Universität zu Köln

Oliverio, Matteo ORCID: 0000-0002-7969-2796, Schmidt, Elena ORCID: 0000-0003-0829-1423, Mauer, Jan ORCID: 0000-0002-0189-5876, Baitzel, Catherina, Hansmeier, Nils, Khani, Sajjad, Konieczka, Sandra, Pradas-Juni, Marta, Brodesser, Susanne, Bartsch, Deniz ORCID: 0000-0003-3299-8330, Broenneke, Hella S., Heine, Markus, Hilpert, Hans, Tarcitano, Emilio, Garinis, George A. ORCID: 0000-0002-3200-5004, Frommolt, Peter ORCID: 0000-0002-1966-8014, Heeren, Joerg, Mori, Marcelo A., Bruening, Jens C. and Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442 (2016). Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nat. Cell Biol., 18 (3). S. 328 - 348. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4679

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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(1-4). 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 beta-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Oliverio, Matteo UNSPECIFIED orcid.org/0000-0002-7969-2796 UNSPECIFIED Schmidt, Elena UNSPECIFIED orcid.org/0000-0003-0829-1423 UNSPECIFIED Mauer, Jan UNSPECIFIED orcid.org/0000-0002-0189-5876 UNSPECIFIED Baitzel, Catherina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansmeier, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Khani, Sajjad UNSPECIFIED UNSPECIFIED UNSPECIFIED Konieczka, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Pradas-Juni, Marta UNSPECIFIED UNSPECIFIED UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartsch, Deniz UNSPECIFIED orcid.org/0000-0003-3299-8330 UNSPECIFIED Broenneke, Hella S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heine, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Hilpert, Hans UNSPECIFIED UNSPECIFIED UNSPECIFIED Tarcitano, Emilio UNSPECIFIED UNSPECIFIED UNSPECIFIED Garinis, George A. UNSPECIFIED orcid.org/0000-0002-3200-5004 UNSPECIFIED Frommolt, Peter UNSPECIFIED orcid.org/0000-0002-1966-8014 UNSPECIFIED Heeren, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Mori, Marcelo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kornfeld, Jan-Wilhelm UNSPECIFIED orcid.org/0000-0002-6802-4442 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-283963
DOI:	10.1038/ncb3316
Journal or Publication Title:	Nat. Cell Biol.
Volume:	18
Number:	3
Page Range:	S. 328 - 348
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4679
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TRANSGENIC MICE; BODY-WEIGHT; OBESITY; FAT; THERMOGENESIS; WHITE; ADIPOCYTES; BIOGENESIS; REDUCTION; ABLATION Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28396