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

Nature Cell Biology volume 18, pages 328–336 (2016)Cite this article

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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 mellitus1,2,3,4. 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 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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Figure 1: Brown-fat-specific Dicer1 haploinsufficiency recapitulates obesity- and ageing-associated decline in microRNA expression.
Figure 2: Partial Dicer1 deficiency in BAT predisposes mice to obesity-associated deterioration of glucose homeostasis.
Figure 3: In vitro/in vivo filtering approach identifies miR-328 as a BAT-regulatory microRNA.
Figure 4: miR-328 and miR-193b support brown adipogenesis and repress myoblast differentiation in vitro, partly through silencing of Bace1.
Figure 5: In vivo inhibition of Bace1 activates BAT and ameliorates obesity-associated deterioration of glucose metabolism.

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Acknowledgements

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).

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Author notes

  1. Matteo Oliverio and Elena Schmidt: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute for Metabolism Research, D-50931 Cologne, Germany

    Matteo Oliverio, Elena Schmidt, Jan Mauer, Catherina Baitzel, Nils Hansmeier, Sajjad Khani, Sandra Konieczka, Marta Pradas-Juni, Deniz Bartsch, Hella S. Brönneke, Jens C. Brüning & Jan-Wilhelm Kornfeld

  2. Cologne Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), D-50931 Cologne, Germany

    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, Peter Frommolt, Jens C. Brüning & Jan-Wilhelm Kornfeld

  3. Department of Pharmacology, Weill Medical College, Cornell University, New York 10035, USA

    Jan Mauer

  4. Department of Biochemistry and Molecular Cell Biology, University Hospital Hamburg-Eppendorf, D-20246, Germany

    Markus Heine & Joerg Heeren

  5. F. Hoffmann-La Roche Ltd, Discovery Chemistry, Pharma Research and Early Development, CH-4070 Basel, Switzerland

    Hans Hilpert

  6. Department of Biophysics, Federal University of Sao Paulo, Brazil

    Emilio Tarcitano & Marcelo A. Mori

  7. Institute of Molecular Biology and Biotechnology (IMBB) Foundation for Research and Technology - Hellas (FORTH) Heraklion, GR-70013, Crete, Greece

    George A. Garinis

  8. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, D-50937, Germany

    Jens C. Brüning

  9. German Center for Diabetes Research (DZD), Germany

    Jens C. Brüning

Authors
  1. Matteo Oliverio
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Contributions

M.O., E.S., J.M., C.B., N.H., S.Khani, S.Konieczka, M.P.-J., S.B., T.-M.V., D.B., H.S.B., M.H., E.T., P.F. and J.-W.K. performed experiments. H.H., M.A.M., J.C.B. and J.-W.K. designed the experimental set-up. H.H., J.C.B., G.A.G. and J.H. contributed discussions.

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Correspondence to Jan-Wilhelm Kornfeld.

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Integrated supplementary information

Supplementary Figure 1

(a) Relative expression of Cidea, Dio2, Elovl3 and Ucp1 in BAT of adult (6 months, n = 4) versus old (18 months, n = 5) mice (left). Photomicrograph of BAT from adult versus old mice. A representative image is shown (right). (b) Network illustration of IPA pathways changes on RNA-Seq based mRNA expression in BAT in NCD-fed (n = 4) versus HFD-fed (n = 4) male C57BL/6 mice. (c) Breeding scheme for the generation of BAT-specific Dicer1 heterozygous knockouts (Dicer1ΔBAT/+). (d) Relative Ucp1 expression in SCAT of Dicer1ΔBAT/+ mice (n = 5) versus control mice (n = 3). If not stated otherwise, boxplots indicate median ± min/max and an unpaired two-tailed Student’s t-test was used to assess statistical significance. *p < 0.05.

Supplementary Figure 2

(a) Body weight curves of female, NCD-fed Dicer1ΔBAT/+ (n = 11; black circle) versus control (n = 11; white circle) or female, HFD-fed Dicer1ΔBAT/+ (n = 10, black diamond) versus control (n = 13; white diamond) mice. No statistically significant interaction was found using two-way ANOVAs for repeated measures (2WA-RM). (b) Relative expression of indicated genes in BAT of male, NCD-fed Dicer1ΔBAT/+ mice (n = 7) versus control mice (n = 8).(c) Core body temperature on cold (4 °C) exposure for indicated time points of female, Dicer1ΔBAT/+ (n = 7) versus control (n = 13) mice determined by rectal thermometry. No statistically significant interaction was found using 2WA-RM. (d) Glucose tolerance test of NCD-fed, male Dicer1ΔBAT/+ (n = 13) versus control animals (n = 20, left) or NCD-fed, female Dicer1ΔBAT/+ (n = 14) versus control animals (n = 21, right). A statistically significant interaction was found using 2WA-RM for male (P < 0.01; F = 4.165; Df = 4) mice and a borderline significant interaction for female (P < 0.07; F = 2.222; Df = 4) mice. (e) Insulin tolerance test of NCD-fed, male Dicer1ΔBAT/+ (n = 13) versus control animals (n = 15, left) or NCD-fed, female Dicer1ΔBAT/+ (n = 14) versus control animals (n = 16, right). No statistically significant interaction was found using 2WA-RM. (f) Serum insulin level of NCD-fed, male Dicer1ΔBAT/+ (n = 9) versus control mice (n = 10) and HFD-fed, male Dicer1ΔBAT/+ (n = 5) versus control mice (n = 8, left) or NCD-fed, female Dicer1ΔBAT/+ (n = 8) versus control mice (n = 9) and HFD-fed, female Dicer1ΔBAT/+ (n = 5) versus control mice (n = 12, right). (g) Serum leptin level of NCD-fed, male Dicer1ΔBAT/+ (n = 10) versus control mice (n = 9) and HFD-fed, male Dicer1ΔBAT/+ (n = 7) versus control mice (n = 13, left) or NCD-fed, female Dicer1ΔBAT/+ (n = 9) versus control mice (n = 9) and HFD-fed, female Dicer1ΔBAT/+(n = 10) versus control mice (n = 11, right). (h) Tissue weight/body weight (BW) ratio of indicated tissues in HFD-fed Dicer1ΔBAT/+ (Liver, n = 10; BAT, n = 4; SCAT, n = 3; VAT, n = 11) versus control (Liver, n = 18; BAT, n = 4; SCAT, n = 4; VAT, n = 17) mice. (i) Thin-layer chromatography-mediated quantification of lipid species (Chol, cholesterole; FFA, free fatty acids; TG, triglycerides) in indicated tissues of HFD-fed Dicer1ΔBAT/+ (n = 5) versus control (n = 6) mice. (j) Photomicrograph of indicated tissues in HFD-fed Dicer1ΔBAT/+ and control mice. A representative image is shown. Scale bar, 100 μm. If not stated otherwise, dots indicate mean ± s.e.m., boxplots indicate median ± min/max and an unpaired two-tailed Student’s t-test was used to assess statistical significance. *p < 0.05, **p < 0.01, ***p < 0.001, ∗∗∗∗p < 0.0001.

