第二军医大学学报  2019, Vol. 40 Issue (1): 68-73   PDF    
Omega-3多不饱和脂肪酸对脂肪代谢调节作用研究进展
周晶晶, 李家速, 王奇金     
海军军医大学(第二军医大学)长海医院内分泌科, 上海 200433
摘要: 肥胖是2型糖尿病、心血管病和多种癌症的危险因素,其防治形势十分严峻。Omega-3多不饱和脂肪酸(n-3 PUFA)是一种从深海鱼类中提取出来的多不饱和脂肪酸,具有显著的抗炎和降低三酰甘油的作用,但其抗肥胖作用仍有争议。在动物模型中发现,n-3 PUFA可以有效降低脂肪含量;然而人体研究却表明n-3 PUFA可能无助于减肥,但可能会减少体质量进一步增加。n-3 PUFA可通过调节肠道菌群、调节脂质代谢、抑制食欲、缓解脂肪组织炎症和表观遗传改变等机制改善与肥胖相关的代谢变化,从而在肥胖与其相关代谢性疾病的防治中发挥重要作用。
关键词: 肥胖症     代谢综合征     ω-3脂肪酸类     脂类     炎症    
Advances in regulation of omega-3 polyunsaturated fatty acids on fat metabolism
ZHOU Jing-jing, LI Jia-su, WANG Qi-jin     
Department of Endocrinology, Changhai Hospital, Naval Medical University(Second Military Medical University), Shanghai 200433, China
Supported by National Natural Science Foundation of China (81670741) and the "1255" Subject Construction and Scientific Innovation Program of Changhai Hospital (CH125541900).
Abstract: Obesity is a risk factor for type 2 diabetes, cardiovascular diseases, and various cancers. The prevention and treatment of obesity have become the focus of public health. Omega-3 polyunsaturated fatty acids (n-3 PUFA) are polyunsaturated fatty acids extracted from deep-sea fish. The anti-inflammatory and triglyceride-lowering properties of n-3 PUFA are well known, but its role in the treatment of obesity is still controversial. In animal models, n-3 PUFA can effectively reduce fat. However, in humans, existing studies have shown that n-3 PUFA may not contribute to weight loss, but may slow down weight gain. N-3 PUFA can improve the metabolic changes associated with obesity by regulating intestinal flora, regulating lipid metabolism, suppressing appetite, alleviating adipose tissue inflammation and altering epigenetic mechanisms, thus playing an important role in the prevention and treatment of obesity and the related metabolic diseases.
Key words: obesity     metabolic syndrome     omega-3 fatty acids     lipids     inflammation    

代谢综合征(metabolic syndrome)是一组以中心性肥胖、高血糖、高血压和血脂紊乱等为主要表现的临床综合征,其病因尚未完全明确,与遗传、免疫、饮食等因素均有关系[1]。肥胖会增加心血管疾病、2型糖尿病和某些类型癌症的发病风险[2]。据世界卫生组织统计,2016年全球约39%的成年人超重,超过13%的成年人肥胖[3],肥胖的防治刻不容缓。脂质是饮食中重要的常量营养素,脂质代谢与人体脂肪组织代谢以及体质量的变化相关,对人的健康具有重要作用。研究表明,饱和脂肪酸(saturated fatty acid,SFA)的摄入不利于健康,而单不饱和脂肪酸(monounsaturated fatty acid,MUFA)或多不饱和脂肪酸(polyunsaturated fatty acid,PUFA)的摄入有益于健康[4]

Omega-3 PUFA(n-3 PUFA)因其第一个不饱和键出现在碳链甲基端的第3位而得名,主要包括α-亚麻酸(α-linolenic acid,ALA)、二十碳五烯酸(eicosapentaenoic acid,EPA)和二十二碳六烯酸(docosahexaenoic acid,DHA)。陆地动物体内几乎不含n-3 PUFA,普通鱼体内含量极低,而寒冷地区深海里的鱼如三文鱼、沙丁鱼等体内n-3 PUFA含量丰富。研究发现,n-3 PUFA可能在肥胖症和相关疾病的发病机制中发挥作用[5]。美国2015年膳食指南中,推荐每周摄入8盎司(226.8 g)海鲜以确保250 mg/d的EPA和DHA摄入[6]。本文对n-3 PUFA在动物和人体研究中的最新进展作一综述,为了解n-3 PUFA对脂肪代谢的调节作用及相关机制提供参考。

