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Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity

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  • Bam D. Paneru

    (Children’s Hospital of Philadelphia)

  • Julia Chini

    (Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Sam J. McCright

    (Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine)

  • Nicole DeMarco

    (Children’s Hospital of Philadelphia)

  • Jessica Miller

    (Children’s Hospital of Philadelphia)

  • Leonel D. Joannas

    (University of Pennsylvania Perelman School of Medicine)

  • Jorge Henao-Mejia

    (University of Pennsylvania Perelman School of Medicine)

  • Paul M. Titchenell

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

  • David M. Merrick

    (University of Pennsylvania Perelman School of Medicine)

  • Hee-Woong Lim

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Mitchell A. Lazar

    (University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

  • David A. Hill

    (Children’s Hospital of Philadelphia
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania Perelman School of Medicine)

Abstract

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.

Suggested Citation

  • Bam D. Paneru & Julia Chini & Sam J. McCright & Nicole DeMarco & Jessica Miller & Leonel D. Joannas & Jorge Henao-Mejia & Paul M. Titchenell & David M. Merrick & Hee-Woong Lim & Mitchell A. Lazar & Da, 2024. "Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49632-z
    DOI: 10.1038/s41467-024-49632-z
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    References listed on IDEAS

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    1. E. Dale Abel & Odile Peroni & Jason K. Kim & Young-Bum Kim & Olivier Boss & Ed Hadro & Timo Minnemann & Gerald I. Shulman & Barbara B. Kahn, 2001. "Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver," Nature, Nature, vol. 409(6821), pages 729-733, February.
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