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关于“肥胖是不是病”的问题可不是那么简单就有答案的,目前学术界对此并无统一认识,反正“公说公有理,婆说婆有理”,关键是谁也说不清是先有肥胖还是先有炎症,对于肥胖是否与肠道菌群有关仍各执一词,莫衷一是。姑且不论科学最终将如何回答这个问题,若仅从哲学的角度围绕“肥”与“瘦”进行辩证分析,居然发现此问题符合唯物辩证法的三大规律及其若干范畴,并可由此得出一些有趣的推论。
规律一:对立统一
肥胖与消瘦显然是一对矛盾,即凡事“一分为二”,人的身材也有胖瘦之分,但二者是可以相互转化的。肥胖者体内iNOS活化,eNOS失活,褐色脂肪变成白色脂肪,也就是脂肪组织中无线粒体,脂肪只能贮存而不被消耗。相反,瘦削者体内iNOS失活,eNOS活化,白色脂肪变成褐色脂肪,也就是脂肪组织中有线粒体,脂肪可以“燃烧”并产生能量消耗掉。
按照上述对应关系,只要控制好iNOS与eNOS的活性,就能灵活调节人的体重了。实际上,肠道生态失调引起的炎症正是控制iNOS/eNOS活性的枢纽,只要除菌消炎就能提高eNOS活性和降低iNOS活性,从而达到消脂减肥的目的。因此,以除菌为靶点的减肥药治标由治本,而以消炎为靶点的减肥药只能治标。
规律二:质量互变
在小鼠中的研究发现,单纯饲喂高脂饲料或在饲喂高脂饲料的同时肌注高剂量内毒素(1.2毫克/公斤)都能诱发肥胖,但外周组织检测不到炎症,可称之为“非炎症性肥胖”。反之,高脂饲料与低剂量内毒素(0.25毫克/公斤)诱导的肥胖,在内脏组织能检测到炎症,可称之为“炎症性肥胖”。假如把炎症性肥胖定义为不健康肥胖,那么非炎症性肥胖就是健康肥胖。仅仅因为内毒素剂量由高到低的量变,就造成健康肥胖到不健康肥胖的质变。
高剂量内毒素肌注小鼠可使肝脏的促炎细胞因子升高数十倍(高度炎症),而低剂量内毒素腹腔注射仅使小鼠肝脏的促炎细胞因子升高2-3倍(低度炎症),说明肠道内产内毒素细菌的多寡以及肠壁屏障完整与否决定诱发的是高度炎症还是低度炎症。高度炎症是急性的,内毒素易被免疫清除,低度炎症则为慢性,难以清除内毒素。
规律三:否定之否定
合理饮食、无炎症是对健康状况最有力的肯定,而饮食不节、有炎症是对健康状况最有力的否定,减肥药通过抗炎复健则是对良好健康状况的否定之否定(肯定)。从表面上看,似乎改变饮食习惯就能决定肥瘦,但本质原因还是得归结于肠道菌群上。产硫酸盐及硫酸盐还原菌等革兰氏阴性菌可以形象地称为“肥菌”,而产丁酸细菌等革兰氏阳性菌则可相应地称为“瘦菌”。
高脂饲料肯定可以喂肥小鼠,因为肠道中“肥菌”增加,“瘦菌”减少,但在肥鼠中并不一定能检测到炎症,一方面是产内毒素细菌本身具有免疫抑制作用,另一方面过高的内毒素足以刺激免疫系统活化并予以清除。所以严格地说,非炎症肥胖小鼠最初是有急性炎症的,只不过随后急性炎症消失而变成无炎症状态而已。
范畴一:本质与现象
肥胖或瘦削都是形容体重和身材的一种表面观感,或者说只是体内脂肪或多或少的反映,肥胖的本质是脂肪不能消耗,而瘦削的本质是脂肪无法积累。脂肪能不能消耗,要看脂肪组织中有没有线粒体,无线粒体的白色脂肪组织是不能分解脂肪的,只有含线粒体的褐色脂肪组织才能分解脂肪。不过,白色脂肪组织在无炎症、有iNOS抑制剂或eNOS激活剂的条件下可以转变成浅褐色脂肪组织。因此,抗炎药可以减肥,精氨酸类似物(iNOS抑制剂)和2,4-二硝基苯酚、精氨酸、硝普钠、硝酸甘油、低剂量青蒿素或过氧化氢等(eNOS激活剂)也能减肥。
范畴二:内容与形式
肥胖或瘦削作为体重与身材的不同表现形式,其内容体现在肠道菌群的差异及肠壁渗漏性上,而两者又决定了炎症的有无。肥胖有炎症者的肠道生态失调,内毒素及产内毒素细菌从肠道泄漏入血并进入脂肪组织而促进脂肪再生,形成大量白色脂肪组织;瘦削无炎症者肠道生态平衡,无内毒素泄漏发生,仅有少量白色脂肪组织,并可转变成浅褐色脂肪组织。
范畴三:原因与结果
肥胖或瘦削只是脂肪积累或消耗的结果,其原因为促炎活性高或抗炎活性强。肥胖者体内促炎细胞因子活性高,导致iNOS活化,eNOS失活,线粒体功能失调,结果引起脂肪组织白化。瘦削者体内促炎细胞因子活性低,使eNOS活化,iNOS失活,线粒体功能正常,脂肪组织褐化。
范畴四:外因与内因
外因是变化的条件,内因是变化的依据。这个外因就是食物种类,内因则是肠道菌群。肥胖者喜吃荤,肠道菌群以产硫酸盐细菌及硫酸盐还原菌为主,瘦削者喜吃素,肠道菌群以产丁酸细菌为主。但是,如果肥胖者改吃素,产硫酸盐细菌中的硫酸酯酶就不表达,细菌的“食谱”就会变成五谷杂粮,有利于减肥。
范畴五:定性与定量
一般人也许只听说过炎症这个“定性”概念,而很少知道高度炎症与低度炎症这样的“定量”概念。有趣的是,大剂量内毒素进入体内可以调动机体免疫系统彻底清除内毒素,反而从急性炎症变成无炎症,而低剂量内毒素不利于免疫清除,表现为持续的慢性炎症,这就是“物极必反”的道理。
范畴六:局部与整体
高剂量脂多糖注射小鼠却使外周组织中的促炎细胞因子普遍下调(免疫抑制),当然也就谈不上有任何炎症表现了。不过,在内脏组织还是可以检测到急性高度炎症。相反,低剂量内毒素能使脂肪组织的促炎细胞因子表达显著上调,完全称得上是急性高度炎症,但在肝脏却只是轻微上调促炎细胞因子表达,属于慢性低度炎症。因此,高度炎症或低度炎症的分布在不同组织中是不一致的,此处肝脏就是低度炎症的发源地。
范畴七:必然与偶然
肥胖或瘦削本身具有偶然性,因为它们既不完全是由遗传决定的,而且子女的身材也不一定跟父母相同,因为肥瘦在很大程度上取决于肠道菌群的组成。若出生时是自然分娩方式,则婴儿肠道菌群跟母亲一致,若为剖腹产,则婴儿肠菌会有医院机会细菌污染。更重要的是,在人的一生中都会不可避免地使用抗生素,这样会使每个人的肠菌组成大相径庭。
范畴八:可能与现实
通过节食和运动可以减肥,但肥胖者往往因为没有毅力而很难坚持。不过,减肥药的推出为减肥者提供了现实的选择。
从现有研究结果来看,肥胖确实有炎症性肥胖与非炎症性肥胖之分,所以适当的表述是“炎症性肥胖是病”,“非炎症性肥胖不是病”,两者的本质区别在于高剂量内毒素引起的急性高度炎症以及低剂量内毒素引起的慢性低度炎症。若是前者,炎症将在短期内消除,表现为胰岛素敏感;若是后者,炎症会长期持续,最后可能发展为2型糖尿病及其他并发症。
附:
Anti-inflammatory drug counters obesity in mice
Date:February 19, 2015
Source:EMBO - excellence in life sciences
