MicroRNAs Are Required for the Feature Maintenance and Differentiation of Brown Adipocytes

Kim, Hye-Jin; Cho, Hyunjii; Alexander, R. S.; Patterson, Heide Christine; Gu, Minxia; Lo, Kinyui Alice; Xu, Dan; Goh, Vera J.; Nguyen, Long N.; Chai, Xiaoran; Huang, Chen; Kovalik, Jean‐Paul; Ghosh, Sujoy; Trajkovski, Mirko; Silver, David L.; Lodish, Harvey F.; Sun, Li

doi:10.2337/db14-0466

Cited by 99 publications

(86 citation statements)

References 42 publications

(54 reference statements)

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“…In some experiments, the primary white and brown preadipocytes, isolated from mouse WAT and interscapular BAT, were also used. After digestion with 0.2% collagenase and centrifugation (1,500 rpm, 5 min), the stromal vascular fraction/ preadipose cells from WAT and BAT were isolated as described before (32). Preadipose cells were seeded in 6-well plates and cultured with the basal growth medium (DMEM supplemented with 10% fetal bovine serum (FBS), 1 nM 3,5,3Ј-triiodothyronine, 1% penicillin and streptomycin) at 37°C and in a humidified atmosphere containing 5% CO 2 and 95% air.…”

Section: Methodsmentioning

confidence: 99%

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

Than

Chua

et al. 2015

Journal of Biological Chemistry

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104

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Background:The autocrine regulatory effects of apelin on self-remodeling of adipose tissue are not known. Results: Apelin enhances not only the differentiation and metabolic activity of brown adipocytes but also the browning of white adipocytes. Conclusion: Apelin-APJ signaling promotes adipose tissue browning. Significance: Apelin signaling may serve as a potential therapeutic target for obesity and associated metabolic diseases.

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Section: Methodsmentioning

confidence: 99%

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

Than

Chua

et al. 2015

Journal of Biological Chemistry

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104

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“…Recent studies have demonstrated that miRNAs, such as miR -27, -133, -155, -193b, -196, and -203, are deeply associated with brown adipocyte and beige adipocyte differentiation (8,(13)(14)(15). However, the roles of only a few miRNAs in fat browning have been verified.…”

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confidence: 99%

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

et al. 2016

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There has been great interest in the browning of fat for the treatment of obesity. Although b-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet. Consistently, BLC-treated mice showed significantly higher energy expenditure compared with control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the upregulation of its direct target, Dio2. Upregulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC-mediated increase in the browning of WAT and the thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity.

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“…Deletion of adiposespecific dicer promotes white-like phenotype of brown precursor cells (8). Similarly, disruption of miRNA biogenesis by deleting fat-specific Dgcr8, a molecular anchor necessary for the recognition of pri-miRNA, results in defective BAT formation and severe cold intolerance (9). Recently, miR-193b/365 cluster was identified to be enriched in BAT and demonstrated as a key regulator to promote brown adipogenesis by targeting Runx1t1, a transcription factor that drives myocyte formation (10).…”

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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

101

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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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MicroRNAs Are Required for the Feature Maintenance and Differentiation of Brown Adipocytes

Cited by 99 publications

References 42 publications

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

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

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