional dual function in adipogenesis: after promoting the formation of both white and brown pre-adipocytes, Bmp4 drives terminal differentiation into mature white rather than brown fat cells. Besides this, Bmp4 seems to have a dual role in metabolism either promoting or repressing oxidative metabolism in a cell context dependent manner.

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miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit

Cited by 240 publications

References 58 publications

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

NF-κB–driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

The dual role of BMP4 in adipogenesis and metabolism

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