A long-term high fat diet induces differential gene expression changes in spatially distinct adipose tissues.

The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, mice were fed either a high fat or normal laboratory diet for 12-14 months. Mesenteric VAT and hindlimb SAT were isolated from four lean controls and four obese mice for bulk RNA- sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited a total of 308 differentially expressed genes (164 upregulated, 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated, 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT vs. downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/ upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT vs. VAT with obesity. Hindlimb subcutaneous adipose tissue and mestenteric visceral adipose tissue were isolated from lean and diet-induced obese WT C57Bl/6 mice. Obesity was induced by feeding a high fat (42% kcall saturated fat, 0.2% cholesterol) diet for 12-14 months. Lean controls were maintained on a normal rodent laboratory diet for the same duration. Diets were started at 10 weeks of age. We did gene expression profiling using 4 different adipose tissues samples (subcutaneous adipose tissue from lean mice, visceral adipose tissue from lean mice, subcutaneous adipose tissue from obese mice and visceral adipose tissue from obese mice). High fat diet-induced changes in VAT vs. SAT were evaluated via pair-wise analyses relative to corresponding lean mouse gene expression values.