Retinoid X receptor activation during adipogenesis of female mesenchymal stem cells programs a dysfunctional adipocyte

Early life exposure to endocrine disrupting chemicals (EDCs) is an emerging risk factor for the development of obesity and diabetes later in life. We previously showed that prenatal exposure to the EDC tributyltin (TBT) results in increased adiposity in the offspring. These effects linger into adulthood and are propagated through successive generations. TBT activates two nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ) and its heterodimeric partner retinoid X receptor (RXR), that promote adipogenesis in vivo and in vitro. We recently employed a mesenchymal stem cell (MSC) model to show that TBT promotes adipose lineage commitment by activating RXR, not PPARγ. This led us to consider the functional consequences of PPARγ versus RXR activation in developing adipocytes.We used a transcriptomal approach to characterize genome-wide differences in MSCs differentiated with the PPARγ agonist rosiglitazone (ROSI) or TBT. Pathway analysis suggested functional deficits in TBT-treated cells. We then compared adipocytes differentiated with ROSI, TBT, or a pure RXR agonist IRX4204 (4204). Our data show that RXR activators (‘rexinoids’, 4204 and TBT) attenuate glucose uptake, blunt expression of the anti-diabetic hormone adiponectin, and fail to down-regulate pro-inflammatory and pro-fibrotic transcripts as does ROSI. Finally, 4204 and TBT treatment results in an inability to induce markers of adipocyte browning, in part due to sustained interferon signaling. Taken together, these data implicate rexinoids in the development of dysfunctional white adipose tissue that could potentially exacerbate obesity and/or diabetes risk in vivo. These data warrant further screening and characterization of EDCs that activate RXR.

生命早期暴露于内分泌干扰化学物（endocrine disrupting chemicals, EDCs）是日后罹患肥胖与糖尿病的新兴风险因素。本团队前期研究证实，产前暴露于内分泌干扰化学物三丁基锡（tributyltin, TBT）可导致子代脂肪量增加，该效应可持续至成年期且可跨代传递。三丁基锡可激活两种核受体——过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ, PPARγ）及其异二聚体伴侣维甲酸X受体（retinoid X receptor, RXR），二者在体内外均可促进脂肪生成。近期我们借助间充质干细胞（mesenchymal stem cell, MSC）模型证实，三丁基锡通过激活RXR而非PPARγ促进脂肪谱系定向分化，这促使我们探究脂肪细胞发育过程中PPARγ与RXR激活所产生的功能性差异。我们采用转录组学方法，对经PPARγ激动剂罗格列酮（rosiglitazone, ROSI）或三丁基锡诱导分化的间充质干细胞开展全基因组表达差异分析，通路富集分析显示三丁基锡处理的细胞存在功能缺陷。随后我们对比了经罗格列酮、三丁基锡或纯RXR激动剂IRX4204（简称4204）诱导分化的脂肪细胞。研究数据表明，维甲酸X受体激动剂类（rexinoids，涵盖4204与TBT）会减弱葡萄糖摄取、抑制抗糖尿病激素脂联素的表达，且无法像罗格列酮一样下调促炎与促纤维化转录本。最终，4204与三丁基锡处理会导致脂肪细胞褐变标志物无法被诱导，这在一定程度上源于干扰素信号的持续活化。综上，本研究数据表明维甲酸X受体激动剂类化合物可诱导功能异常的白色脂肪组织生成，可能在体内加剧肥胖或糖尿病风险，上述结果提示需对激活RXR的内分泌干扰化学物开展进一步的筛选与表征。