Summary:Obesity represents a global health problem with limited options available for its prevention or treatment. The finding that a key regulator of energy expenditure and body weight is controlled by a drug-targeted inflammatory enzyme opens new possibilities for pharmacologically modulating body weight, conclude researchers.
Obesity represents a global health problem with limited options available for its prevention or treatment. The finding that a key regulator of energy expenditure and body weight is controlled by a drug-targeted inflammatory enzyme opens new possibilities for pharmacologically modulating body weight. This is the conclusion of a study led by Toshihiro Nakajima of Tokyo Medical University in Japan, reported in The EMBO Journal.
Energy spending in human cells is controlled by organelles called mitochondria, which are the major sites for burning of nutrients such as fatty acids. Mitochondria therefore play key roles in the fat cells that form white adipose tissue, an excess of which characterizes obesity. Earlier research has shown that mitochondrial biogenesis and fatty acid breakdown is regulated by hormone receptors known as peroxisome proliferator-activated receptors (PPARs). Pharmacological activators of PPARs have been tried as promising clinical treatments for obesity, but such trials have been hindered by undesirable side effects.
Nakajima's team had been studying a gene called Synoviolin, which is causally linked to the inflammatory condition of rheumatoid arthritis. In previous work, they developed a chemical compound, LS-102, that inhibits the enzyme encoded by the Synoviolin gene and suppresses rheumatoid arthritis in mouse disease models. Given the close associations of inflammation and metabolic diseases, including obesity and diabetes, the authors now tested the role of the Synoviolin gene in mouse models for such disorders. Loss of Synoviolin led to decreased white fat tissue and reduced body weight, which was traced to mitochondrial up-regulation. Importantly, the authors could show that loss or inhibition of SYVN1, the enzyme encoded by the Synoviolin gene, led to stabilization of an endogenous cellular PPAR activator, thus turning on PPAR-dependent energy control pathways. Therefore, treatment with the LS-102 inhibitor may provide an alternative to the side effect-troubled chemical PPAR activators for treating obese patients.
"Obesity is a known risk factor for other chronic disorders," says Nakajima. "Our findings indicate that Synoviolin may be a key for understanding the common features of obesity and chronic inflammatory disease such as rheumatoid arthritis."
Story Source:
The above story is based on materials provided by EMBO - excellence in life sciences. Note: Materials may be edited for content and length.
Journal Reference:
Toshihiro Nakajima et al. The E3 ligase synoviolin controls body weight and mitochondrial biogenesis through negative regulation of PGC‐1β. The EMBO Journal, February 2015 DOI:10.15252/embj.201489897
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