Blumberg B
Department of Developmental and Cell Biology and Pharmaceutical Sciences, University of California, Irvine, Biological Sciences 3, Irvine, CA, USA.
J Dev Orig Health Dis. 2011 Feb;2(1):3-8. doi: 10.1017/S2040174410000589.
Obesity and metabolic syndrome diseases have exploded into a global epidemic. Consumption of calorie-dense food and diminished physical activity are the generally accepted causes for obesity. But, could environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The environmental obesogen model proposes that chemical exposure during critical developmental stages influences subsequent adipogenesis, lipid balance and obesity. Obesogens are chemicals that stimulate adipogenesis and fat storage or alter the control of metabolism, appetite and satiety to promote weight gain. Tributyltin (TBT) is a high-affinity agonistic ligand for the retinoid X receptor (RXR) and peroxisome proliferator activated receptor gamma (PPARγ). RXR-PPARγ signaling is a key component in adipogenesis and the function of adipocytes; activation of this heterodimer increases adipose mass in rodents and humans. Thus, inappropriate activation of RXR-PPARγ can directly alter adipose tissue homeostasis. TBT exposure promoted adipocyte differentiation, modulated adipogenic genes and increased adiposity in mice after exposure. These results suggest that organotin exposure is a previously unappreciated risk factor for the development of obesity and related disorders. Based on the observed effects of TBT on adipogenesis, we hypothesized that organotin exposure during prenatal adipose tissue development would create an environment that led to more adipocytes. We observed that the multipotent stromal cell compartment was altered by prenatal TBT exposure leading to an increased number of preadipocytes. This increase in the number of preadipocytes could correspondingly increase the steady state number of adipocytes in the adult, which could favor the development of obesity over time.
肥胖症和代谢综合征疾病已演变成一场全球流行病。高热量食物的摄入和身体活动的减少是公认的肥胖成因。但是，环境因素会否暴露已有的基因差异或加剧饮食和运动的根本原因呢？环境致肥胖物模型提出，在关键发育阶段接触化学物质会影响随后的脂肪生成、脂质平衡和肥胖。致肥胖物是刺激脂肪生成和脂肪储存或改变新陈代谢、食欲和饱腹感控制以促进体重增加的化学物质。三丁基锡（TBT）是维甲酸X受体（RXR）和过氧化物酶体增殖物激活受体γ（PPARγ）的高亲和力激动配体。RXR-PPARγ信号传导是脂肪生成和脂肪细胞功能的关键组成部分；这种异二聚体的激活会增加啮齿动物和人类的脂肪量。因此，RXR-PPARγ的不适当激活会直接改变脂肪组织的稳态。TBT暴露促进了小鼠脂肪细胞的分化，调节了脂肪生成基因并增加了脂肪量。这些结果表明，有机锡暴露是肥胖症及相关疾病发展中一个此前未被重视的风险因素。基于观察到的TBT对脂肪生成的影响，我们推测产前脂肪组织发育期间接触有机锡会营造一个导致更多脂肪细胞产生的环境。我们观察到，产前TBT暴露改变了多能基质细胞区室，导致前脂肪细胞数量增加。前脂肪细胞数量的这种增加可能相应地增加成年期脂肪细胞的稳态数量，随着时间的推移可能有利于肥胖症的发展。
