I have read the article by Lee et al.¹ with great interest. This article reported favourable post-operative overall survival among obese patients with lung adenocarcinoma, a phenomenon known as the obesity paradox. Besides lung cancer, a better prognosis among overweight or obese patients has been repeatedly observed among patients with a broad range of diseases. For example, in 2021, this journal published several articles regarding the obesity paradox among patients with stroke,² sepsis,³ and heart failure.⁴

Among several possible explanations for the obesity paradox, the methodological limitation of body mass index (BMI) as a marker of obesity has been considered a major underlying mechanism.⁵ BMI does not delineate adipose tissue distribution or distinguish between fat and lean body mass. Thus, body composition phenotypes have been considered as missing links in the obesity paradox.⁶

However, Lee et al.¹ clearly demonstrated that a better prognosis among obese lung cancer patients was observed regardless of skeletal muscle mass, which was objectively assessed using computed tomography. They also observed that an increase in visceral adiposity was related to the improved overall survival despite the well-known adverse effect of visceral obesity on cardiometabolic risk. These findings suggest the possibility of the real benefit of increased adiposity among patients with lung cancer.

Although largely unknown to researchers and clinicians, human adipose tissue plays a role as a storage organ for various lipophilic environmental contaminants. The most well-known chemicals are compounds classified as persistent organic pollutants (POPs), which show strong lipophilicity, resistance to degradation, and long half-lives of several years to decades.⁷ Examples of POPs are organochlorine pesticides, polychlorinated biphenyls (PCBs), dioxins, and polybrominated diphenyl ethers.^{7, 8} In addition to POPs, many less lipophilic chemicals with short half-lives have been detected in human adipose tissue, including polyaromatic hydrocarbons, bisphenol A, phthalates, triclosans, and nonylphenols.^{9, 10} Therefore, human adipose tissue in modern society can be seen as a dump to accumulate exogenous chemicals that are not easily metabolized and excreted from the body.

The production and use of many individual chemicals belonging to POPs have been banned for several decades because of possible harm to wild animals and humans.¹¹ However, humans are still living with continuous exposure to a complicated mixture of these chemicals, primarily due to the wide contamination of the food chain.¹² Exposure to POPs begins at the fetal stage because POPs can be easily transported from the mother to the fetus.¹³ Infants are continuously exposed to POPs through breastfeeding after birth because breast milk contains high concentrations of POPs.¹⁴

Compared with the earlier period when POPs were actively used, the exposure dose of POPs in contemporary society is much lower. Recently, however, chronic exposure to low-dose POPs has become a great concern to human health. For example, in epidemiological studies based on the general population with only background exposure to these chemicals, chronic exposure to low-dose POPs has been linked to the increased risk of many diseases of the endocrine, immune, nervous, and reproductive systems.^15-18 Importantly, low-dose POPs can act as mitochondrial toxins.^{19, 20}

The toxico kinetics of POPs can explain puzzling findings that suggest the benefit of increased adiposity, such as the obesity paradox.²¹ Once lipophilic chemicals with long half-lives, such as POPs, enter the human body from external exposure sources, they are primarily stored in adipose tissue and are very slowly released into the circulation for elimination.²² From the viewpoint of the whole-body system, it can be seen as a protective mechanism because adipose tissue may be the safest place to store POPs. Therefore, if humans are exposed to the same levels of environmental POPs, having more adipose tissue can be beneficial because the storage of POPs in adipose tissue can reduce their burden on other critical organs.²¹

Several animal experiments have demonstrated the protective roles of adipose tissues against POPs. For example, diet-induced obesity in rats increased survival time after exposure to a lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin, the most toxic compound among POPs.²³ Moreover, treatment with PCBs induced impaired glucose homoeostasis only in lean mice, but not in obese mice; however, weight loss in obese mice developed glucose impairment.²⁴

In addition, POPs in adipose tissue can explain the worse prognosis of lung cancer or other cancer patients who experience unintentional weight loss during pre-diagnosis, peri-diagnosis, and post-diagnosis.^25-27 Currently, there are several explanations for this phenomenon, such as poor tolerance to treatment, high severity, decreased performance status, or co-morbid conditions. However, POPs are released from adipose tissue into circulation during weight loss due to adipose tissue shrinkage, and the amount of POPs released is proportional to the magnitude of weight loss.²⁸ Therefore, the dynamics of POPs may be a possible mechanism linking unintentional weight loss and poor prognosis in cancer patients.