1 n-3 PUFA对动物肥胖和代谢的作用

Bidu等[7]的研究发现,具有产n-3 PUFA能力的雄性fat-1转基因小鼠在连续18周高糖高脂饮食下也不会发生肥胖、血糖调节受损和肝脂肪变性,将其肠道菌群移植到对照组小鼠体内后,能阻止高糖高脂饮食对对照组小鼠造成的肥胖和血糖调节受损,表明n-3 PUFA可能通过对肠道菌群的调节影响体质量和血糖等代谢指标。而在另外的一项针对雄性小鼠的研究中,虽然并没有发现高脂饮食组小鼠与PUFA补充饮食组小鼠体质量有明显差异,但高脂饮食组小鼠与PUFA补充饮食组小鼠相比增加了异位脂肪储存、肝损伤和平均脂肪细胞大小,并且降低了雄性小鼠的代谢灵活性[8]。Bertrand等[9]则发现,与高脂饮食小鼠相比,补充EPA的小鼠体质量增加变慢,脂肪量明显减少,低血糖、胰岛素血症和肝脏脂肪变性等方面明显改善。在这些具有减脂效果的实验中,大多数是从实验开始就补充了高脂饮食并诱发肥胖。关于n-3 PUFA补充时机与体质量关系的研究不多,Kalupahana等[10]研究发现,在6周高脂饮食肥胖已经诱导形成后再补充EPA的小鼠其体质量与高脂饮食对照组小鼠相似,但可改善高脂饮食诱导的胰岛素抵抗。基于以上研究,我们认为n-3 PUFA在改善代谢方面作用确切,但其抗肥胖作用可能主要体现在肥胖形成过程中,提示n-3 PUFA可能对于预防肥胖意义较大。

2 n-3 PUFA改善肥胖和代谢的机制

n-3 PUFA在降低体质量和改善代谢方面发挥作用,其可能的机制包括调节肠道菌群[7]、调控脂肪组织基因的表达、改变脂肪细胞因子释放或影响其介导的相关信号通路、抑制食欲、改变脂质代谢与能量代谢、促进肌肉合成代谢等,分述如下。

2.1 n-3 PUFA与脂肪形成

脂肪组织通过脂肪细胞的体积增大、数目增多而增长,其中脂肪细胞数目增多和更小的细胞体积与健康代谢表型有关。n-3 PUFA和n-6 PUFA都可以参与调控前脂肪细胞分化基因的转录因子,同时可激活过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptor,PPAR)-γ和PPAR-δ,提高脂蛋白脂肪酶表达,诱导脂肪细胞分化和加速成熟[11]。在克隆脂肪细胞(3T3-L1)中进行的研究也证实添加n-3 PUFA后可上调PPAR-γ表达,促进脂肪形成和脂滴形成[12]。Garaulet等[13]对不同饮食习惯的84名接受腹部手术的肥胖患者手术期间获得的腹部脂肪组织进行评估,发现人脂肪组织中n-6 PUFA和n-3 PUFA的浓度与脂肪细胞大小呈负相关。这表明n-3 PUFA虽然加速脂肪形成,但是更多的是促进脂肪细胞向数目增加但体积减小的健康代谢表型转变。

2.2 n-3 PUFA与脂肪组织炎症

慢性低度炎症和脂肪细胞因子的释放是肥胖代谢紊乱发病机制中的关键因素。研究发现,n-3 PUFA不仅可通过抑制炎症相关蛋白编码基因关键转录因子核因子κB(nuclear factor kappa B,NF-κB)和减少白细胞介素(interleukin,IL)-1、IL-6、肿瘤坏死因子α(tumor necrosis factor α,TNF-α)等细胞因子的产生起到抗炎作用,还可作为游离脂肪酸受体家族(free fatty acid receptors,FFARs)激动剂在涉及能量稳态和炎症反应的多种细胞类型中激活FFAR1和FFAR4[14-15]。FFAR4又称G蛋白偶联受体120(G protein-coupled receptor 120,GPR120),其激活后可抑制巨噬细胞样细胞系RAW264.7在脂多糖介导下炎性细胞因子TNF-α和IL-6的释放;在喂养富含n-3 PUFA饮食的小鼠中,可能通过激活FFAR4减少巨噬细胞在脂肪组织中的浸润,而在FFAR4基因敲除小鼠则观察不到这个现象[16]。此外,肥胖人群中补充4 g/d的n-3 PUFA可使脂肪组织中M1巨噬细胞减少进而使IL-8等促炎标志物减少[17]。Montserrat-de la Paz等[18]研究表明,当人体进食富含饱和脂肪酸饮食时单核细胞优先分化为M1巨噬细胞,而进食不饱和脂肪酸后它们更倾向于分化为M2巨噬细胞。此外,DHA可通过激动FFAR1或FFAR4形成β-抑制蛋白2/NLRP3或NLRP1b复合物来抑制半胱天冬酶1活性,从而减少促炎细胞因子的释放[19]。因此,n-3 PUFA可能通过以上机制减轻组织炎症反应,从而改善肥胖相关的代谢紊乱。

