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

Abstract

28 Adipose is a dynamic endocrine organ that is critical for regulating metabolism and is highly 29 responsive to nutritional environment. Brown adipose tissue is an exciting potential therapeutic 30 target, however there are no systematic studies of gene-by-environment interactions affecting 31 function of this organ. We leveraged a weighted gene co-expression network analysis to identify 32 transcriptional networks in brown adipose tissue from LG/J and SM/J inbred mice fed high or low 33 fat diets, and correlate these networks with metabolic phenotypes. We identified 8 primary gene 34 network modules associated with variation in obesity and diabetes-related traits. Four modules 35 were enriched for metabolically relevant processes such as immune and cytokine response, cell 36 division, peroxisome functions, and organic molecule metabolic processes. The relative 37 expression of genes in these modules is highly dependent on both genetic background and 38 dietary environment. Genes in the immune/cytokine response and cell division modules are 39 particularly highly expressed in high fat-fed SM/J mice, which show unique brown adipose-40 dependent remission of diabetes. The interconnectivity of genes in these modules is also heavily 41 dependent on diet and strain, with most genes showing both higher expression and co-expression 42 under the same context. We highlight 4 candidate genes, Col28a1, Cyp26b1, Bmp8b, and Kcnj14, 43 that have distinct expression patterns among strain-by-diet contexts and fall under metabolic QTL 44 previously mapped in an F 16 generation of an advanced intercross between these two strains.45 Each of these genes have some connection to obesity and diabetes-related traits, but have not 46 been studied in brown adipose tissue. In summary, our results provide important insights into the 47 relationship between brown adipose and systemic metabolism by being the first gene-by-48 environment study of brown adipose transcriptional networks and introducing novel candidate 49 genes for follow-up studies of biological mechanisms of action.50 51 52 3 53 Author Summary 54 Research on brown adipose tissue is a promising new avenue for understanding and potentially55 treating metabolic dysfunction. However, we do not know how genetic background interacts with 56 dietary environment to affect the brown adipose transcriptional response, and how this might 57 affect systemic metabolism. Here we report the first investigation of gene-by-environment 58 interactions on brown adipose gene expression networks associating with multiple obesity and 59 diabetes-related traits. We identified 8 primary networks correlated with variation in these traits in 60 mice, including networks enriched for immune and cytokine response, cell division, organic 61 molecule metabolism, and peroxisome genes. Characterizing these networks and their distinct 62 diet-by-strain expression and co-expression patterns is an important step towards understanding 63 how brown adipose tissue responds to an obesogenic diet, how this response a...