title: 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.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Lee
authors.forename: Susanna
authors.initials: S
authors.lastname: Lallukka
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Martin
authors.initials: M
authors.lastname: Torriani
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grinspoon
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism*; D052438:Adipocytes, White / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004734:Energy Metabolism; D005260:Female; D039682:HIV-Associated Lipodystrophy Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases