RESUMO
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.
Assuntos
Adipócitos , Hiperglicemia , Resistência à Insulina , Insulina , MicroRNAs , Obesidade , PTEN Fosfo-Hidrolase , Transdução de Sinais , MicroRNAs/metabolismo , MicroRNAs/genética , Obesidade/metabolismo , Obesidade/genética , Animais , Adipócitos/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/genética , Humanos , Insulina/metabolismo , Resistência à Insulina/genética , Camundongos , Masculino , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Camundongos Endogâmicos C57BL , Macrófagos/metabolismo , Tecido Adiposo/metabolismo , Células Mieloides/metabolismo , Camundongos Knockout , Hiperinsulinismo/metabolismo , Hiperinsulinismo/genéticaRESUMO
Polycystin-1 (PC1), the product of the PKD1 gene mutated in the majority of autosomal dominant polycystic kidney disease (ADPKD) cases, undergoes a cleavage resulting in the intracellular release of its C-terminal tail (CTT). Here, we demonstrate that the PC1 CTT co-localizes with and binds to beta-catenin in the nucleus. This interaction requires a nuclear localization motif present in the PC1 CTT as well as the N-terminal portion of beta-catenin. The PC1 CTT inhibits the ability of both beta-catenin and Wnt ligands to activate T-cell factor (TCF)-dependent gene transcription, a major effector of the canonical Wnt signaling pathway. The PC1 CTT may produce this effect by reducing the apparent affinity of the interaction between beta-catenin and the TCF protein. DNA microarray analysis reveals that the canonical Wnt signaling pathway is activated in ADPKD patient cysts. Our results suggest a novel mechanism through which PC1 cleavage may impact upon Wnt-dependent signaling and thereby modulate both developmental processes and cystogenesis.