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

Author(s):Show less -

Oliverio, Matteo ^{[1, 2]} ; Schmidt, Elena ^{[1, 2]} ; Mauer, Jan ^{[1, 2, 3]} ; Baitzel, Catherina ^{[1, 2]} ; Hansmeier, Nils ^{[1, 2]} ; Khani, Sajjad ^{[1, 2]} ; Konieczka, Sandra ^{[1, 2]} ; Pradas-Juni, Marta ^{[1, 2]} ; Brodesser, Susanne ^[2] ; Van, Trieu-My ; Bartsch, Deniz ^{[1, 4]} ; Broenneke, Hella S. ^{[1, 4]} ; Heine, Markus ^[5] ; Hilpert, Hans ^[6] ; Tarcitano, Emilio ^[7] ; Garinis, George A. ^[8] ; Frommolt, Peter ^[4] ; Heeren, Joerg ^[5] ; Mori, Marcelo A. ^[7] ; Bruening, Jens C. ^{[1, 4, 9, 10]} ; Kornfeld, Jan-Wilhelm ^{[1, 4]}

Affiliation

^[1] Max Planck Inst Metab Res, D-50931 Cologne - Germany

^[2] Cologne Cluster Excellence Cellular Stress Respon, D-50931 Cologne - Germany

^[3] Cornell Univ, Dept Pharmacol, Weill Med Coll, New York, NY 10035 - USA

^[4] Trieu-My Van, Cologne Cluster Excellence Cellular Stress Respon, D-50931 Cologne - Germany

^[5] Univ Hosp Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, D-20246 Hamburg - Germany

^[6] F Hoffmann La Roche & Co Ltd, Discovery Chem, Pharma Res & Early Dev, CH-4070 Basel - Switzerland

^[7] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil

^[8] Fdn Res & Technol Hellas FORTH Heraklion, IMBB, GR-70013 Iraklion - Greece

^[9] Univ Hosp Cologne, Ctr Endocrinol Diabet & Prevent Med CEDP, D-50937 Cologne - Germany

^[10] German Ctr Diabet Res DZD, Berlin - Germany

• Document type: Journal article
• Source: Nature Cell Biology; v. 18, n. 3, p. 328+, MAR 2016.
• Web of Science Citations: 34

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. (AU)

• FAPESP's process: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Grants - Young Investigators Grants