Genetic background and diet affect brown adipose gene co-expression – metabolic associations

Abstract 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/cytkine 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 co-expression under the same context. We highlight 4 candidate genes, Col28a1, Cyp26b1, Bmp8b , and Kcnj14 , that have distinct expression patterns among strain-by-diet contexts and fall under metabolic QTL previously mapped in an F 16 generation of an advanced intercross between these two strains. Each of these genes have some connection to obesity and diabetes-related traits, but have not been studied in brown adipose tissue. 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 and introducing novel candidate genes for follow-up studies of biological mechanisms of action. Author Summary Research on brown adipose tissue is a promising new avenue for understanding and potentially treating metabolic dysfunction. However, we do not know how genetic background interacts with dietary environment to affect the brown adipose transcriptional response, and how this might affect systemic metabolism. Here we report the first investigation of gene-by-environment interactions on brown adipose gene expression networks associating with multiple obesity and diabetes-related traits. We identified 8 primary networks correlated with variation in these traits in mice, including networks enriched for immune and cytokine response, cell division, organic molecule metabolism, and peroxisome genes. Characterizing these networks and their distinct diet-by-strain expression and co-expression patterns is an important step towards understanding how brown adipose tissue responds to an obesogenic diet, how this response affects metabolism, and how this can be modified by genetic variation.