2.3 n-3 PUFA与脂肪细胞因子

瘦素(leptin)是一种由脂肪细胞分泌的蛋白质类激素,它参与糖、脂肪及能量代谢的调节,促使机体减少摄食,增加能量释放,抑制脂肪细胞的合成,进而使体质量减轻。肥胖者血浆瘦素水平高,体质量减轻后可使血浆瘦素水平下降[20]。这种体质量下降引起的瘦素减少可能导致饥饿和较低的代谢率,并最终使体质量回升[21]。补充EPA可减轻肥胖女性体质量下降期间血液瘦素水平的降低,这表明EPA在维持体质量减轻中具有潜在的重要作用[22]

脂肪酸结合蛋白是一种胞质蛋白,可结合长链脂肪酸并促进其转运至数个细胞器内。脂肪酸结合蛋白4(fatty acid-binding protein 4,FABP4)是一种由巨噬细胞和脂肪细胞分泌的细胞因子。血清FABP4浓度升高与肥胖、胰岛素抵抗和高血压有关[23]。n-3 PUFA可剂量依赖性地降低3T3-L1脂肪细胞中FABP4的分泌,并降低人体血清FABP4浓度[24],从而改善胰岛素抵抗和调节血压。

2.4 n-3 PUFA与食欲

有报道表明服用较高n-3 PUFA含量膳食者较服用较低n-3 PUFA含量膳食者饥饿感低[25]。n-3 PUFA可能通过激动FFAR4,同时引发小肠分泌具有抑制食欲作用的胆囊收缩素从而达到抑制食欲的目的[26]。因此,n-3 PUFA可能通过增加餐后饱腹感、减少随后的食物摄入来帮助减轻体质量。n-3 PUFA对食欲与摄食影响的机制还需进一步研究。

2.5 n-3 PUFA与胰岛素抵抗

脂肪组织炎症是肥胖相关的胰岛素抵抗的原因之一。由肝脏、脂肪组织和骨骼肌产生的成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)可降低肝葡萄糖输出和血浆葡萄糖水平,同时它也增加胰岛素敏感性和促进脂肪细胞摄取葡萄糖[27]。在饮食诱导的肥胖小鼠以及肥胖合并2型糖尿病患者中,循环的FGF21水平升高[28],提示FGF21具有与肥胖相关的抵抗作用。n-3 PUFA可能通过激动PPARγ增加肝脏FGF21敏感性和β-klotho表达[29],降低高血糖、高三酰甘油血症和血浆胰岛素水平,减少高脂饮食诱导的FGF21增加[30-31],这可能是n-3 PUFA改善胰岛素抵抗的潜在机制。

此外,n-3 PUFA还可调节脂质代谢、促进脂肪酸氧化和抑制脂肪生成[32],诱导能量消耗和预防体内脂肪积累[33],改变蛋白质动力学以增加肌肉蛋白合成[34],调节微RNA表达进行表观遗传学的修饰[35],从而在肥胖和代谢综合征中起到重要作用,但确切的机制还需要进一步研究。

