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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

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 3

Bioenergetic profile and brown fat whitening in Adicer-KO mice.

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Bioenergetic profile and brown fat whitening in Adicer-KO mice.
(A) Six-...
(A) Six-month-old female mice were subjected to comprehensive lab animal monitoring system (CLAMS) analysis, in which O2 consumption was measured (n = 4 mice per group). Mice were fasted during the last 24 hours of the experiment. Values were normalized by lean mass. (B) UCP1 immunohistochemistry (IHC) of interscapular BAT from 4-month-old mice at room temperature (23°C). UCP1 staining (brown, cytoplasmic); hematoxylin counterstaining (blue, nuclear). Images (original magnification, ×400) are representative of at least 3 mice per group. (C and d) Four-month-old mice were subjected to 4-day chronic exposure to 6°C (n = 5 mice per group). (C) UCP1 expression in interscapular BAT from mice at room temperature (RT) or after chronic cold exposure (Cold) as assessed by Western blotting. β-Tubulin was used as the loading control. (D) Markers of brown and white adipocytes were assessed in the interscapular BAT by qPCR. (E and F) Five-month-old mice were injected with CL-316,243, and (E) O2 consumption and (F) rectal temperature were measured (n = 4–8 mice per group). (G and H) Rectal temperature of 4-month-old or 2-month-old mice was measured during exposure to 6°C (G, n = 5 mice per group; H, n = 5–6 mice per group). (I) Shivering time of 2-month-old mice during a 1-minute period after 36 hours of cold (6°C) exposure (n = 5–6 mice per group). (J) UCP1 IHC of inguinal WAT from 4-month-old mice subjected to 4 days of cold exposure (n = 5 mice per group). UCP1 staining with hematoxylin counterstaining. Representative images (original magnification, ×400) of at least 3 mice per group. *P < 0.05; ***P < 0.001. Values are the mean ± SEM.

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