Adipose Tissue Inflammation, Oxidative Stress, and Altered Adipogenesis Are Drivers of Dyslipidemia - A Multi-Omics Overview of Dyslipidemia in Obesity

BackgroundObesity is an important risk factor for cardiometabolic disease including dyslipidemia and atherosclerotic cardiovascular disease. While the role of the liver in dyslipidemia is established, the contribution of adipose tissue is less clear. This study aims to clarify the role of adipose tissue in lipid metabolism and its impact on dyslipidemia development. MethodsWe conducted a cross-sectional analysis of 125 patients from the BARIA longitudinal cohort study, consisting of patients with obesity undergoing bariatric surgery. Comprehensive phenotyping with fasting untargeted plasma metabolomics and lipid, lipoprotein, adipokine, RNA sequencing, and fecal sample shotgun metagenomic analysis was performed. We then compared tissue transcriptomic and plasma metabolites in individuals with and without dyslipidemia, exploring protective and pathogenic mechanisms. ResultsDyslipidemia was present in 43 patients (34.4%), with elevations in triglycerides, ApoB, and reductions in HDL-C and ApoAI. Plasma adipokines were less reliable markers of dyslipidemia: leptin levels were unexpectedly reduced in dyslipidemia, and after adjusting for gender, age, and body weight, adipokines did not differ between patients with and without dyslipidemia. In relation to plasma lipids or dyslipidemia, RNA sequencing identified altered gene expression of liver, jejunum, visceral and subcutaneous adipose tissue. Adipose tissue of patients with dyslipidemia was characterized by gene alterations of 3 pathways: inflammation, oxidative stress, and adipogenesis. Untargeted plasma metabolomics revealed associations of plasma lipids with endocannabinoid-like, secondary bile acid, plasmalogen, butyrate, and sphingolipid metabolites. Gut metagenome analysis in dyslipidemia found only correlation on bacterial order level. ConclusionsThis study provides novel insights into the role of adipose tissue in dyslipidemia of obesity. Our findings highlight the importance of not only visceral, but also subcutaneous adipose tissue in regulating plasma lipids. We found that fasting dyslipidemia associated with adipose tissue inflammation, oxidative stress, and altered adipogenesis, providing new insights into metabolic regulation of plasma lipids beyond hepatic pathways.