Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function
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Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. / Oliverio, Matteo; Schmidt, Elena; Mauer, Jan; Baitzel, Catherina; Hansmeier, Nils; Khani, Sajjad; Konieczka, Sandra; Pradas-Juni, Marta; Brodesser, Susanne; Van, Trieu-My; Bartsch, Deniz; Brönneke, Hella S; Heine, Markus; Hilpert, Hans; Tarcitano, Emilio; Garinis, George A; Frommolt, Peter; Heeren, Joerg; Mori, Marcelo A; Brüning, Jens C; Kornfeld, Jan-Wilhelm.
In: NAT CELL BIOL, Vol. 18, No. 3, 03.2016, p. 328-36.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function
AU - Oliverio, Matteo
AU - Schmidt, Elena
AU - Mauer, Jan
AU - Baitzel, Catherina
AU - Hansmeier, Nils
AU - Khani, Sajjad
AU - Konieczka, Sandra
AU - Pradas-Juni, Marta
AU - Brodesser, Susanne
AU - Van, Trieu-My
AU - Bartsch, Deniz
AU - Brönneke, Hella S
AU - Heine, Markus
AU - Hilpert, Hans
AU - Tarcitano, Emilio
AU - Garinis, George A
AU - Frommolt, Peter
AU - Heeren, Joerg
AU - Mori, Marcelo A
AU - Brüning, Jens C
AU - Kornfeld, Jan-Wilhelm
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
KW - Adipose Tissue, Brown
KW - Amyloid Precursor Protein Secretases
KW - Animals
KW - Aspartic Acid Endopeptidases
KW - Cell Differentiation
KW - DEAD-box RNA Helicases
KW - Energy Metabolism
KW - Homeostasis
KW - Insulin Resistance
KW - Mice, Inbred C57BL
KW - MicroRNAs
KW - Obesity
KW - Ribonuclease III
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/ncb3316
DO - 10.1038/ncb3316
M3 - SCORING: Journal article
C2 - 26900752
VL - 18
SP - 328
EP - 336
JO - NAT CELL BIOL
JF - NAT CELL BIOL
SN - 1465-7392
IS - 3
ER -