Genetic background and diet affect brown adipose gene co-expression networks associated with metabolic phenotypes.

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 co-expression 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 8 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 dependent on diet and strain, with most genes showing both higher expression and co-expression 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 QTL previously mapped in an F generation of an advanced intercross between LG/J and SM/J. In summary, 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.