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

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 and David A. Hill ()
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Bam D. Paneru: Children’s Hospital of Philadelphia
Julia Chini: Children’s Hospital of Philadelphia
Sam J. McCright: Children’s Hospital of Philadelphia
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
David M. Merrick: University of Pennsylvania Perelman School of Medicine
Hee-Woong Lim: Cincinnati Children’s Hospital Medical Center
Mitchell A. Lazar: University of Pennsylvania Perelman School of Medicine
David A. Hill: Children’s Hospital of Philadelphia

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49632-z

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