3 n-3 PUFA对人体的影响

n-3 PUFA可优化人体组织脂肪结构,减少能量摄入。Noreen等[36]研究表明鱼油补充饮食组与安慰剂补充对照组相比,尽管总体质量、静息代谢率和呼吸交换比率没有变化,但脂肪总量减少,这提示n-3 PUFA可能有助于调整人体体脂比例,优化身体组织构成。Harden等[37]研究表明,在超重和肥胖女性中,补充n-3 PUFA可减少碳水化合物、脂肪和总能量摄入。但也有研究认为补充鱼油对能量摄入总量无变化[38-39]。这可能是由于摄入鱼类不同、鱼油n-3 PUFA含量水平不同(特别是EPA和DHA)以及持续时间不同,参与者的情况也不尽相同(如健康或肥胖,伴或不伴有包括2型糖尿病、高胰岛素血症在内的其他代谢综合征,是否有饮食干预,是否有锻炼方案等),导致研究结论不太一致。为进一步明确n-3 PUFA在体质量减轻中的作用,应在大样本中研究n-3 PUFA补充对大量营养素和能量摄入的影响。n-3 PUFA结合膳食干预、运动等,对肥胖和体质量控制具有很好的效果,分述如下。

3.1 n-3 PUFA与膳食干预

当n-3 PUFA补充剂与能量限制相结合时,效果更为显著。Lee等[40]研究评估了能量限制饮食与2.1365 g/d n-3 PUFA补充剂对代谢综合征患者的影响。188名受试者被随机分配4种能量限制饮食中的1种,为期12周,结果显示所有组的腰围、血压和心脏代谢参数均降低。另有研究表明,n-3多不饱和脂肪酸的补充结合能量摄入控制可改善肥胖患者的胰岛素敏感性[41]

3.2 n-3 PUFA与运动

提供有效的非药物治疗手段防止老年人肌肉萎缩具有重要意义,目前已有部分研究探索了补充n-3 PUFA结合运动对人体肌肉的影响。在一项针对65~70岁健康和喜欢运动的老年女性为期24周的三臂随机对照试验中,将受试者随机分为阻力训练+健康饮食组、阻力训练组和对照组。结果发现在阻力训练+健康饮食组中,腿部瘦体质量增加,同时促炎前体花生四烯酸的血清水平降低[42]。另有研究表明,n-3 PUFA可增加老年女性的肌肉功能和质量,但对老年男性无效[43]。提示n-3 PUFA对人体的影响可能与性别有一定关系。

总之,关于n-3 PUFA对人体体质量和身体组成的影响还没充分明确,性别、代谢情况、人种差异等可能对结果有一定影响,研究设计和分析方法仍需改进。现有的研究未能具体评估在限制总能量摄入状态下以及身体处于能量消耗、体质量下降状态下n-3 PUFA对体质量的影响。同时,使用更可靠的人体测量方法,根据体质量给药以达到组织膜n-3 PUFA磷脂富集的阈值[44],以及使用标准化方法(如n-3指数)来评估体内n-3 PUFA状态与浓度对人体的影响,将使研究结论更确切。

4 n-3 PUFA的临床应用 4.1 n-3 PUFA与非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)

NAFLD是指除乙醇和其他明确的肝损伤因素所致的以肝细胞内脂肪过度沉积为主要特征的临床病理综合征,胰岛素抵抗是NAFLD的主要危险因素。NAFLD现已成为欧美等发达国家和我国富裕地区慢性肝病的重要病因。已知n-3 PUFA具有抗炎以及调节脂质代谢的作用,n-3 PUFA可能通过这些潜在的作用治疗NAFLD。Boyraz等[45]在一项双盲、随机、安慰剂对照试验中研究了n-3 PUFA对NAFLD肥胖青少年的治疗作用。研究者将108名肥胖且伴有转氨酶升高的NAFLD青少年随机分为n-3 PUFA干预组(每天口服1 000 mg n-3 PUFA)以及安慰剂对照组,两组均结合生活方式干预。12个月后,n-3 PUFA干预组较安慰剂对照组能改善胰岛素抵抗指数、收缩压、丙氨酸转氨酶、天冬氨酸转氨酶、空腹胰岛素和三酰甘油水平,超声检查结果也显示n-3 PUFA干预组更加健康。

