Mir193b–365 is essential for brown fat differentiation

Sun, Li; Xie, Huangming; Mori, Marcelo A.; Alexander, R. S.; Yuan, Bingbing; Hattangadi, Shilpa M.; Liu, Qingqing; Kahn, C. Ronald; Lodish, Harvey F.

doi:10.1038/ncb2286

Cited by 286 publications

(285 citation statements)

References 42 publications

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“…These inflammatory markers have direct effects on cellular metabolism, leading to decreased AT expandability, development of fibrosis, and dysfunction [8][9][10][11] . Similar to other inflammatory processes, white AT (WAT) inflammation is intrinsically linked to oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

et al. 2018

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Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg −1 day −1 ) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.

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Section: Introductionmentioning

confidence: 99%

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

et al. 2018

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“…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). In addition to suppression of myogenic lineage commitment, miR-196a promotes brown adipogenesis by inhibiting white adipocyte commitment (11).…”

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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

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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“…Noncoding RNAs are known to play a regulatory role in many developmental contexts, including adipogenesis, and several microRNAs have been identified that positively or negatively regulate adipogenesis (11,12). Recently we and others have identified a class of long noncoding RNAs (lncRNAs) (13)(14)(15).…”

mentioning

confidence: 99%

Long noncoding RNAs regulate adipogenesis

Sun

Goff

Trapnell

et al. 2013

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

Self Cite

387

338

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The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.

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Mir193b–365 is essential for brown fat differentiation

Cited by 286 publications

References 42 publications

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C

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

Long noncoding RNAs regulate adipogenesis

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