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Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy
Marcelo A. Mori, … , Aaron M. Cypess, C. Ronald Kahn
Marcelo A. Mori, … , Aaron M. Cypess, C. Ronald Kahn
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3339-3351. https://doi.org/10.1172/JCI73468.
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Research Article Metabolism Article has an altmetric score of 72

Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy

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Abstract

miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and “whitening” of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte–like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.

Authors

Marcelo A. Mori, Thomas Thomou, Jeremie Boucher, Kevin Y. Lee, Susanna Lallukka, Jason K. Kim, Martin Torriani, Hannele Yki-Järvinen, Steven K. Grinspoon, Aaron M. Cypess, C. Ronald Kahn

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Figure 5

Brown to white identity switch upon dicer KO in adipocytes.

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Brown to white identity switch upon dicer KO in adipocytes.
Immortalized...
Immortalized interscapular brown preadipocytes of dicerfl/fl mice were transduced with adenoviruses harboring GFP (Lox) or Cre recombinase (dicer KO, denoted in the figure as KO), and 4 days later (day 0, D0), cells were differentiated in vitro into adipocytes (D8). (A) Adipocyte markers were assessed by qPCR (n = 3 per group). (B and C) Lipid accumulation during differentiation was measured using Oil Red O staining on day 8. Visualization at (B) lower (original magnification, ×1 scanning the bottom of the plate with an optical scanner) and (C) higher magnifications (original magnification, ×200 using an optical microscope). Representative images of 3 independent cell lines per group. (D) Differentiated cells were treated for 4 hours with 500 μM cAMP or 10 μM isoproterenol. Ucp1 mRNA expression was measured by qPCR, and fold induction versus the nonstimulated control was calculated (n = 3 per group). (E) Uncoupled respiration was measured using a Seahorse Bioscience XF24-3 Extracellular Flux Analyzer (n = 5 per group). Values represent the amount of O2 consumed by cells when incubated with the ATP synthase inhibitor oligomycin A. (F and G) Three days after adenoviral transduction, Lox and dicer-KO preadipocytes were transfected with miRNA mimics or a scramble, nonsilencing control (NS). Adipocyte differentiation started on the following day (D0), and (F) Ucp1 and (G) Cebpb mRNAs were measured by qPCR when cells were fully differentiated (D8) (n = 3 per group). In F and G, gene expression was normalized by aP2 mRNA levels to avoid small differences in adipocyte differentiation. *P < 0.05. Values are the mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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