Glucocorticoids increase adipocytes in muscle by affecting IL-4 regulated FAP activity
Glucocorticoids increase adipocytes in muscle by affecting IL-4 regulated FAP activity
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DOI：
10.1096/fj.14-254011
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发表时间：
2014-09-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Liping
中科院分区：
文献类型：
--
作者：
Dong, Yanjun;Santos Silva, Kleiton Augusto;Zhang, Liping
肌内脂肪细胞组织（IMAT）的增加与葡萄糖失调、肌肉力量下降和残疾风险增加有关。不幸的是，刺激肌内脂肪形成的机制仍不清楚。我们发现，地塞米松（Dex）的管理与肌肉损伤的小鼠刺激IMAT的积累。为了鉴定这些脂肪细胞的前体，我们从肌肉中分离出卫星细胞和成脂/成脂祖细胞（FAP）;即使在Dex处理后，卫星细胞也不分化成脂肪细胞。相反，Dex刺激FAP分化为脂肪细胞。在体内，我们将来自转基因EGFP小鼠的纯化FAP移植到C57/BL 6小鼠的损伤肌肉中，发现Dex给药刺激FAP-EGFP的脂肪形成。脂肪形成的增加依赖于右旋糖酐诱导的白细胞介素-4（IL-4）抑制。在IL-4敲除小鼠的受损肌肉中，脂肪细胞的水平增加，而在用IL-4注射的Dex治疗小鼠的受损肌肉中，脂肪形成被抑制。在培养的FAP中，IL-4抑制Dex诱导的FAP转化为脂肪细胞;这在表达IL-4受体敲低的FAP中没有发生。因此，我们得出结论，糖皮质激素刺激FAPs分化为受损肌肉中的脂肪细胞。这一过程被IL-4阻断，表明干扰IL-4信号传导可以阻止肌肉中的脂肪形成。
An increase in intramuscular adipocyte tissue (IMAT) is associated with glucose dysregulation, decreased muscle strength, and increased risk of disability. Unfortunately, the mechanisms stimulating intramuscular adipogenesis remain unclear. We found that dexamethasone (Dex) administration to mice with injured muscles stimulates the accumulation of IMAT. To identify precursors of these adipocytes, we isolated satellite cells and fibro/adipogenic progenitors (FAPs) from muscle; satellite cells did not differentiate into adipocytes even following Dex treatment. In contrast, Dex stimulated FAP differentiation into adipocytes. In vivo, we transplanted purified FAPs from transgenic, EGFP mice into the injured muscles of C57/BL6 mice and found that Dex administration stimulated adipogenesis from FAP-EGFP. The increase in adipogenesis depended on Dex-induced inhibition of interleukin-4 (IL-4). In the injured muscle of IL-4-knockout mice, the levels of adipocytes were increased, while in the injured muscles of Dex-treated mice with IL-4 injections, adipogenesis was suppressed. In cultured FAPs, IL-4 inhibited Dex-induced conversion of FAPs into adipocytes; this did not occur in FAPs expressing knockdown of the IL-4 receptor. Thus, we concluded that glucocorticoids stimulate FAPs to differentiate into adipocytes in injured muscles. This process is blocked by IL-4, suggesting that interfering with IL-4 signaling could prevent adipogenesis in muscle.