MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression.

MicroRNA-221-3p（miR-221-3p）与代谢性疾病和癌症有关。然而，其在终末脂肪细胞分化和脂质代谢中的作用尚不明确。将miR-221-3p或其抑制剂转染到分化或成熟的人类脂肪细胞中。监测甘油三酸酯（TG）含量和成脂基因表达，进行全局脂质组分析，并研究miR-221-3p影响的潜在机制。最后，研究了表达miR-221-3p的脂肪细胞与MCF-7乳腺癌（BC）细胞之间的相互影响，并分析了来自BC患者的肿瘤近端脂肪活检组织中miR-221-3p的表达。从降低的TG储存和成脂标志物SCD1的基因表达判断，miR-221-3p过表达抑制了脂肪细胞的终末分化，GLUT4，FAS，DGAT1 / 2，AP2，ATGL和AdipoQ，而miR-221-3p抑制剂可增加TG的储存量。敲低预测的miR-221-3p靶标14-3-3γ具有与miR-221-3p过表达相似的抗脂肪形成作用，表明它是mir-221-3p功能的潜在介体。重要的是，miR-221-3p过表达会从头抑制脂肪生成，但增加了神经酰胺和鞘磷脂的浓度，同时减少了二酰基甘油，同时抑制了鞘磷脂磷酸二酯酶，ATP柠檬酸裂合酶和酸性神经酰胺酶。侵袭性BC患者的肿瘤近端脂肪组织中miR-221-3p表达升高。miR-221-3p过度表达的脂肪细胞的条件培养基刺激了BC细胞的侵袭和增殖，而BC细胞的培养基增强了脂肪细胞中miR-221-3p的表达。升高的miR-221-3p会损害脂肪细胞的脂质存储和分化，并改变其神经酰胺，鞘磷脂和二酰基甘油的含量。这些改变与代谢性疾病有关，但也可能影响癌症的进展。