PCBs worsen obesity/metabolic syndrome through 'toxic metabolic endotoxemia'

描述（由申请人提供）：68%的美国成年人超重或肥胖，超过1亿的美国人患有糖尿病或糖尿病前期。这些情况可能导致心血管疾病和癌症。最近的研究表明，多氯联苯（PCBs）是肥胖和糖尿病的持久性有机污染物，具有潜在的作用。多氯联苯以前用于电力变压器。尽管多氯联苯在30多年前就被禁止了，但它仍然存在于美国的食品供应和所有成年美国人体内。我们小组和其他人进行的初步研究表明，多氯联苯会导致“漏肠”，破坏肠道：肝脏：脂肪轴。随后，肠道衍生的细菌产物进入血液，引起炎症、肝脏疾病，并导致肥胖和糖尿病。我们称这个问题为“毒性代谢内毒素血症”。我们假设多氯联苯通过毒性代谢性内毒素血症与高脂肪或高碳水化合物饮食相互作用，加重肥胖和糖尿病；研究这一假设是这项资助的总体目标。这个新型营养：毒素相互作用转化项目的具体目的是：！！1)确定小鼠多氯联苯破坏肠道：肝脏：脂肪轴增加代谢性内毒素血症和加重饮食性肥胖/胰岛素抵抗的机制。2)确定细胞受体在小鼠和细胞培养模型中与多氯联苯相关的毒性代谢内毒素血症中的潜在作用。3)研究大量高接触多氯联苯人群储存血液样本中毒性代谢性内毒素血症的机制。我们期望在小鼠和人类中发现多氯联苯激活受体，扰乱肠道：肝脏：脂肪轴，并通过毒性代谢性内毒素血症加重肥胖/糖尿病。这个创新的项目是第一个研究肥胖/糖尿病中多氯联苯相关的内毒素血症，并有望导致对这些疾病的新认识。这项建议与所有暴露在环境污染中的超重/肥胖人群有关。

DESCRIPTION (provided by applicant): 68% of US adults are either overweight or obese, and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs), which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago, PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a "leaky gut" to disrupt the gut:liver:adipose axis. Subsequently, intestinal-derived bacterial products enter the bloodstream causing inflammation, liver disease and contribute to obesity and diabetes. We call this problem "toxic-metabolic endotoxemia". We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to:!! 1) Determine in mice, mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors, perturb the gut:liver:adipose axis, and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.