CN102802428B - 油组合物,包含所述油组合物的制剂,及其减少内脏脂肪蓄积、改善葡萄糖耐量和预防或治疗肥胖相关疾病和病症的应用 - Google Patents
油组合物,包含所述油组合物的制剂,及其减少内脏脂肪蓄积、改善葡萄糖耐量和预防或治疗肥胖相关疾病和病症的应用 Download PDFInfo
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Abstract
本发明涉及油组合物,优选从桡足动物获得的油组合物,以及其用于减少肥胖诱导型西式膳食引起的内脏脂肪蓄积和对抗所述膳食引起的心脏功能损伤的应用。因此本发明的油组合物能够用于减少腹型肥胖和改善葡萄糖耐量,并进而降低肥胖相关疾病例如但不限于2型糖尿病或心血管疾病的风险,或预防或治疗这样的疾病。
Description
技术领域
本发明涉及油组合物,特别是减少体内内脏脂肪蓄积和改善葡萄糖耐量并因此可以用来预防或治疗肥胖相关疾病的油组合物。本发明的油组合物包含在药物制剂、膳食增补剂以及功能性食品和饲料配方中。
背景技术
在过去的二三十年间,所有工业化和城市化国家中人们的肥胖发生率显著增加,并且肥胖也是对发展中国家采取西方生活方式和膳食习惯的人们正在浮现的健康威胁。尚没有现象表明当前世界范围的肥胖流行处于控制下,也没有现象表明目前趋势向好的方面转变。
肥胖具有许多人类健康隐患,例如年龄相关的代谢衰退、胰岛素抵抗、2型糖尿病、心血管疾病、卒中、代谢综合征和早期突然死亡。
肥胖的明显原因是膳食能量吸收和身体能量消耗的长时间的净不平衡。当人摄入的能量比他们消耗的多时,多余的能量将作为脂肪储存起来。这种能量不平衡的生理学和医学后果被静坐生活方式和被过多食用富含糖和饱和脂肪的食物所加重。
内脏肥胖对人类死亡的风险系数比普通肥胖高得多;在肥胖相关疾病和内脏脂肪蓄积之间存在强相关性。聚积许多内脏脂肪和产生脂肪分布模式的个体临床上被称为中心型肥胖或腹型肥胖,并且例如特别倾向于发生糖尿病(D.Callagher等.Adiposetissuedistributionisdifferentintype2diabetes(2型糖尿病中脂肪组织分布不同).AmericanJournalofClinicalNutrition2009;89:807-814)。糖尿病与内脏脂肪蓄积之间的直接因果联系已经通过研究手术去除内脏脂肪的效果得以证明(Barzilai,N.andG.Gupta.InteractionbetweenAgingandSyndromeX:NewInsightsonthePathophysiologyofFatDistribution(衰老与X综合征之间的相互作用:对脂肪分布病理生理的新见解).AnnalsNewYorkAcademyofSciences1999;58-72;D.M.Huffman,N.Barzilai,Roleofvisceraladiposetissueinaging(内脏脂肪组织在衰老中的作用),Biochim.Biophys.Acta1790,2009:1117-1123)。这样的研究证明了内脏脂肪组织代谢非常活跃,并在肥胖相关的健康问题的发展中发挥主要作用,而且皮下脂肪组织的基因表达在内脏脂肪组织的控制之下。为了控制并减少世界上肥胖流行病的健康影响,相应地应该特别关注找到对抗中心型身体肥胖的发展和内脏脂肪蓄积的途径。
在健康专业人员当中,更有益健康的生活方式和改善总体营养无疑将对肥胖相关疾病具有最重要的正面影响。除静坐生活方式之外,对当前肥胖流行病最经常被怪罪的是进食量以及西餐采用糖类和脂质的性质。但一直难以预知各个膳食组分如何影响体内脂肪蓄积模式和肥胖相关疾病。例如,对于该领域专家而言,根据生物化学和生理学的最佳现有知识几乎不可能预知食用果糖加甜而不是葡萄糖加甜的饮料将促发血脂异常并引起肥胖者内脏肥胖增加和胰岛素敏感性降低(K.L.Stanhope等.Consumingfructose-sweetened,notglucose-sweetened,beveragesincreasevisceraladiposityandlipidsanddecreaseinsulinsensitivityinoverweight/obesehumans(食用果糖加甜而不是葡萄糖加甜的饮料增加过重/肥胖者的内脏肥胖和降低其胰岛素敏感性).J.Clin.Invest.2009;119(5):1322-1334)。目前对于什么决定身体内部脂肪蓄积模式的知识最主要是根据经验产生的。这也适用于对肥胖相关疾病与膳食脂质中n-6/n-3脂肪酸的比率之间的相关性正在积累的证据。当这个比率过高、例如在西方膳食中时,对人类健康的影响是负面的(A.P.Simpoulos.TheimportanceoftheOmega-6/Omega-3FattyAcidRatioinCardiovascularDiseaseandOtherChronicDiseases(ω-6/ω-3脂肪酸比率在心血管疾病及其他慢性病中的重要性).SocietyforExperimentalBiologyandMedicine2008;674-688;G.Ailhaud等.Anemergingriskfactorforobesity:doesdisequilibriumofpolyunsaturatedfattyacidmetabolismcontributetoexcessiveadiposetissuedevelopment?(正在浮现的肥胖风险因素:多不饱和脂肪酸代谢的失衡促进脂肪组织过度发展吗?)BritishJournalofNutrition2008;100:461-470),特别是在由“必需脂肪酸”亚油酸(C18:3n-6)构成的膳食中有高比例的n-6脂肪酸的情况下。
在西方膳食中,n-6/n-3脂肪酸的比率可以高达15/1,而在人类发展中,膳食中这个比率最可能是在1/1左右,并且这已经塑造了我们营养相关的遗传结构。因此,营养学家推荐,通过使食物富含富于n-3脂肪酸的植物油或海产油,从而使得膳食中n-6/n-3比率接近人类已经变得遗传适应的比率,来对抗西方膳食的负面影响。富于n-3脂肪酸的油:海产油和植物油,均可用于将膳食脂质的n-6/n-3平衡向更健康的方向调节。
1993年,Belzung和共同作者发表了在用n-6/n-3脂肪酸比率为6.85/1(牛脂和橄榄油的1∶1混合物)、0.3/1(鲱鱼油)和0.14/1(EPA(二十碳五烯酸=C20:5n-3)和DHA(二十二碳六烯酸=C22:6n-3)的浓缩物)的高脂膳食(20%w/w)喂养的Wistar大鼠中,比较脂肪蓄积模式的营养研究(F.Belzung等.Fishoiln-3fattyacidsselectivelylimitthehypertrophyofabdominalfatdepotsingrowingratsfedhigh-fatdiets(鱼油n-3脂肪酸在高脂膳食喂养的生长大鼠中选择性限制腹部脂肪库的过度增长).TheAmericanPhysiologicalSociety1993;R1111-R1118)。他们证明了对全部这三种高脂膳食,动物的生长相同,而且它们的皮下和肠系膜脂肪组织未受影响。但是,鲱鱼油或EPA/DHA浓缩物代替牛脂/橄榄油喂养的动物,腹部脂肪组织的蓄积比牛脂和橄榄油混合物喂养的动物少。作者推测,他们观察到的差异与这三种脂质源的代谢高度不同有关,包括膳食引起的动物的膜脂肪酸组成的差异,以及脂肪酸合成、前列腺素生成与肝脏酶活性调节的差异。应该注意,在这些研究中,ω-3占总膳食脂质(>20%w/w)的多达40%(作为浓缩物使用)和20%(鲱鱼油),相当于每天摄入0.7至1.4克的ω-3。在用大鼠进行的EPA或DHA对参与白色脂肪组织中脂质和葡萄糖代谢的基因的表达研究中(T.Raclot等.Site-specificregulationofgeneexpressionbyn-3polyunsaturatedfattyacidsinratwhiteadiposetissues(在大鼠白色脂肪组织中n-3多不饱和脂肪酸对基因表达的位点特异性调控).JournalofLipidResearch1997;38:1963-1971),这些脂肪酸的每日摄入量是0.9克。总之,食用很高量的鱼油或浓缩ω-3的Wistar大鼠,内脏脂肪的蓄积比用牛脂/橄榄油膳食喂养的大鼠少。
尽管我们有对生活方式和营养对人类健康重要性的认识,但当它成为改变坏习惯的意愿时,有高度的心理-社会学障碍。转变社会中已形成的食物偏好尤其难,即便是在了解并接受他们的生活方式和膳食习惯是不健康的人们当中也是如此。在这种情况下,可取的可能是具有几种策略,与坚决主张人们必须转变他们的整个生活方式互补,加以贯彻来对抗当前的肥胖流行病,特别是内脏肥胖导致的糖尿病及其他健康问题。存在针对糖尿病的药物,但没有主要通过抑制内脏脂肪组织的蓄积而起作用的药物,而已知内脏脂肪组织的蓄积参与了2型糖尿病和其它疾病的发展。总称为噻唑烷二酮类的抗糖尿病药物通过例如增加身体对胰岛素的敏感性起作用,并结合膳食和锻炼用于治疗2型糖尿病。但是,这些药物引起全身肥胖症增加,从内脏肥胖症是2型糖尿病发展的条件性因素的一般理解来看,是自相矛盾的。已考虑过他汀类药物用于防止肥胖和糖尿病,因为这类药物抑制体重增加和脂肪蓄积。但是,它们不会选择性抑制内脏肥胖症,并且它们抗肥胖的作用方式与它们增强呼吸耗氧和代谢降解脂肪的能力明显相关。
因此,非常需要本发明的油组合物,因为它减少内脏脂肪蓄积,即使在用作现行高脂西式膳食的少量补充剂时也是如此,特别是因为它同时没有毒副作用。
附图说明
图1显示在低脂参比膳食(对照)、肥胖诱导型高脂膳食(HF)和含有1.5重量%本发明油组合物的肥胖诱导型高脂膳食CO(桡足动物油)(HF+1.5%CO)喂养的大鼠中,总肾周脂肪为体重的函数(n=10)。
图2显示低脂参比膳食(对照)、肥胖诱导型高脂膳食(HF)和含有1.5重量%本发明油组合物的肥胖诱导型高脂膳食(HF+1.5%CO)喂养的大鼠的心肌组织的葡萄糖氧化能力(以μmol/min/g干重计)。值是平均值±95%C.I.(对照、HF和HF+1.5%CO分别为n=8、6和6)。
图3(A)显示了分别给予对照膳食(对照)、高脂膳食(HF)和含有1.5重量%本发明油组合物的高脂膳食(HF+1.5%CO)的小鼠在腹膜内葡萄糖耐量试验期间的血糖水平。
图3(B)显示图3(A)说明的相同组的小鼠在腹膜内葡萄糖耐量试验期间的血糖水平曲线下面积。数据表示为平均值±S.E。*P<0.05,HF对比对照;#P<0.05,HF+1.5%CO对比HF。
发明的详细说明
以下术语在本文中应该具有下面表明的含意,除非另有专门陈诉:
蜡酯:蜡酯是长链或极长链酸(脂肪酸)和长链或极长链醇(脂肪醇)的酯。在这里长链是指14至22碳,而极长链是指24个以上碳原子。
蜡酯是蜡中的重要组分。通常,术语“蜡”是指一大类以在室温下是固体为特征的脂质,例如当它看来像蜂窝材料或蜂蜡时。但是,蜡可以是固体和液体。它们由动物(蜂蜡,羊毛蜡(羊毛脂),抹香鲸蜡和橙连鳍鲑油)和植物(小烛树蜡、巴西棕榈、水稻糠、甘蔗(甘蔗原素)和希蒙德木)产生。所有叶片表面和许多植物与水果由蜡的微晶层覆盖。蜡用于食品、药品和美容行业供保护表面。
本发明的蜡酯是长链不饱和脂肪醇与长链不饱和脂肪酸、特别是ω-3脂肪酸的单酯,本发明的油组合物在室温下完全可溶并自由流动。
已经证明,本发明的油组合物用作高脂、肥胖诱导型西式膳食中的少量补充剂,专门抑制由这样的膳食引起的内脏脂肪蓄积。另外,已经表现出本发明的油组合物能够对抗由这样的膳食引起的心脏功能的损害。换句话说,本发明的油组合物可以用来对抗肥胖诱导型西方膳食的最有害效应。
本发明的油组合物已从海产桡足动物飞马哲水蚤(Calanusfinmarchicus)获得。这种油的化学组成与其它油明显不同,并研究了在它可以引起的可能的生物医学反应方面,它是否也有不同。但是,现有技术中没有什么能导致所属技术领域的专业人员考虑到,在肥胖诱导型高脂(24%w/w)西式膳食中包含少到1.5%(w/w)的本发明油组合物,将可能产生大鼠中内脏脂肪蓄积的高度统计显著性地降低,并且不影响其它脂肪组织中的脂肪生长或沉积。另外,并同样出乎意料的是,本发明的油组合物将这种高脂膳食喂养的大鼠的内脏脂肪蓄积降低到与用作参比膳食的低脂(4%w/w)膳食喂养的大鼠相同的水平,不引起肥胖。同样明显的是,本发明的油组合物可以对抗典型见于肥胖诱导的2型糖尿病中的健康心脏功能损害,这通过即使在肥胖诱导型高脂膳食长时间喂养之后,仍有心脏的高葡萄糖代谢所证明。
膳食脂质中脂肪酸的n-6/n-3比例影响体内脂肪蓄积的模式。这种比例高(例如>5/1)的膳食,如高脂西方膳食,引起中心型肥胖和内脏脂肪蓄积的倾向比n-6/n-3比率较低的膳食强。为了比较,由于本发明的油组合物只占肥胖诱导型高脂西式膳食的少部分,所以在我们的试验膳食中n-6/n-3脂肪酸比率仍然高达5/1。
像其它海产油一样,本发明的油组合物包含n-3脂肪酸EPA(二十碳五烯酸=C20:5n-3)和DHA(二十二碳六烯酸=C22:6n-3)。但是,EPA和DHA的水平略低于鱼油和磷虾油(表1),但它富含十八碳四烯酸(SDA=C18:4n-3)。不过,可以辩论所观察到的抑制膳食诱导的内脏肥胖可能应归于EPA和DHA的存在。但是,必须意识到,蜡酯、包括海产蜡酯在内,与甘油三酯和磷脂相比消化非常缓慢,而且蜡酯中的EPA和DHA不容易作为游离酸有效吸收。事实上,本领域技术人员的共同理解是蜡酯是不可消化的,因此富海产蜡酯的油像来自飞马哲水蚤的油是差的EPA和DHA源。另外,在上面描述的belzung等(1993)的实验中,动物摄取的ω-3的量在每日0.7-1.4克的范围内。比较起来,本发明的油组合物对肥胖诱导型高脂膳食喂养的大鼠只贡献每日0.06克的ω-3。因此,可以得出结论,本发明显示出的抑制内脏脂肪蓄积既不能像Belzung等的实验中那样归因于ω-3,也不能归于n-6/n-3脂肪酸的比率向更健康的方向改变。
本发明的油组合物能够源自于海生桡足动物,优选哲水蚤(Calanus)属桡足动物,例如飞马哲水蚤。使用本技术领域专业人员已知的任何方法,例如但不限于传统的鱼油生产技术、生物技术方法、有机溶剂或超临界流体提取和冷榨,能够将新鲜收获的、冷冻/解冻或脱水的原材料用作原材料,以获得所述油组合物。不依赖于获得油和生产油的程序,典型的总组成如表1所示。
表1.三种不同海产油的典型化学组成:(A)来自挪威海域捕捉的飞马哲水蚤的桡足动物油,(B)来自大西洋鳕(Gadusmorhua)的鳕鱼肝油,和(C)来自南大洋捕捉的南极磷虾(Euphausiasuperba)的磷虾油,以mg/g油给出。
脂质类别和选择的脂肪酸 | A1 | B2,4 | Ca3,5 |
甘油三酯 | 10 | 955 | 260 |
游离脂肪酸 | 90 | 14 | 13 |
饱和脂肪酸 | 160 | 160 | 300 |
单不饱和脂肪酸 | 120 | 385 | 300 |
多不饱和脂肪酸 | 250 | 475 | 387 |
n-3脂肪酸 | 240 | 395 | 332 |
n-6脂肪酸 | 10 | 50 | 55 |
18:4n-3脂肪酸(SDA) | 86 | 21 | 51 |
20:5n-3脂肪酸(EPA) | 67 | 72 | 128 |
22:6n-3脂肪酸(DHA) | 49 | 188 | 101 |
蜡酯 | 670 | 0 | 0 |
极性脂质 | <50 | 18 | 670 |
中性脂质 | >750 | 967 | 310 |
1CalanusAS生产的桡足动物油(www.calanus.no)
2来自Falch,等.,ProcessBiochemistry2006;41:666-674
3来自Phleger,等.ComparativeBiochemistryandPhysiologyPartB2002;131:733-747
4来自Standal等.,J.AmOilChemSoc2008;85:105-112
5来自Hagen等.,MarineBiology2001;139:95-104
除总化学组成的显著差异以外,在此用于举例说明目的的这三种海产油,它们的n-3脂肪酸含量也是不同的(表1)。
为了说明本发明的油组合物的独特性,显示了传统的鳕鱼肝油和磷虾油的相应组成供比较。从总化学分析明显看出,这些油高度不同,特别是在它们的蜡酯、甘油三酯、磷脂含量和虾青素含量(未显示)方面。应该注意,与鳕鱼肝油和磷虾油不同,蜡酯构成本发明的桡足动物油中的主要脂质组分。
三种油之间脂肪酸组成最显著的差异是桡足动物油中十八碳四烯酸(SDA)越高,则二十二碳六烯酸(DHA)含量越低。
本发明的油组合物中,SDA、EPA和DHA在很大程度上作为与不饱和长链脂肪醇的酯存在。总之,本发明的桡足动物油在总化学组成和脂肪酸含量上与典型的鱼油和磷虾油显著不同。但是,它的n-3脂肪酸总水平与其它海产油相似。
表2显示了本发明的油组合物中蜡酯和脂肪醇/脂肪酸组合的典型组成。
表2.来源于飞马哲水蚤的桡足动物油中蜡酯与脂肪醇/脂肪酸组合的典型组成(%(w/w))。1
蜡酯 | 主要脂肪醇/脂肪酸 | 次要脂肪醇/脂肪酸 | %(w/w) |
30:1 | 14:0/16:1 | 16:1/14:0 | 0.8 |
32:1 | 16:0/16:1 | 14:0/18:1 | 1.9 |
32:2 | 16:1/16:1 | 14:0/18:2 | 0.65 --> |
32:4 | 14:0/18:4 | 16:0/16:4 | 0.9 |
34:1 | 16:0/18:1 | 14:0/20:1 | - |
20:1/14:0 | 17.6 | ||
34:2 | 16:0/18:2 | 16:1/18:1 | 0.9 |
34:3 | 16:0/18:3 | 16:1/18:2 | - |
34:4 | 16:0/18:4 | 16:1/18:3 | 2.7 |
34:5 | 14:0/20:5 | 16:1/18:4 | 0.4 |
36:1 | 20:1/16:0 | 16:0/20:1 | - |
22:1/14:0 | 21.9 | ||
36:2 | 20:1/16:1 | 16:1/20:1 | 2.3 |
36:5 | 16:0/20:5 | 20:1/16:4 | 1.1 |
36:6 | 16:1/20:5 | 14:0/22:6 | 0.3 |
38:1 | 22:1/16:0 | 16:0/22:1 | 2.8 |
38:2 | 22:1/16:1 | 20:1/18:1 | 3.9 |
38:3 | 20:1/18:2 | 22:1/16:2 | 0.4 |
38:4 | 20:1/18:3 | 22:1/16:3 | 0.9 |
38:5 | 20:1/18:4 | 22:1/16:4 | 5.4 |
38:6 | 16:0/22:6 | 16:1/22:5 | - |
40:2 | 20:1/20:1 | 22:1/18:1 | 5.9 |
40:3 | 22:1/18:2 | 0.7 | |
40:5 | 22:1/18:4 | 20:1/20:4 | 4.7 |
40:6 | 20:1/20:5 | 1.5 | |
42:2 | 22:1/20:1 | 20:1/22:1 | 12.7 |
42.6 | 22:1/20:5 | 20:1/22:5 | 1.5 |
42:7 | 20:1/22:6 | 2.0 | |
44:2 | 22:1/22:1 | 4.9 | |
44:7 | 22:1/22:6 | 0.6 |
1从Graeve,M.和Kattner,G.Species-specificdifferencesinintactwaxestersofCalanushyperboreusandC.finmarchicusfromFramStrait-GreenlandSea(来自Fram海峡-格陵兰海的极北哲水蚤(Calanushyperboreus)与飞马哲水蚤(C.finmarchicus)的完整蜡酯中的物种特异性差异).MarineChemistry1992;39:269-281.
本发明的油组合物中海产蜡酯的特征在于是单或多不饱和的,具有长链单不饱和脂肪醇(主要是C16:1、C20:1和C22:1脂肪醇),和高比例的单和多不饱和脂肪酸(主要是C16至C22),包括n-3脂肪酸SDA(C18:4)、EPA(C20:5)和DHA(C22:6)。因此,本发明的油组合物在室温下是低粘性的和完全自由流动的液体。
取决于使用的分析方法,本发明油组合物的蜡酯的典型含量是60-90%,而它包含10-20%的其它组分,例如游离脂肪酸、甘油三酯、磷脂和它们的残基、甾醇和色素。在某些应用中,通过本领域技术人员已知的适当方法除去游离脂肪酸及其他组分可能是有利的乃至可取的。因此,在本发明的一种实施方案中,油组合物可以包含高达100%的蜡酯。
已经显示出,本发明的油组合物可以抑制西式高脂膳食诱导的内脏脂肪蓄积和对抗其诱导的健康心脏功能的损害,如图1-3所示。因此,本发明的组合物可以用于预防和治疗肥胖诱导的疾病,例如但不限于2型糖尿病。
本发明的油组合物包含20、25、30、35、40、45、50、55、60、65、70重量%直至75、80、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100重量%的蜡酯。优选所述油组合物包含80、81、82、83、84、85、86、87、88、89重量%直至90、91、92、93、94、95、96、97、98、99、99.5、100重量%的蜡酯。
本发明的油组合物还包含5、6、7、8、9、10重量%直至11、12、13、14、15、16、17、18、19、20重量%的SDA。
所述油组合物中EPA的含量可以是3、4、5、6、7重量%直至8、9、10、11、12、13、14、15重量%。所述组合物可以包含2、3、4、5重量%直至6、7、8、9、10重量%的DHA。
在本发明的实施方案中,提供了包含20-100重量%的蜡酯、优选40-85重量%的蜡酯的油组合物,其中所述蜡酯由主要是单或多不饱和C16至C22脂肪酸和主要是单不饱和C16、C20和C22脂肪醇的单酯组成,供用作预防或治疗腹型肥胖和肥胖相关疾病的药物。
在本发明的油组合物的一种实施方案中,蜡酯的70%以上的单不饱和脂肪醇是C16:1、C20:1和C22:1。
在另一种实施方案中,提供了组合物,其中肥胖相关疾病是2型糖尿病。
在另一种实施方案中,提供了另外包含5-20重量%的十八碳四烯酸(SDA)的组合物。本发明的又一种实施方案中提供了还包含3-20重量%的二十碳五烯酸(EPA)和2-15重量%的二十二碳六烯酸(DHA)的油组合物。
在本发明的另一种实施方案中,所述油组合物包含作为单酯的脂肪醇与SDA、DHA和EPA。
在本发明的又一个实施方案中,提供了还含有500-4000ppm虾青素的组合物。
在本发明的实施方案中,提供了油组合物,其中所述油组合物从桡足动物中分离,在另一种实施方案中,桡足动物是哲水蚤属的桡足动物。在又一个实施方案中,桡足动物是飞马哲水蚤种的桡足动物。
还提供了包含根据本发明的油组合物的膳食增补制剂和功能性食品或饲料制剂,作为本发明的附加实施方案。
在本发明的一个实施方案中,提供了包含本发明的油组合物的药物制剂。所述药物制剂可以作为胶囊、片剂、乳液或滋补剂(tonics)被提供。所述制剂还包含一种或多种可药用的添加剂,其选自佐剂、稳定剂、抗氧化剂、乳化剂、表面活性剂和载体。
在本发明的实施方案中,提供了上文的油组合物在制造预防或治疗腹型肥胖的药物中的应用。还提供了所述油组合物在制造预防或治疗肥胖相关疾病中的应用,所述肥胖相关疾病是2型糖尿病。
在本发明的又一个实施方案中,提供了预防或治疗腹型肥胖的方法,其中上文的油组合物以每日0.5-5g的量施用于需要这样的治疗的人类对象。还提供了预防或治疗肥胖相关疾病的方法;所述肥胖相关疾病是2型糖尿病。
