Defining the pathways of cardiometabolic health after weight loss

PROJECT SUMMARY Cardiovascular disease (CVD) and Type 2 diabetes (T2D) are leading causes of morbidity and mortality impacting individuals across all ethnic groups in the US. CVD and T2D are largely driven by the rising prevalence of obesity, but also impacted by genetics and environmental exposures. Weight loss surgery (WLS) is a safe effective treatment that can sustainably reduce CVD risk and T2D incidence, but the underlying mechanisms are not well understood. Sleeve gastrectomy is currently more popular WLS procedure, but growing evidence shows that sustained improvement of higher magnitude is achieved with Roux-en-Y gastric bypass (RYGB). Hence, RYGB is a useful model to study biomarkers and/or pathways of metabolic risk improvement in a high-risk population. Although surgical changes are made to the gut anatomy, the body weight “set point” is lowered, long- term weight and cardiometabolic disease risk are reduced, albeit with a range of success among individuals. Human and animal studies have shown that changes in hormones, bile acids, diet, gut tissue expression and the microbiome are conveyed to metabolically relevant organs and can provide clues on the pathways of improved cardiometabolic health post-WLS. Because no single critical change has been identified so far, it is possible that multiple parallel pathways convey the signals via the circulation. Metabolites are small molecules determined by the integration of genomic, epigenetic, transcriptomic, and proteomic variation, while being responsive to environmental factors such as diet, gut microbiota, xenobiotics, and other exposures. Metabolites such as branched-chain amino acids, monounsaturated fatty acids, and phosphatidylcholines are known markers of increased CVD risk and T2D, but markers of risk reduction are not yet well characterized. For Aim 1 of the proposed project, we will identify the markers associated with CVD risk reduction and T2D resolution in a large cohort (~1000) of individuals with RYGB from the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) study 1 year after RYGB. Integrated analysis of differentially expressed metabolites and genes from human gut transcriptome before and after RYGB will identify gut specific changes. For Aim 2, we will assess the markers of sustained CVD and T2D risk reduction at 1 and 5 years after surgery and validate them in subjects with metabolite data before and after medical or surgical weight loss. For Aim 3, we will identify the causal role of known and newly identified metabolites and/or associated pathways with cardiometabolic health by mendelian randomization. This unprecedented integration of genetics, metabolomics, transcriptomics, and clinical data in WLS will lead to identification of biomarkers, pathways and causal links that may help devise novel non-surgical methods to improve cardiometabolic health or preventive strategies with broad public health implications.