Supplementary Figure 3

(a) Expression of indicated genes in differentiated PIBA cells after transfection with LNAs against indicated microRNAs versus scramble (scr) controls across n = 3 (miR-96) or 2 independent experiments. Bars indicate the mean of the experiments. (b) Immunoblots against indicated proteins after transfection of PIBA cells with LNAs against indicated microRNAs versus scr. Image is representative of three (UCP1) or two (others) independent experiments. (c) Relative expression of indicated genes in 3T3-L1 cells six days after transfection with LNAs against indicated microRNAs versus scr controls or microRNA mimics versus scr. All experiments were performed in triplicate and represent the average of n = 3 independent experiments. (d) Immunoblots against indicated proteins after transfection of 3T3-L1 cells with microRNA LNAs versus scr or microRNA mimics versus scr. Image is representative of two independent experiments. If not stated otherwise, boxplots indicate median ± min/max and a paired two-tailed Student’s t-test was used to assess statistical significance. Uncropped images of blots are shown in Supplementary Fig. 6. Source data values for panel a are available in Supplementary Table 5.

Supplementary Figure 4

(a) Sequences of mmu-miR-193b and mmu-miR-328, comparison of miR-193b versus miR-328 seed sequences (top) and overlap of in silico predicted miR-193b (grey) and miR-328 mRNA (black) targets (bottom). The statistical significance for the overlap of miR-193b and miR-328 target genesets is given in Methods. (b) Relative luciferase activity in HEK293 cells after co-transfection of pmiRGlo reporter constructs harbouring wild-type 3′UTR fragments of indicated genes together with 100 nM of scr, miR-193b or miR-328 mimics across n = 3 independent experiments. (c) Relative expression of Bace1 (n = 6) and Gprc5b (n = 8) in indicated tissues (BAT, brown adipose tissue; H, heart; Liv, liver; SM, skeletal muscle; WAT, white adipose tissue). Expression levels in BAT were set to unity = 1. (d) Relative expression of Bace1 and Gprc5b in C2C12 cells seven days after transfection with 80 nM of indicated longRNA GapmeRs across n = 4 (Bace1) or n = 5 (Gprc5b) independent experiments, left). Relative expression of Bace1 in PIBA cells two days after transfection with 80 nM of indicated longRNA GapmeRs across n = 3 independent experiments, right). (e) Photomicrograph of C2C12 cells seven days after transfection with 80 nM of indicated longRNA Gapmers. Image is representative of three independent experiments. Scale bar, 100 μm. (f) Relative expression of Myf5, Myod1, Pax3 and Runx1t1 in C2C12 cells seven days after transfection with 80 nM of indicated longRNA GapmeRs. (g) Relative expression of indicated genes in 3T3-L1 cells two days after transfection with LNAs against Bace1 versus scr across n = 4 independent experiments. If not stated otherwise, boxplots indicate median ± min/max and a paired two-tailed Student’s t-test was used to assess statistical significance. * = p < 0.05.

Supplementary Figure 5

(a) Average food intake quantified by manual recordings of HFD-fed (n = 15) and HFD + RO5508887-fed (n = 15) mice during the course of the feeding experiment (12 weeks). (b) Glucose-stimulated insulin secretion of HFD-fed (n = 7) versus HFD + RO5508887-fed (n = 7) mice. (c) Percentage of insulin-positive (ins +) cells in pancreatic sections from HFD-fed (n = 6) and HFD + RO5508887-fed (n = 6) mice (left). Insulin staining and H&E counterstaining of pancreatic islets in HFD and HFD + RO5508887-fed mice (right). A representative image is shown. Scale bar, 100 μm. (d) Body composition measured by nuclear magnetic resonance of HFD-fed control (n = 15) versus HFD + RO5508887-fed (n = 14) male C57BL/6 mice. (e) H&E staining of SCAT paraffine section in HFD-fed (n = 5) and HFD + RO5508887-fed (n = 5) mice analyzed in using Zeiss Axiovision 4.2 software and adipocyte area cumulatively plotted in 10 increments. If not stated otherwise, boxplots indicate median ± min/max and an unpaired two-tailed Student’s t-test was used to assess statistical significance. *p < 0.05.

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Oliverio, M., Schmidt, E., Mauer, J. et al. Dicer1–miR-328–Bace1 signalling controls brown adipose tissue differentiation and function. Nat Cell Biol 18, 328–336 (2016). https://doi.org/10.1038/ncb3316

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