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:
CreatorsEmailORCIDORCID Put Code
Oliverio, MatteoUNSPECIFIEDorcid.org/0000-0002-7969-2796UNSPECIFIED
Schmidt, ElenaUNSPECIFIEDorcid.org/0000-0003-0829-1423UNSPECIFIED
Mauer, JanUNSPECIFIEDorcid.org/0000-0002-0189-5876UNSPECIFIED
Baitzel, CatherinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansmeier, NilsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khani, SajjadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konieczka, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pradas-Juni, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartsch, DenizUNSPECIFIEDorcid.org/0000-0003-3299-8330UNSPECIFIED
Broenneke, Hella S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heine, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilpert, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarcitano, EmilioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garinis, George A.UNSPECIFIEDorcid.org/0000-0002-3200-5004UNSPECIFIED
Frommolt, PeterUNSPECIFIEDorcid.org/0000-0002-1966-8014UNSPECIFIED
Heeren, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mori, Marcelo A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornfeld, Jan-WilhelmUNSPECIFIEDorcid.org/0000-0002-6802-4442UNSPECIFIED
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:
KeywordsLanguage
TRANSGENIC MICE; BODY-WEIGHT; OBESITY; FAT; THERMOGENESIS; WHITE; ADIPOCYTES; BIOGENESIS; REDUCTION; ABLATIONMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/28396

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