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

Author(s):Show less -

Mori, Marcelo A. ^{[1, 2, 3]} ; Thomou, Thomas ^[2] ; Boucher, Jeremie ^{[2, 4]} ; Lee, Kevin Y. ^[2] ; Lallukka, Susanna ^{[5, 6]} ; Kim, Jason K. ^[7] ; Torriani, Martin ^{[8, 9]} ; Yki-Jaervinen, Hannele ^[7] ; Grinspoon, Steven K. ^{[8, 9]} ; Cypess, Aaron M. ^[2] ; Kahn, C. Ronald ^[2]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil

^[2] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 - USA

^[3] Univ Fed Sao Paulo, Program Mol Biol, Sao Paulo - Brazil

^[4] AstraZeneca R&D, Cardiovasc & Metab Dis iMed, Molndal - Sweden

^[5] Univ Helsinki, Dept Med, Helsinki - Finland

^[6] Minerva Fdn, Inst Med Res, Helsinki - Finland

^[7] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA - USA

^[8] Harvard Univ, Sch Med, Boston, MA - USA

^[9] Massachusetts Gen Hosp, Program Nutr Metab, Boston, MA 02114 - USA

• Document type: Journal article
• Source: Journal of Clinical Investigation; v. 124, n. 8, p. 3339-3351, AUG 2014.
• Web of Science Citations: 65

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. (AU)

• FAPESP's process: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Grants - Young Investigators Grants