4.2 n-3 PUFA与心脑血管疾病

我国在最新的《中国成人血脂异常防治指南》中指出,经他汀治疗后如非高密度脂蛋白胆固醇仍不能达到目标值,可在他汀类基础上加用高纯度鱼油制剂[46]。美国心脏协会也在一份最新的科学建议中再次强调,每周食用2次富含n-3 PUFA的鱼类可降低冠心病、心力衰竭、心脏骤停和缺血性卒中的发生风险[47]。但Aung等[48]对10项大型随机临床试验共77 917名高危人群观察4年的结果进行荟萃分析,表明n-3 PUFA与致死性或非致死性冠心病或任何主要心血管事件无明显关联。Manson等[49-50]在一项纳入25 871名未患心血管疾病或癌症的50岁及以上的男性和55岁及以上的女性开展的2×2析因设计的双盲、随机、对照干预试验中,经过5.3年(中位数)随访后,发现未患心血管疾病和癌症的普通人群补充n-3 PUFA(1 g/d)并不会降低心血管疾病和癌症的发病率,但可以降低心肌梗死及冠心病的发病率;而维生素D不会降低心血管疾病和癌症的发病率。这些不同研究的差异可能与n-3 PUFA具体剂量、剂型、药物纯度以及观察时间有关。

综上所述,n-3 PUFA对人体的代谢有着广泛的作用,它可能通过对炎症因子的调节和降低人体血清FABP4浓度等机制改善胰岛素抵抗,对NAFLD的治疗有着广阔的应用前景;还可能通过调节肠道菌群、血浆瘦素水平以及对食欲的影响控制体质量、调节血糖和脂类代谢,进而预防心脑血管疾病的发生发展。