除了它对哺乳动物、特别是人类有用之外,本发明还有一种实施方案是它可以用于预防水产养殖的鱼、包括但不限于鲑鱼和鳟鱼的一个主要问题。鱼类养殖者和熟悉养鱼的其他人之中都知道,像鲑鱼和鳟鱼这样的鱼当它们以混合干饲料粒为食时,蓄积了大量的肠脂肪,而养殖鲑鱼的这种“品质问题”在以海洋中天然可得的食物生物为食的野生鲑鱼中并不明显。内脏脂肪蓄积可以高得使在去除内脏的养殖鱼中,肠子有时仅可分辨。野生和养殖鱼例如鲑鱼和鳟鱼之间这种品质差异的原因完全不为国际饲料制造商或在水产养殖部门内工作的其它人所知。然而,公认的是必须解决人工饲料中的某种不平衡、或野生鱼从它们在海洋中的天然食物获得的一种或多种成分的缺少。因此,本发明的另一个实施方案是使鱼饲料富含作为完全的桡足动物制剂或作为本发明的油组合物的这种食物源,以同样预防养殖鱼的内脏脂肪蓄积。
以下非限制性试验部分和实施例说明和证明了本发明。
实施例
试验
动物试验在挪威大学的药学院进行。六周龄Wistar大鼠,平均重量162克,被单个装笼并放置在保持21℃、55%湿度和12:12小时明暗周期(从上午7点至下午7点照明)的房间中。动物自由进食饮水。全部程序经挪威实验动物委员会批准,并符合保护用于试验及其他科学目的的脊椎动物的欧洲公约(ESTNR.123,1986)。大鼠用TestDiet(www.testdiet.com)生产的三种不同膳食喂养110天:1)对照膳食,含有4%脂肪(2.37%大豆油和1.89%猪油,w/w)),相当于膳食总含能量的10%(对照,3.75kcal/g);2)肥胖诱导型高脂膳食,含有24%脂肪(2.89%大豆油和20.68%猪油,w/w),相当于膳食总含能量的45%(HF,4.65kcal/g);3)试验高脂膳食,含有24%脂肪(2.91%大豆油、19.15%猪油和1.5%本发明的油制剂),相当于膳食总能量的45%(HF+1.5%CO,4.47kcal/g饲料)。制备所述膳食不用抗氧化剂或防腐剂,在给食之前冷冻储存。
在处死当天,施用肝素并麻醉之后,记录总体重。肝脏和心脏在从身体取出之后记录重量,解剖出内脏(肾周)脂肪并称重。数据显示在表3和图1中。心脏代谢根据标准方法以分离的灌注心脏中的葡萄糖氧化来度量(E.Aasum,A.M.Khalid,O.A.Gudbrandsen,O.-J.How,R.K.Berge,T.Larsen.Fenofibratemodulatescardiacandhepaticmetabolismandincreasesischemictoleranceindiet-inducedobesemice(非诺贝特调节心脏和肝脏代谢并增加膳食诱导的肥胖小鼠的缺血耐受性).JournalofMolecularandCellularCardiology2008;44:201-209)。结果示于图2。
在另一组实验中,小鼠用对大鼠所描述的相同膳食喂养50天。对于葡萄糖耐量试验,小鼠被禁食5小时并腹膜内注射葡萄糖(1.3g/kg)。注射之前以及注射之后15、30、60和120分钟从隐静脉取血样。使用糖度计(BayerAscensiaContourGlucoseMeter)测定血糖水平。结果示于图3。
生物效应
表3:低脂参比膳食(对照)、肥胖诱导型高脂膳食(HF)和含有1.5重量%本发明油制剂的试验高脂膳食(HF+1.5%CO)喂养的大鼠的生物统计数据。分别给出饲养试验开始时的体重值(开始时体重)、饲养试验结束时的体重(处死时体重)、饲养试验结束时的肝脏重量(肝脏重量)、饲养试验结束时的心脏重量(心脏重量)、以及饲养试验结束时心脏重量分别与体重和胫骨长度(以mm为单位)之间的比率。值是平均值±95%C.I.(n=10)。
*湿重,以克计;干重,以克计。值已乘以1000。
如表3所示,正如预期,两种高脂(高能量)膳食喂养的大鼠在110天后的平均总体重(和因此的增重)相同,而较低能量的参比膳食喂养的大鼠增重较少。
其它生物统计数据显示所述组之间没有显著的差异。两个高脂膳食组中的大鼠每日进食量相同,它们的进水量也相同(数据未显示)。参比组消耗的饲料比两个高脂组稍多,但它们的每日能量摄取较低,解释了它们增重较少。总之,实验显示,本发明的油组合物不影响高脂膳食喂养的大鼠的行为,并且没有对所述动物具有不良影响的迹象。
