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

Matteo Oliverio; Elena Schmidt; Jan Mauer; Catherina Baitzel; Nils Hansmeier; Sajjad Khani; Sandra Konieczka; Marta Pradas-Juni; Susanne Brodesser; Trieu My Van; Deniz Bartsch; Hella S. Brönneke; Markus Heine; Hans Hilpert; Emilio Tarcitano; George A. Garinis; Peter Frommolt; Joerg Heeren; Marcelo A. Mori; Jens C. Brüning; Jan Wilhelm Kornfeld

doi:10.1038/ncb3316

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

Matteo Oliverio
, Elena Schmidt
, Jan Mauer
, Catherina Baitzel
, Nils Hansmeier
, Sajjad Khani
, Sandra Konieczka
, Marta Pradas-Juni
, Susanne Brodesser
, Trieu My Van
, Deniz Bartsch
, Hella S. Brönneke
, Markus Heine
, Hans Hilpert
, Emilio Tarcitano
, George A. Garinis
, Peter Frommolt
, Joerg Heeren
, Marcelo A. Mori
, Jens C. Brüning

Jan Wilhelm Kornfeld

Research output: Contribution to journal › Article › peer-review

89 Scopus citations

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.

Original language	English (US)
Pages (from-to)	328-336
Number of pages	9
Journal	Nature Cell Biology
Volume	18
Issue number	3
DOIs	https://doi.org/10.1038/ncb3316
State	Published - Feb 25 2016
Externally published	Yes

Bibliographical note

Funding Information:
We thank B. Hampel, A. Schauss, H. Jacobsen, J. Altmüller and J. Alber for technical assistance and A. Tarakhovsky (Rockefeller University, USA) for providing Dicer1loxP/loxP mice. We are grateful for Amesdf mice from A. Bartke (Southern Illinois University School of Medicine, USA). J.-W.K., M.O., N.H. and S.Konieczka are supported by the Emmy-Noether Program (DFG; KO4728/1.1) and CECAD. E.S. is supported by Evangelisches Studienwerk Villigst. S.Khani appreciates support from DAAD. E.T. and M.A.M. are supported by CNPq, CAPES and FAPESP (2010/52557- 0). J.C.B. is supported by the Leibniz Preis (BR1492/7-1), CECAD, Cologne Center for Molecular Medicine Cologne (CMMC) and through financial support from ''Systems Biology of Ageing Cologne'' (Sybacol).

Publisher Copyright:
© 2016 Macmillan Publishers Limited.

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Oliverio, M., Schmidt, E., Mauer, J., Baitzel, C., Hansmeier, N., Khani, S., Konieczka, S., Pradas-Juni, M., Brodesser, S., Van, T. M., Bartsch, D., Brönneke, H. S., Heine, M., Hilpert, H., Tarcitano, E., Garinis, G. A., Frommolt, P., Heeren, J., Mori, M. A., ... Kornfeld, J. W. (2016). Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nature Cell Biology, 18(3), 328-336. https://doi.org/10.1038/ncb3316

Oliverio, M, Schmidt, E, Mauer, J, Baitzel, C, Hansmeier, N, Khani, S, Konieczka, S, Pradas-Juni, M, Brodesser, S, Van, TM, Bartsch, D, Brönneke, HS, Heine, M, Hilpert, H, Tarcitano, E, Garinis, GA, Frommolt, P, Heeren, J, Mori, MA, Brüning, JC & Kornfeld, JW 2016, 'Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function', Nature Cell Biology, vol. 18, no. 3, pp. 328-336. https://doi.org/10.1038/ncb3316

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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.",

author = "Matteo Oliverio and Elena Schmidt and Jan Mauer and Catherina Baitzel and Nils Hansmeier and Sajjad Khani and Sandra Konieczka and Marta Pradas-Juni and Susanne Brodesser and Van, \{Trieu My\} and Deniz Bartsch and Br{\"o}nneke, \{Hella S.\} and Markus Heine and Hans Hilpert and Emilio Tarcitano and Garinis, \{George A.\} and Peter Frommolt and Joerg Heeren and Mori, \{Marcelo A.\} and Br{\"u}ning, \{Jens C.\} and Kornfeld, \{Jan Wilhelm\}",

note = "Funding Information: We thank B. Hampel, A. Schauss, H. Jacobsen, J. Altm{\"u}ller and J. Alber for technical assistance and A. Tarakhovsky (Rockefeller University, USA) for providing Dicer1loxP/loxP mice. We are grateful for Amesdf mice from A. Bartke (Southern Illinois University School of Medicine, USA). J.-W.K., M.O., N.H. and S.Konieczka are supported by the Emmy-Noether Program (DFG; KO4728/1.1) and CECAD. E.S. is supported by Evangelisches Studienwerk Villigst. S.Khani appreciates support from DAAD. E.T. and M.A.M. are supported by CNPq, CAPES and FAPESP (2010/52557- 0). J.C.B. is supported by the Leibniz Preis (BR1492/7-1), CECAD, Cologne Center for Molecular Medicine Cologne (CMMC) and through financial support from ''Systems Biology of Ageing Cologne'' (Sybacol). Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

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doi = "10.1038/ncb3316",

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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

N1 - Funding Information: We thank B. Hampel, A. Schauss, H. Jacobsen, J. Altmüller and J. Alber for technical assistance and A. Tarakhovsky (Rockefeller University, USA) for providing Dicer1loxP/loxP mice. We are grateful for Amesdf mice from A. Bartke (Southern Illinois University School of Medicine, USA). J.-W.K., M.O., N.H. and S.Konieczka are supported by the Emmy-Noether Program (DFG; KO4728/1.1) and CECAD. E.S. is supported by Evangelisches Studienwerk Villigst. S.Khani appreciates support from DAAD. E.T. and M.A.M. are supported by CNPq, CAPES and FAPESP (2010/52557- 0). J.C.B. is supported by the Leibniz Preis (BR1492/7-1), CECAD, Cologne Center for Molecular Medicine Cologne (CMMC) and through financial support from ''Systems Biology of Ageing Cologne'' (Sybacol). Publisher Copyright: © 2016 Macmillan Publishers Limited.

PY - 2016/2/25

Y1 - 2016/2/25

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.

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JO - Nature Cell Biology

JF - Nature Cell Biology

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

Abstract

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