Ma_2025_Lipids.Health.Dis_24_81

Subclinical hypothyroidism (SCH) contributes to obesity, with the liver acting as a crucial metabolic regulator. Thyroid-stimulating hormone (TSH) affects systemic lipid balance, potentially linking SCH to obesity. While the direct impact of TSH on hepatic lipid metabolism has been extensively documented, its role in modulating lipid dynamics in peripheral organs through liver-mediated pathways remains insufficiently understood. This study identifies TSH-stimulated hepatocyte-derived exosomes (exosomes(TSH)) as key mediators in liver-adipose communication, promoting triglyceride accumulation in adipocytes via the transforming growth factor-beta 1 (TGF-beta1)/adipose triglyceride lipase (ATGL) axis. Exosomes(TSH) enhance lipid storage in adipocytes, significantly increasing triglyceride content and lipid droplet formation while reducing lipolysis, effects that are dependent on TSH receptor (TSHR) activation in hepatocytes. In vivo, exosomes(TSH) induce weight gain and adipose tissue expansion, impairing glucose metabolism in both chow- and high-fat diet-fed mice. Mechanistically, exosomes(TSH) upregulate TGF-beta1 and downregulate ATGL in adipocytes, establishing the TGF-beta1/ATGL pathway as essential for exosome-mediated lipid accumulation. Further, miR-139-5p is identified as a modulator of TGF-beta1 expression within this pathway, with overexpression of miR-139-5p alleviating exosomes(TSH)-induced lipid accumulation in adipocytes. This study elucidates a novel miR-139-5p-dependent mechanism through which TSH modulates lipid metabolism via liver-derived exosomes, highlighting the pivotal role of miR-139-5p in linking SCH to adipose lipid accumulation through the TGF-beta1/ATGL signaling axis.