在喂养110天后处死动物并打开腹部时,可以用肉眼观察到两个高脂组之间的显著差异:当体格大小大致相同的大鼠进行比较时,补充了本发明油组合物的试验高脂膳食喂养的大鼠,看得出内脏脂肪比对应的高脂组少,内脏脂肪蓄积更类似低脂参比膳食喂养的大鼠。三个组的内脏重量的统计分析证实了这种直接视觉观察。因为内脏脂肪量随着体格大小增加,与饲养方案无关,三个膳食组中肾周脂肪的原始数据已经按照处死时体重进行作图,如图1所示。
这些重量数据的统计处理揭示了以下结果:在全部三个组中,内脏脂肪重量与体重内脏有明确的线性相关,其中参比组(对照)的统计显著性水平为p=0.034,高脂组(HF)为p=0.003,且含有本发明油组合物的实验组(HF+1.5%CO)为p=0.018。根据内脏脂肪重量与体重之间存在统计显著的相关性的事实,可以通过ANCOVA分析,使用重量作为协变量,计算组间的统计差异。所述分析显示,包含试验油的组与对应高脂膳食之间的差异是有统计显著性的(p=0.00241),而试验油组与低脂组之间没有统计显著性差异。试验油组与低脂参比组合在一起与高脂组有显著差异(p=0.0084)。因此,总之,本发明的油作为高脂肥胖诱导型膳食的少量补充剂提供,抑制了内脏脂肪的蓄积。
图2显示了用三种膳食喂养的大鼠的心肌组织的葡萄糖氧化能力。高脂膳食(HF)的大鼠与低脂对照膳食(对照)的大鼠相比葡萄糖氧化能力降低,而在含有1.5%本发明油组合物的高脂膳食(HF+1.5%CO)喂养的大鼠中,葡萄糖氧化能力与低脂对照大鼠相当。因此,显然,本发明的油组合物即使在以肥胖诱导型高脂膳食长期喂养之后,仍可以对抗健康心脏功能的损害。
图3(A)显示了分别给予对照膳食(对照)、高脂膳食(HF)和含有油组合物的高脂膳食(HF+1.5%CO)的小鼠在腹膜内葡萄糖耐量试验期间的血糖水平。图3(B)显示了图A中所示的葡萄糖耐量曲线下面积。数据表示为平均值±SE。*P<0.05,HF对比对照;#P<0.05,HF+1.5%CO对比HF。
与对照小鼠比较,HF小鼠在腹膜内葡萄糖耐量试验期间血糖水平显著增加。这些结果表明,用高脂膳食喂养50天诱导了2型糖尿病的胰岛素抵抗特征。重要的是,在高脂膳食中包含1.5%的本发明油组合物对抗了胰岛素抵抗的产生。
高脂膳食(HF)的小鼠与对照膳食(对照)的小鼠相比,心肌葡萄糖氧化速率降低(p<0.05)。但是在用含有1.5%本发明油组合物的高脂膳食(HF+1.5%CO)喂养的小鼠中,葡萄糖氧化发生部分恢复(p<0.05)。因此,显然,本发明的油组合物可以对抗用高脂膳食喂养之后发生的心肌葡萄糖氧化能力的降低。
Claims (8)
1.油组合物在制备用于预防或治疗腹型肥胖和2型糖尿病的药物中的应用,其中所述油组合物包含20-100重量%的蜡酯以及所述蜡酯由单或多不饱和C16至C22脂肪酸与单不饱和C16至C22脂肪醇的单酯组成,其中所述脂肪酸包含5-20重量%的十八碳四烯酸(SDA)、3-20重量%的二十碳五烯酸(EPA)和2-15重量%的二十二碳六烯酸(DHA)。
2.权利要求1的应用,其中所述油组合物包含40-85重量%的蜡酯。
3.权利要求1的应用,其中所述蜡酯的70%以上的单不饱和脂肪醇是C16:1、C20:1和C22:1。
4.权利要求1的应用,其中所述蜡酯的70%以上的脂肪醇是单不饱和的,并且其中所述蜡酯的50%以上的脂肪酸是单或多不饱和的n-3脂肪酸。
5.权利要求1至4任一项的应用,其中所述油组合物包含500-4000ppm的虾青素。
6.权利要求1至4任一项的应用,其中所述油组合物从桡足动物中分离。
7.权利要求6的应用,其中所述桡足动物属于哲水蚤属(Calanus)。
8.权利要求7的应用,其中所述桡足动物属于飞马哲水蚤种(Calanusfinmarchicus)。
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