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MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance

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Abstract

Endothelial cells (ECs) within the microvasculature of brown adipose tissue (BAT) are important in regulating the plasticity of adipocytes in response to increased metabolic demand by modulating the angiogenic response. However, the mechanism of EC-adipocyte crosstalk during this process is not completely understood. We used RNA sequencing to profile microRNAs derived from BAT ECs of obese mice and identified an anti-angiogenic microRNA, miR-409-3p. MiR-409-3p overexpression inhibited EC angiogenic properties; whereas, its inhibition had the opposite effects. Mechanistic studies revealed that miR-409-3p targets ZEB1 and MAP4K3. Knockdown of ZEB1/MAP4K3 phenocopied the angiogenic effects of miR-409-3p. Adipocytes co-cultured with conditioned media from ECs deficient in miR-409-3p showed increased expression of BAT markers, UCP1 and CIDEA. We identified a pro-angiogenic growth factor, placental growth factor (PLGF), released from ECs in response to miR-409-3p inhibition. Deficiency of ZEB1 or MAP4K3 blocked the release of PLGF from ECs and PLGF stimulation of 3T3-L1 adipocytes increased UCP1 expression in a miR-409-3p dependent manner. MiR-409-3p neutralization improved BAT angiogenesis, glucose and insulin tolerance, and energy expenditure in mice with diet-induced obesity. These findings establish miR-409-3p as a critical regulator of EC-BAT crosstalk by modulating a ZEB1-MAP4K3-PLGF signaling axis, providing new insights for therapeutic intervention in obesity.

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The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

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Abbreviations

SiRNA:

Small interfering RNA

3’-UTR:

3’-Untranslated region

ZEB1:

Zinc Finger E-Box Binding Homeobox

MAP4K3:

Mitogen-activated protein kinase kinase kinase kinase 3

UCP1:

Uncoupling Protein 1

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Acknowledgements

We thank Lay-Hong Ang and Aniket Gad for Confocal Microscopy technical assistance (NIH P30DK034854), Yevgenia Tesmenitsky for i.v. injections, Merve Kurt with her technical assistance in EC scratch assays.

Funding

This work was supported by the American Diabetes Association grant #1-16-JDF-046 (to B.I.), a Behrakis Junior Faculty Development Award (to B.I.), a Watkins Discovery Award (to B.I.), a National Institutes of Health (HL149999 to B.I.), a National Institutes of Health (HL115141, HL134849, HL148207, HL148355, HL153356 to M.W.F), an American Heart Association grant (18SFRN33900144 and 20SFRN35200163 to M.W.F.), the Arthur K. Watson Charitable Trust (to M.W.F).

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Louis Pasteur Avenue 77, Boston, MA, 02115, USA

    Dakota Becker-Greene, Hao Li, Daniel Perez-Cremades, Winona Wu, Denizhan Ozdemir, Ceren Aydogan, Mark W. Feinberg & Basak Icli

  2. Department of Physiology, University of Valencia and INCLIVA Biomedical Research Institute, Valencia, Spain

    Daniel Perez-Cremades

  3. Molecular Cardiology Research Institute, Tufts University School of Medicine, 800 Washington St, Boston, MA, 02111, USA

    Furkan Bestepe, Carolyn E. Niosi & Basak Icli

  4. Department of Medical Biology, Hacettepe University, Ankara, Turkey

    Denizhan Ozdemir

  5. Cerrahpasa Faculty of Medicine, Istanbul, Turkey

    Ceren Aydogan

  6. Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Dennis P. Orgill

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  1. Dakota Becker-Greene
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Contributions

MWF and BI designed research; BI, DBG, HL, DPC, WW, FB, CEN and DOz, carried out the experiments; DO, contributed critical reagents; DBG, HL, DPC, WW, FB, MWF and BI analyzed and interpreted the data; and DBG, MWF and BI wrote the manuscript.

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Correspondence to Mark W. Feinberg or Basak Icli.

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All animal protocols were approved through the Brigham & Women’s Hospital Institutional Animal Care and Use Committee. All human cell lines were obtained from indicated life science company or post-operative discarded tissue.

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Becker-Greene, D., Li, H., Perez-Cremades, D. et al. MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance. Cell. Mol. Life Sci. 78, 7663–7679 (2021). https://doi.org/10.1007/s00018-021-03960-1

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