Molecular Mechanisms and Experimental Therapy in Oncology-Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908, Spain.
Anatomy Unit, Department of Pathology and Experimental Therapy, School of Medicine, University of Barcelona (UB), L'Hospitalet de Llobregat, 08907, Spain.
Adv Sci (Weinh). 2022 Feb;9(4):e2104759. doi: 10.1002/advs.202104759. Epub 2021 Dec 13.
The H19X-encoded miR-424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR-424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR-424(322)/503 targets γ-Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR-424(322) in mice and obese humans co-segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism of fat mass expansion tightly controlled by the miR-424(322)/503 through SNCG.
H19X 编码的 miR-424(322)/503 簇调节多种细胞功能。首次报道其也是脂肪质量扩张的关键关键。该 miRNA 簇在小鼠中的缺失会导致肥胖，而增加早期脂肪细胞祖细胞和肥大的脂肪细胞。互补缺失和功能获得实验和 RNA 测序表明，miR-424(322)/503 调节涉及白色脂肪细胞分化和定型的保守遗传程序。从机制上讲，已经证明 miR-424(322)/503 靶向 γ-突触核蛋白（SNCG），这是一种通过控制脂肪细胞中的代谢功能来介导该程序重排的因子，允许脂肪细胞分化和脂肪组织增大。因此，小鼠中 miR-424(322)的减少和肥胖患者中 SNCG 在脂肪和外周血中的增加在肥胖中共同分离，并且在减肥后恢复正常。这些数据揭示了脂肪质量扩张的一个以前未知的调节机制，该机制通过 SNCG 受到 miR-424(322)/503 的严格控制。
