Format

Send to

Choose Destination
Nat Cell Biol. 2016 Mar;18(3):328-36. doi: 10.1038/ncb3316. Epub 2016 Feb 22.

Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function.

Author information

1
Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.
2
Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
3
Department of Pharmacology, Weill Medical College, Cornell University, New York 10035, USA.
4
Department of Biochemistry and Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246, Germany.
5
F. Hoffmann-La Roche Ltd, Discovery Chemistry, Pharma Research and Early Development, CH-4070 Basel, Switzerland.
6
Department of Biophysics, Federal University of Sao Paulo, Brazil.
7
Institute of Molecular Biology and Biotechnology (IMBB) Foundation for Research and Technology - Hellas (FORTH) Heraklion, GR-70013, Crete, Greece.
8
Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, D-50937, Germany.
9
German Center for Diabetes Research (DZD), Germany.

Abstract

Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus. Here we show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the β-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.

Comment in

PMID:
26900752
DOI:
10.1038/ncb3316
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center