FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes
FNDC4, a novel adipokine that reduces lipogenesis and promotes fat browning in human visceral adipocytes
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DOI：
10.1016/j.metabol.2020.154261
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发表时间：
2020-07-01
影响因子：
9.8
通讯作者：
Rodriguez, Amaia
中科院分区：
文献类型：
--
作者：
Fruhbeck, Gema;Fernandez-Quintana, Blanca;Rodriguez, Amaia
纤维连接蛋白III型结构域包含蛋白4(FNDC4)是一种分泌因子，在纤维连接蛋白III型和跨膜区与运动相关的肌动蛋白虹膜蛋白(FNDC5)有很高的同源性。方法采用78例病态肥胖症患者和26例正常体重者的血浆和脂肪组织标本。结果病态肥胖症患者血浆和脂肪组织中FNDC4水平降低，与肥胖相关的全身炎症反应有关，术后6个月血浆和脂肪组织中FNDC4水平无明显变化。病态肥胖症患者内脏脂肪组织中FNDC4及其受体GPR116的表达增加，与胰岛素抵抗程度无关。人内脏脂肪细胞中FNDC4的含量受生脂、脂解和促炎刺激的调节。FNDC4减少了人脂肪细胞胞浆内的脂质积累，并刺激了脂肪细胞的棕色样图案，UCP-1和棕色/米色脂肪细胞标记物PRDM16、TMEM26和CD137的表达上调。此外，FNDC4处理还上调了线粒体DNA含量和参与线粒体生物发生的因子(TFAM、NRF1和NRF2)。人FNDC4基因敲除的脂肪细胞表现出脂肪生成增加，棕色/米色特异性脂肪标志物减少，以及参与线粒体生物发生的因素。结论新型脂肪因子FNDC4降低了人内脏脂肪细胞的脂肪生成，增加了脂肪褐变。人类内脏脂肪中FNDC4的上调可能是为了减轻肥胖状态下脂肪细胞的肥大、炎症和受损的米色脂肪生成。
BackgroundFibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue.MethodsPlasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study.ResultsPlasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markersPRDM16, TMEM26andCD137.Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1andNRF2). HumanFNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis.ConclusionsTaken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.