Adipose Depot‐Specific Differences in Transcriptome and MicroRNA Expression in High Fat Diet Induced Obese Mice

Abstract

Obesity is characterized by white adipose tissue (WAT) expansion which contributes to chronic diseases such as diabetes and cardiovascular disease. Two main types of adipose tissue are WAT (subcutaneous, SAT and visceral adipose tissue, VAT) and brown adipose tissue (BAT). These exhibit anatomical, physiological and metabolic differences that contributes to energy balance, metabolic regulation and immunity. Our aim was to compare transcriptomic and microRNA (miRNA) signatures of SAT, VAT and BAT to gain mechanistic insight into the role of these depots in metabolic disorders. We performed RNA‐sequencing and miRNA profiling of SAT, VAT and BAT depots from diet‐induced obese C57BL/6J male mice fed high fat diets (45% kcal fat). We used a transcriptomic approach to dissect adipose depot‐specific genetic and functional signatures in obesity. RNA sequencing was performed using Illumina Hi‐Seq and differential gene expression was studied by pair wise comparisons of fat depots. Functional and pathway analyses performed using Ingenuity® Pathway Analysis software revealed inflammatory pathways such as cytokine and integrin signaling increased along with immune‐related processes in VAT compared to BAT. In contrast, pathways involved in fatty acid oxidation, apoptosis and energy expenditure (peroxisome proliferator activated receptor (Ppar)/retinoid X receptor (Rxr‐α)) were higher in BAT than in VAT. X‐box binding protein‐1 (Xbp1), an unfolded protein response (UPR) mediator in endoplasmic reticulum (ER) stress, was a common upstream regulator that was consistently activated in both VAT and SAT in comparison to BAT. Xbp‐1 targets include ER related genes such as glucose‐regulated protein 78 and 94 (Grp78, Grp94), calreticulin, protein disulfide isomerase family A 3 and 6 (Pdia3 and Pdia6) all of which showed higher expression in VAT than BAT. Interestingly, miR‐30c‐2‐3p which causes downregulation of Xbp1 was lower in VAT than in BAT, in agreement with higher Xbp1 levels in VAT compared to BAT. Furthermore, other miRNA‐mRNA pairs involved in UPR such as miR‐455‐calreticulin were also identified. Additionally, miRNAs miR‐221‐3p and miR‐222‐3p, related to higher inflammation and ER stress were activated in VAT compared to BAT, suggesting more inflammation and ER stress in VAT compared to BAT as expected. In summary, high fat diets differentially regulate specific miRNAs and gene expression in different adipose tissue depots with significant induction of ER stress and inflammation in VAT. Currently, studies are ongoing to validate these findings which would provide insight into the contribution of different fat depots to various metabolic pathways and will potentially impact various diseases associated with obesity.Support or Funding InformationStartup funds from TTU