参考文献
[1]
顾庆, 刘志民. 运动和代谢综合征[J]. 第二军医大学学报, 2015, 36: 434-438.
GU Q, LIU Z M. Exercise and metabolic syndrome[J]. Acad J Sec Mil Med Univ, 2015, 36: 434-438.
[2]
KELLY T, YANG W, CHEN C S, REYNOLDS K, HE J. Global burden of obesity in 2005 and projections to 2030[J]. Int J Obes (Lond), 2008, 32: 1431-1437. DOI:10.1038/ijo.2008.102
[3]
World Health Organization. Overweight and obesity[EB/OL]. (2018-02-16)[2018-12-21].https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight.
[4]
SIRIWARDHANA N, KALUPAHANA N S, MOUSTAID-MOUSSA N. Health benefits of n-3 polyunsaturated fatty acids:eicosapentaenoic acid and docosahexaenoic acid[J]. Adv Food Nutr Res, 2012, 65: 211-222. DOI:10.1016/B978-0-12-416003-3.00013-5
[5]
SIMOPOULOS A P. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity[J/OL]. Nutrients, 2016, 8: 128. doi: 10.3390/nu8030128. https://www.mdpi.com/2072-6643/8/3/128#citedby
[6]
TAGTOW A, RAHAVI E, BARD S, STOODY E E, CASAVALE K, MOSHER A. Coming together to communicate the 2015-2020 dietary guidelines for Americans[J]. J Acad Nutr Diet, 2016, 116: 209-212. DOI:10.1016/j.jand.2015.12.010
[7]
BIDU C, ESCOULA Q, BELLENGER S, SPOR A, GALAN M, GEISSLER A, et al. The transplantation of ω3 PUFA-altered gut microbiota of fat-1 mice to wildtype littermates prevents obesity and associated metabolic disorders[J]. Diabetes, 2018, 67: 1512-1523. DOI:10.2337/db17-1488
[8]
DUIVENVOORDE L P, VAN SCHOTHORST E M, SWARTS H M, KUDA O, STEENBERGH E, TERMEULEN S, et al. A difference in fatty acid composition of isocaloric high-fat diets alters metabolic flexibility in male C57BL/6JOlaHsd mice[J/OL]. PLoS One, 2015, 10: e0128515. doi: 10.1371/journal.pone.0128515.
[9]
BERTRAND C, PIGNALOSA A, WANECQ E, RANCOULE C, BATUT A, DELERUYELLE S, et al. Effects of dietary eicosapentaenoic acid (EPA) supplementation in high-fat fed mice on lipid metabolism and apelin/APJ system in skeletal muscle[J/OL]. PLoS One, 2013, 8: e78874. doi: 10.1371/journal.pone.0078874.eCollection2013.
[10]
KALUPAHANA N S, CLAYCOMBE K, NEWMAN SJ, STEWART T, SIRIWARDHANA N, MATTHAN N, et al. Eicosapentaenoic acid prevents and reverses insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation[J]. J Nutr, 2010, 140: 1915-1922. DOI:10.3945/jn.110.125732
[11]
FORMAN B M, TONTONOZ P, CHEN J, BRUN R P, SPIEGELMAN B M, EVANS R M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma[J]. Cell, 1995, 83: 803-812. DOI:10.1016/0092-8674(95)90193-0
[12]
OSTER R T, TISHINSKY J M, YUAN Z, ROBINSON L E. Docosahexaenoic acid increases cellular adiponectin mRNA and secreted adiponectin protein, as well as PPARγ mRNA, in 3T3-L1 adipocytes[J]. Appl Physiol Nutr Metab, 2010, 35: 783-789. DOI:10.1139/H10-076
[13]
GARAULET M, HERNANDEZ-MORANTE J J, LUJAN J, TEBAR F J, ZAMORA S. Relationship between fat cell size and number and fatty acid composition in adipose tissue from different fat depots in overweight/obese humans[J]. Int J Obes (Lond), 2006, 30: 899-905. DOI:10.1038/sj.ijo.0803219
[14]
HARA T, KASHIHARA D, ICHIMURA A, KIMURA I, TSUJIMOTO G, HIRASAWA A. Role of free fatty acid receptors in the regulation of energy metabolism[J]. Biochim Biophys Acta, 2014, 1841: 1292-1300. DOI:10.1016/j.bbalip.2014.06.002
[15]
ICHIMURA A, HASEGAWA S, KASUBUCHI M, KIMURA I. Free fatty acid receptors as therapeutic targets for the treatment of diabetes[J]. Front Pharmacol, 2014, 5: 236. DOI:10.3389/fphar.2014.00236
[16]
OH D Y, TALUKDAR S, BAE E J, IMAMURA T, MORINAGA H, FAN W, et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects[J]. Cell, 2010, 142: 687-698. DOI:10.1016/j.cell.2010.07.041
[17]
SPENCER M, FINLIN B S, UNAL R, ZHU B, MORRIS A J, SHIPP L R, et al. Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance[J]. Diabetes, 2013, 62: 1709-1717. DOI:10.2337/db12-1042
[18]
MONTSERRAT-DE LA PAZ S, RODRIGUEZ D, CARDELO M P, NARANJO M C, BERMUDEZ B, ABIA R, et al. The effects of exogenous fatty acids and niacin on human monocyte-macrophage plasticity[J/OL]. Mol Nutr Food Res, 2017, 61. doi: 10.1002/mnfr.201600824.
[19]
