Format

Send to

Choose Destination
Cell Rep. 2018 Feb 20;22(8):2133-2145. doi: 10.1016/j.celrep.2018.01.074.

Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance.

Author information

1
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
3
Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, CT, USA.
4
Translational Gerontology Branch, National Institute of Aging, NIH, Baltimore, MD, USA.
5
Edward A. Doisy Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, USA.
6
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
7
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA.
8
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA; Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: carlos.fernandez@yale.edu.

Abstract

While therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies and predisposition of miR-33-/- mice to obesity and metabolic dysfunction exemplify the possible pitfalls of miRNA-based therapies. Our work provides an in-depth characterization of miR-33-/- mice and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1-mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33-/- mice, we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals.

KEYWORDS:

adipocyte; diabetes; food-consumption; insulin-resistance; metabolism; miR-33; micro-RNA; obesity; pair-feeding

Comment in

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center