title: Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function.
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.
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Matteo
authors.identifier: http://orcid.org/0000-0002-7969-2796
authors.initials: M
authors.lastname: Oliverio
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Elena
authors.identifier: http://orcid.org/0000-0003-0829-1423
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.|Department of Pharmacology, Weill Medical College, Cornell University, New York 10035, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Mauer
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Catherina
authors.initials: C
authors.lastname: Baitzel
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Hansmeier
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Sajjad
authors.initials: S
authors.lastname: Khani
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Konieczka
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Pradas-Juni
authors.affiliation: Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Trieu-My
authors.initials: TM
authors.lastname: Van
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Bartsch
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Hella S
authors.initials: HS
authors.lastname: Brönneke
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Heine
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Chemistry, Pharma Research and Early Development, CH-4070 Basel, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Hilpert
authors.affiliation: Department of Biophysics, Federal University of Sao Paulo, Brazil.
authors.forename: Emilio
authors.initials: E
authors.lastname: Tarcitano
authors.affiliation: Institute of Molecular Biology and Biotechnology (IMBB) Foundation for Research and Technology - Hellas (FORTH) Heraklion, GR-70013, Crete, Greece.
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.affiliation: Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: Department of Biophysics, Federal University of Sao Paulo, Brazil.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Mori
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.|Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, D-50937, Germany.|German Center for Diabetes Research (DZD), Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany.|Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany.
authors.forename: Jan-Wilhelm
authors.initials: JW
authors.lastname: Kornfeld
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism
chemical_list: C548169:MIRN328 microRNA, mouse; D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D053487:DEAD-box RNA Helicases