YAN Y, JIANG W, SPINETTI T, TARDIVEL A, CASTILLO R, BOURQUIN C, et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation[J]. Immunity, 2013, 38: 1154-1163. DOI:10.1016/j.immuni.2013.05.015
[20]
ARENT S M, WALKER A J, PELLEGRINO J K, SANDERS D J, MCFADDEN B A, ZIEGENFUSS T N, et al. The combined effects of exercise, diet, and a multiingredient dietary supplement on body composition and adipokine changes in overweight adults[J]. J Am Coll Nutr, 2018, 37: 111-120. DOI:10.1080/07315724.2017.1368039
[21]
HINKLE W, CORDELL M, LEIBEL R, ROSENBAUM M, HIRSCH J. Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans[J/OL]. PLoS One, 2013, 8: e59114. doi: 10.1371/journal.pone.0059114.
[22]
HUERTA A E, NAVAS-CARRETERO S, PRIETOHONTORIA P L, MARTÍNEZ J A, MORENO-ALIAGA M J. Effects of α-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss[J]. Obesity (Silver Spring), 2015, 23: 313-321. DOI:10.1002/oby.v23.2
[23]
OTA H, FURUHASHI M, ISHIMURA S, KOYAMA M, OKAZAKI Y, MITA T, et al. Elevation of fatty acid-binding protein 4 is predisposed by family history of hypertension and contributes to blood pressure elevation[J]. Am J Hypertens, 2012, 25: 1124-1230.
[24]
FURUHASHI M, HIRAMITSU S, MITA T, OMORI A, FUSEYA T, ISHIMURA S, et al. Reduction of circulating FABP4 level by treatment with omega-3 fatty acid ethyl esters[J/OL]. Lipids Health Dis, 2016, 15: 5. doi: 10.1186/s12944-016-0177-8.
[25]
PARRA D, RAMEL A, BANDARRA N, KIELY M, MARTÍNEZ J A, THORSDOTTIR I. A diet rich in long chain omega-3 fatty acids modulates satiety in overweight and obese volunteers during weight loss[J]. Appetite, 2008, 51: 676-680. DOI:10.1016/j.appet.2008.06.003
[26]
TANAKA T, KATSUMA S, ADACHI T, KOSHIMIZU T A, HIRASAWA A, TSUJIMOTO G. Free fatty acids induce cholecystokinin secretion through GPR120[J]. Naunyn Schmiedebergs Arch Pharmacol, 2008, 377(4/5/6): 523-527.
[27]
GAICH G, CHIEN J Y, FU H, GLASS L C, DEEG M A, HOLLAND W L, et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes[J]. Cell Metab, 2013, 18: 333-340. DOI:10.1016/j.cmet.2013.08.005
[28]
ZHANG X, YEUNG D C, KARPISEK M, STEJSKAL D, ZHOU Z G, LIU F, et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans[J]. Diabetes, 2008, 57: 1246-1253. DOI:10.2337/db07-1476
[29]
YANG W, CHEN X, LIU Y, CHEN M, JIANG X, SHEN T, et al. N-3 polyunsaturated fatty acids increase hepatic fibroblast growth factor 21 sensitivity via a PPAR-γ-β-klotho pathway[J/OL]. Mol Nutr Food Res, 2017, 61. doi: 10.1002/mnfr.201601075.
[30]
NONOGAKI K, YAMAZAKI T, MURAKAMI M, KAJI T. Ingestion of eicosapentaenoic acid in the early stage of social isolation reduces a fibroblast growth factor 21 resistant state independently of body weight in KKAy mice[J]. Biochem Biophys Res Commun, 2015, 464: 674-677. DOI:10.1016/j.bbrc.2015.07.058
[31]
QIN Y, ZHOU Y, CHEN S H, ZHAO X L, RAN L, ZENG X L, et al. Fish oil supplements lower serum lipids and glucose in correlation with a reduction in plasma fibroblast growth factor 21 and prostaglandin E2 in nonalcoholic fatty liver disease associated with hyperlipidemia: a randomized clinical trial[J/OL]. PLoS One, 2015, 10: e0133496. doi: 10.1371/journal.pone.0133496.
[32]
LUCERO D, MIKSZTOWICZ V, GUALANO G, LONGO C, LANDEIRA G, ÁLVAREZ E, et al. Nonalcoholic fatty liver disease associated with metabolic syndrome:influence of liver fibrosis stages on characteristics of very low-density lipoproteins[J]. Clin Chim Acta, 2017, 473: 1-8. DOI:10.1016/j.cca.2017.08.006
[33]
PAHLAVANI M, RAZAFIMANJATO F, RAMALINGAM L, KALUPAHANA N S, MOUSSA H, SCOGGIN S, et al. Eicosapentaenoic acid regulates brown adipose tissue metabolism in high-fat-fed mice and in clonal brown adipocytes[J]. J Nutr Biochem, 2017, 39: 101-109. DOI:10.1016/j.jnutbio.2016.08.012
[34]
SMITH G I, ATHERTON P, REEDS D N, MOHAMMED B S, RANKIN D, RENNIE M J, et al. Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults:a randomized controlled trial[J]. Am J Clin Nutr, 2011, 93: 402-412. DOI:10.3945/ajcn.110.005611
[35]