Furthermore, even intentional weight loss can have an unexpected drawback, although intentional weight loss through lifestyle modification is generally recommended to overweight or obese individuals. For example, the Action for Health in Diabetes (Look AHEAD) study, a large randomized controlled trial that investigated the effects of intensive intentional weight loss in obese patients with Type 2 diabetes, did not report any long-term benefits of intentional weight loss on cardiovascular disease or cognition despite many short-term benefits.^{29, 30} This unanticipated consequence can be attributed to the POP dynamics observed during intentional weight loss.^{31, 32} It is important to note that weight fluctuation, a common result of intentional weight loss, can lead to redistribution of POPs from adipose tissue to critical organs, as observed in animal experimental studies.³³

The role of adipose tissue in storing POPs and other environmental pollutants may not be trivial and can explain many puzzling findings on obesity observed in epidemiological studies. In contrast to the prevailing idea of obesity, adipose tissue may be the first line of defence against the possible harmful effects of lipophilic chemical mixtures. If this role of adipose tissue becomes more significant in patients with cancer or other chronic diseases, the obesity paradox can be explained. Investigation of the interrelationship between adipose tissue and lipophilic chemical mixtures is urgently required.

我读过李等人的文章。 ^1、怀着极大的兴趣。本文报道了肥胖肺腺癌患者术后总体生存率良好，这种现象被称为肥胖悖论。除肺癌外，在患有多种疾病的患者中反复观察到超重或肥胖患者的预后较好。例如，2021年，该杂志发表了几篇关于中风、 ²脓毒症、 ³和心力衰竭患者肥胖悖论的文章。 ⁴

在对肥胖悖论的几种可能解释中，体重指数（BMI）作为肥胖标志的方法学限制被认为是主要的潜在机制。 ⁵ BMI 不能描绘脂肪组织分布或区分脂肪和瘦体重。因此，身体成分表型被认为是肥胖悖论中缺失的环节。 ⁶

然而，李等人。^图1清楚地表明，无论骨骼肌质量如何，肥胖肺癌患者的预后都较好，这是使用计算机断层扫描客观评估的。他们还观察到，尽管内脏肥胖对心脏代谢风险有众所周知的不利影响，但内脏肥胖的增加与总体生存率的提高有关。这些发现表明，肥胖增加可能对肺癌患者带来真正的益处。

尽管研究人员和临床医生很大程度上不了解，但人体脂肪组织起着各种亲脂性环境污染物的储存器官的作用。最著名的化学物质是持久性有机污染物（POP）的化合物，它们具有很强的亲脂性、耐降解性和长达数年至数十年的半衰期。 ⁷持久性有机污染物的例子有有机氯农药、多氯联苯 (PCB)、二恶英和多溴二苯醚。 ^{7, 8}除持久性有机污染物外，人体脂肪组织中还检测到了许多半衰期较短的亲脂性较低的化学物质，包括多环芳烃、双酚 A、邻苯二甲酸盐、三氯生和壬基酚。 ^{9, 10}因此，现代社会的人体脂肪组织可以看作是积累不易代谢和排出体外的外源化学物质的垃圾场。

