Adipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic target; however, there are no systematic studies of gene-by-environment interactions affecting function of this organ. We leveraged a weighted gene coexpression network analysis to identify transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high- or low-fat diets and correlate these networks with metabolic phenotypes. We identified eight primary gene network modules associated with variation in obesity and diabetes-related traits. Four modules were enriched for metabolically relevant processes such as immune and cytokine response, cell division, peroxisome functions, and organic molecule metabolic processes. The relative expression of genes in these modules is highly dependent on both genetic background and dietary environment. Genes in the immune/cytokine response and cell division modules are particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily dependent on diet and strain, with most genes showing both higher expression and coexpression under the same context. We highlight several genes of interest, Col28a1, Cyp26b1, Bmp8b, and Ngef, that have distinct expression patterns among strain-by-diet contexts and fall under metabolic quantitative trait loci previously mapped in an F16 generation of an advanced intercross between LG/J and SM/J. Each of these genes have some connection to obesity and diabetes-related traits, but have not been studied in brown adipose tissue. Our results provide important insights into the relationship between brown adipose and systemic metabolism by being the first gene-by-environment study of brown adipose transcriptional networks.

中文翻译：

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遗传背景和饮食影响与代谢表型相关的棕色脂肪基因共表达网络。


脂肪是一种动态的内分泌器官，对于调节新陈代谢至关重要，并且对营养环境高度敏感。棕色脂肪组织是一个令人兴奋的潜在治疗靶点；然而，目前还没有关于影响该器官功能的基因与环境相互作用的系统研究。我们利用加权基因共表达网络分析来识别来自喂食高脂肪或低脂肪饮食的 LG/J 和 SM/J 近交小鼠的棕色脂肪组织中的转录网络，并将这些网络与代谢表型相关联。我们确定了八个与肥胖和糖尿病相关性状变异相关的主要基因网络模块。丰富了代谢相关过程的四个模块，例如免疫和细胞因子反应、细胞分裂、过氧化物酶体功能和有机分子代谢过程。这些模块中基因的相对表达高度依赖于遗传背景和饮食环境。免疫/细胞因子反应和细胞分裂模块中的基因在高脂肪喂养的 SM/J 小鼠中特别高表达，这些小鼠表现出独特的棕色脂肪依赖性糖尿病缓解。这些模块中基因的互连性也严重依赖于饮食和菌株，大多数基因在相同的背景下表现出更高的表达和共表达。我们重点介绍了几个感兴趣的基因，Col28a1、Cyp26b1、Bmp8b 和 Ngef，它们在不同菌株的饮食环境中具有不同的表达模式，并且属于先前在 LG/J 和 LG/J 之间高级杂交的 F16 代中绘制的代谢数量性状位点。 SM/J。这些基因中的每一个都与肥胖和糖尿病相关特征有一定的联系，但尚未在棕色脂肪组织中进行研究。 我们的研究结果为棕色脂肪转录网络的第一个基因与环境研究提供了关于棕色脂肪与全身代谢之间关系的重要见解。