As noted by Lee et al. in this issue, persistent organic pollutants (POPs) released from adipose during weight loss in type 2 diabetic (T2DM) patients may attenuate cardiovascular (CV) benefits^[1^] that should accompany >5% weight reduction and concomitant fall in CV disease risk factors.^[2^] POP contributions to CV complications is a valuable and timely topic to explore, given the slow rate of POP elimination from the food chain and epidemiological evidence that low dose POPs are additional risk factors for metabolic^[3^] and CV diseases.^[4^]

POPs are toxic, lipophilic, semi‐volatile chemicals containing highly stable halogen–carbon bonds not found in nature. They are ubiquitous in the environment, bioaccumulative, and hard to eliminate. They “biomagnify” and act as endocrine disruptors, altering thyroid and steroid hormone transport and signaling, and activate transcription factors central to energy balance regulation. They impair immune and reproductive function and development, and induce inflammation and mitochondrial dysfunction. Humans rarely accumulate high enough levels to experience the worst effects; however, POPs are increasingly recognized as risk factors in metabolic disease.^[3^] Although POPs are often presumed benign once sequestered inside adipocyte lipid droplets, POPs can change adipose phenotype and thus alter fat tissue function, potentially contributing to weight (re)gain through stimulation of adipogenesis and chronic inflammation. POPs can induce insulin resistance and impair pancreatic function, which may exacerbate T2DM. During weight loss, POPs are selectively mobilized from adipose, such that more polar POPs are released into the blood. Hydroxylation then makes POPs easier to excrete, but can increase toxicity and mobility, thus increasing exposure and potential damage to non‐fatty tissues. T2DM patients may be most vulnerable to POP effects through uncontrolled lipolysis, which facilitates greater POP mobilization. Causal impacts of POPs on obesity and T2DM are hard to quantify and test because their levels change dynamically with fat mass,^[3^] and hence intervention studies are vital in order to investigate their role in exacerbating metabolic and CV disease.

Caloric restriction and low‐fat diets for T2DM patients target improved glycemic control and sustained and modest weight loss. While increased consumption of seafood can help in weight management, contaminants therein may offset other benefits.^[5^] A moderate, rather than low‐fat, and largely plant‐based diet with intermittent fasting or caloric restriction is envisaged by Lee et al.^[1^] to facilitate biliary POP excretion, provide protective phytochemicals that induce or enhance cellular defense mechanisms, and reduce POP intake through avoidance of animal‐derived fats. Such POP‐targeted interventions may have additional benefits, such as reducing pancreatic damage and insulin resistance.

Several practical challenges exist. First, the tasks of assessing which POPs, congeners, and mixtures are most problematic—and which to measure to identify effects and ensure studies are comparable—is complicated by the range of compounds involved, the correlation in their levels, variation in biological effects, and “cocktail” effects of POP mixtures with additional chemicals.^[3^] Second, short‐term dietary interventions may not rapidly change legacy chemicals with decadal half‐lives in adipose. Slow POP clearance may require protracted measurement time courses and long‐term diet adherence. Third, if POP‐mediated CV damage has already occurred, intervention benefits may be hard to identify.

Challenges notwithstanding, important clinical insights could arise from quantifying the role of POPs in preventing CV benefits of weight loss, including determining whether POPs can be reduced effectively using dietary interventions, teasing out POP‐mediated health effects, and identifying T2DM patients who would benefit most from POP reduction to provide tailored weight management.

如Lee等人所述。在此问题中，2型糖尿病（T2DM）患者减肥期间从脂肪中释放出的持久性有机污染物（POPs）可能减弱心血管（CV）的益处^[ 1 ^]，体重减轻超过5％并伴随CV疾病危险因素的降低。^[ 2 ^] POP对CV并发症的贡献是一个有价值且及时的话题，因为从食物链中消除POP的速度很慢，并且流行病学证据表明低剂量的POPs是代谢^[ 3 ^]和CV疾病的附加危险因素。^[ 4 ^]

POPs是有毒的，亲脂性的半挥发性化学物质，含有自然界中未发现的高度稳定的卤素-碳键。它们在环境中无处不在，具有生物蓄积性，并且很难消除。它们“生物放大”并充当内分泌干扰物，改变甲状腺和类固醇激素的转运和信号传导，并激活对能量平衡调节至关重要的转录因子。它们损害免疫和生殖功能和发育，并引起炎症和线粒体功能障碍。人类很少积累足够高的水平来经历最坏的影响。然而，持久性有机污染物越来越被认为是代谢疾病的危险因素。^[ 3 ^]尽管POPs一旦被隔离在脂肪细胞脂质滴中通常被认为是良性的，但是POPs可以改变脂肪表型，从而改变脂肪组织的功能，可能通过刺激脂肪形成和慢性炎症来增加体重。POPs可以诱导胰岛素抵抗并损害胰腺功能，从而加剧T2DM。在减肥过程中，POPs从脂肪中有选择地迁移，从而更多的极性POPs释放到血液中。羟基化使POPs更容易排泄，但会增加毒性和流动性，从而增加对非脂肪组织的暴露和潜在损害。T2DM患者可能最容易通过不受控制的脂解作用而受到POP的影响，这将促进更大的POP动员。^[ 3 ^]，因此干预研究对于调查其在加剧代谢和CV疾病中的作用至关重要。

T2DM患者的热量限制和低脂饮食的目标是改善血糖控制以及持续适度的体重减轻。虽然增加海鲜消费量可以帮助减轻体重，但其中的污染物可能会抵消其他好处。^[ 5 ^] Lee等人设想了一种中等，而不是低脂，主要是植物性饮食，且禁食或热量限制断断续续。^[ 1 ^]促进胆汁POP的排出，提供诱导或增强细胞防御机制的保护性植物化学物质，并通过避免动物源性脂肪来减少POP的摄入。此类针对POP的干预措施可能具有其他好处，例如减少胰腺损伤和胰岛素抵抗。

存在一些实际挑战。首先，评估所涉及的POPs，同类物和混合物最成问题的方法，以及评估哪种POPs，同类物和混合物以确保研究结果具有可比性的任务，由于涉及的化合物范围，其水平之间的相关性，生物学效应的变化， POP混合物与其他化学物质的“鸡尾酒”效应。^[ 3 ^]其次，短期饮食干预可能不会迅速改变具有十年半衰期的脂肪的传统化学物质。缓慢的POP清除可能需要延长测量时间和长期饮食习惯。第三，如果POP介导的简历损坏已经发生，则可能难以确定干预的益处。

尽管面临挑战，但量化POPs在预防体重减轻的心血管益处中的作用可能会产生重要的临床见解，包括确定是否可以通过饮食干预措施有效降低POPs，缓解POP介导的健康影响以及确定最能使患者受益的T2DM患者从减少POP到提供量身定制的体重管理。