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

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.