由于可能对野生动物和人类造成伤害，许多属于持久性有机污染物的化学品的生产和使用已被禁止数十年。 ¹¹然而，人类仍然持续接触这些化学物质的复杂混合物，这主要是由于食物链的广泛污染。 ¹²持久性有机污染物的接触从胎儿阶段就开始了，因为持久性有机污染物很容易从母亲转移到胎儿。 ¹³婴儿出生后通过母乳喂养不断接触持久性有机污染物，因为母乳中含有高浓度的持久性有机污染物。 ¹⁴

与早期POPs被积极使用的时期相比，当代社会POPs的暴露剂量要低得多。然而，近年来，长期接触低剂量POPs已成为人类健康的一大担忧。例如，在基于仅背景接触这些化学物质的一般人群的流行病学研究中，长期接触低剂量持久性有机污染物与内分泌、免疫、神经和生殖系统许多疾病的风险增加有关。 ^15-18重要的是，低剂量 POP 可以充当线粒体毒素。 ^{19, 20}

持久性有机污染物的毒理学动力学可以解释令人费解的发现，这些发现表明肥胖增加的好处，例如肥胖悖论。 ²¹持久性有机污染物等半衰期长的亲脂性化学物质一旦从外部暴露源进入人体，它们主要储存在脂肪组织中，并非常缓慢地释放到循环中以消除。 ²²从全身系统的角度来看，它可以被视为一种保护机制，因为脂肪组织可能是储存持久性有机污染物的最安全的地方。因此，如果人类接触相同水平的环境持久性有机污染物，拥有更多的脂肪组织可能是有益的，因为脂肪组织中持久性有机污染物的储存可以减轻对其他关键器官的负担。 ²¹

一些动物实验已经证明了脂肪组织对持久性有机污染物的保护作用。例如，饮食诱发的肥胖大鼠在暴露于致死剂量的 2,3,7,8-四氯二苯并-对-二恶英（持久性有机污染物中毒性最强的化合物）后，存活时间延长。 ²³此外，PCB 治疗仅在瘦小鼠中引起葡萄糖稳态受损，而在肥胖小鼠中则不然；然而，肥胖小鼠体重减轻会出现葡萄糖损伤。 ²⁴

此外，脂肪组织中的持久性有机污染物可以解释肺癌或其他癌症患者在诊断前、诊断中和诊断后出现无意体重减轻的较差预后。 ^25-27目前，这种现象有多种解释，例如治疗耐受性差、严重程度高、体能状态下降或合并症。然而，在减肥过程中，由于脂肪组织收缩，POPs会从脂肪组织释放到循环系统中，并且POPs释放量与体重减轻的程度成正比。 ²⁸因此，持久性有机污染物的动态变化可能是癌症患者无意体重减轻和不良预后之间的联系机制。

此外，即使是有意减肥也可能有意想不到的缺点，尽管通常建议超重或肥胖的人通过改变生活方式来有意减肥。例如，“糖尿病健康行动”（Look AHEAD）研究是一项大型随机对照试验，调查了强烈有意减肥对患有 2 型糖尿病的肥胖患者的影响，但没有报告有意减肥对糖尿病患者的任何长期益处。尽管有许多短期的好处，但心血管疾病或认知能力。 ^{29, 30}这种意想不到的后果可归因于有意减肥过程中观察到的 POP 动态。 ^{31, 32}值得注意的是，体重波动（有意减肥的常见结果）可能导致持久性有机污染物从脂肪组织重新分布到关键器官，正如动物实验研究中所观察到的那样。 ³³

脂肪组织在储存持久性有机污染物和其他环境污染物方面的作用可能并非微不足道，并且可以解释流行病学研究中观察到的许多关于肥胖的令人费解的发现。与流行的肥胖观念相反，脂肪组织可能是抵御亲脂性化学混合物可能产生的有害影响的第一道防线。如果脂肪组织的这种作用在癌症或其他慢性疾病患者中变得更加重要，那么肥胖悖论就可以解释。迫切需要研究脂肪组织和亲脂性化学混合物之间的相互关系。