ZHENG Z, GE Y, ZHANG J, XUE M, LI Q, LIN D, et al. PUFA diets alter the microRNA expression profiles in an inflammation rat model[J]. Mol Med Rep, 2015, 11: 4149-4157. DOI:10.3892/mmr.2015.3318
[36]
NOREEN E E, SASS M J, CROWE M L, PABON V A, BRANDAUER J, AVERILL L K. Effects of supplemental fish oil on resting metabolic rate, body composition, and salivary cortisol in healthy adults[J/OL]. J Int Soc Sports Nutr, 2010, 7: 31. doi: 10.1186/1550-2783-7-31.
[37]
HARDEN C J, DIBLE V A, RUSSELL J M, GARAIOVA I, PLUMMER S F, BARKER M E, et al. Long-chain polyunsaturated fatty acid supplementation had no effect on body weight but reduced energy intake in overweight and obese women[J]. Nutr Res, 2014, 34: 17-24. DOI:10.1016/j.nutres.2013.10.004
[38]
ALBERT B B, DERRAIK J G, BRENNAN C M, BIGGS J B, GARG M L, CAMERON-SMITH D, et al. Supplementation with a blend of krill and salmon oil is associated with increased metabolic risk in overweight men[J]. Am J Clin Nutr, 2015, 102: 49-57. DOI:10.3945/ajcn.114.103028
[39]
HUTCHINS-WIESE H L, KLEPPINGER A, ANNIS K, LIVA E, LAMMI-KEEFE C J, DURHAM H A, et al. The impact of supplemental n-3 long chain polyunsaturated fatty acids and dietary antioxidants on physical performance in postmenopausal women[J]. J Nutr Health Aging, 2013, 17: 76-80. DOI:10.1007/s12603-012-0415-3
[40]
LEE H C, CHENG W Y, HSU Y H, SU H Y, HUANG B E T G, LIN Y K, et al. Effects of calorie restriction with n-3 long-chain polyunsaturated fatty acids on metabolic syndrome severity in obese subjects:a randomizecontrolled trial[J]. J Funct Foods, 2015, 19: 929-940. DOI:10.1016/j.jff.2015.01.040
[41]
RAZNY U, KIEC-WILK B, POLUS A, GORALSKA J, MALCZEWSKA-MALEC M, WNEK D, et al. Effect of caloric restriction with or without n-3 polyunsaturated fatty acids on insulin sensitivity in obese subjects:a randomized placebo controlled trial[J]. BBA Clin, 2015, 4: 7-13. DOI:10.1016/j.bbacli.2015.05.001
[42]
STRANDBERG E, EDHOLM P, PONSOT E, WÅHLINLARSSON B, HELLMÉN E, NILSSON A, et al. Influence of combined resistance training and healthy diet on muscle mass in healthy elderly women:a randomized controlled trial[J]. J Appl Physiol (1985), 2015, 119: 918-925. DOI:10.1152/japplphysiol.00066.2015
[43]
DA BOIT M, SIBSON R, SIVASUBRAMANIAM S, MEAKIN J R, GREIG C A, ASPDEN R M, et al. Sex differences in the effect of fish-oil supplementation on the adaptive response to resistance exercise training in older people:a randomized controlled trial[J]. Am J Clin Nutr, 2017, 105: 151-158. DOI:10.3945/ajcn.116.140780
[44]
FORTIN M, JULIEN P, COUTURE Y, DUBREUIL P, CHOUINARD P Y, LATULIPPE C, et al. Regulation of glucose and protein metabolism in growing steers by longchain n-3 fatty acids in muscle membrane phospholipids is dose-dependent[J]. Animal, 2010, 4: 89-101. DOI:10.1017/S1751731109991042
[45]
BOYRAZ M, PIRGON Ö, DÜNDAR B, ÇEKMEZ F, HATIPOĞLU N. Long-term treatment with n-3 polyunsaturated fatty acids as a monotherapy in children with nonalcoholic fatty liver disease[J]. J Clin Res Pediatr Endocrinol, 2015, 7: 121-127. DOI:10.4274/jcrpe
[46]
中国成人血脂异常防治指南修订联合委员会. 中国成人血脂异常防治指南(2016年修订版)[J]. 中国循环杂志, 2016, 31: 937-953. DOI:10.3969/j.issn.1000-3614.2016.10.001
[47]
RIMM E B, APPEL L J, CHIUVE S E, DJOUSSÉ L, ENGLER M B, KRIS-ETHERTON P M, et al. Seafood long-chain n-3 polyunsaturated fatty acids and cardiovascular disease: a science advisory from the american heart association[J/OL]. Circulation, 2018, 138: e35-e47. doi: 10.1161/CIR.0000000000000574.
[48]
AUNG T, HALSEY J, KROMHOUT D, GERSTEIN H C, MARCHIOLI R, TAVAZZI L, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risks:meta-analysis of 10 trials involving 77917 individuals[J]. JAMA Cardiol, 2018, 3: 225-234. DOI:10.1001/jamacardio.2017.5205
[49]
MANSON J E, COOK N R, LEE I M, CHRISTEN W, BASSUK S S, MORA S, et al. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer[J]. N Engl J Med, 2019, 380: 23-32. DOI:10.1056/NEJMoa1811403
[50]
MANSON J E, COOK N R, LEE I M, CHRISTEN W, BASSUK S S, MORA S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease[J]. N Engl J Med, 2019, 380: 33-44. DOI:10.1056/NEJMoa1809944