The CMDRC supports three major research projects and several pilot research projects of junior investigators who focus on cardiovascular, renal and metabolic diseases, which are the leading causes of mortality and morbidity in the United States, especially in Mississippi which has the highest prevalence in the nation of these diseases.
The CMDRC has assembled a unique team of junior investigators who have previous research experience in obesity, cardiorenal or metabolic diseases, strong records of research productivity, and an excellent scientific background. The team of junior investigators work together in an integrated environment to translate findings from the bench to bedside to significantly impact the epidemic of obesity in the nation. This focused, in-depth research experience promotes continued growth of their research programs and lays the foundation for them to successfully compete for NIH funding.
Obesity is a significant contributor to cardiometabolic diseases including hypertension, non-alcoholic fatty liver disease (NAFLD) and type II diabetes. All of these conditions contribute to the increased morbidity and mortality rates of obesity. Large population studies have demonstrated a negative correlation between serum bilirubin levels and development of cardiovascular disease and metabolic disorders including NAFLD and type II diabetes. Despite these correlative studies, the mechanism by which bilirubin protects against cardiometabolic disease is not known. We have exciting data demonstrating for the first time that bilirubin signals through nuclear hormone receptors such as peroxisome proliferator-activated receptor (PPARa) to protect against cardiometabolic disorders. In addition, bilirubin can also inactivate glycogen synthase kinase-3b (GSK3b) to increase PPARa target genes such as fibroblast growth factor 21 (FGF21); however, the specific roles of GSK3b inactivation/PPARa activation to the anti-hypertensive, anti-steatotic and anti-diabetic actions of moderate hyperbilirubinemia are not known. Biliverdin reductase (BVR) is the enzyme responsible for reduction of biliverdin to bilirubin. It can generate bilirubin found in the plasma and generated inside the cell. The goal of this proposal is to test the central hypothesis that bilirubin and BVRA protect against obesity-induced hepatic steatosis, insulin resistance and hypertension via activation of the PPARa signaling axis. Aim 1 will test the hypothesis that chronic moderate hyperbilirubinemia resulting from bilirubin treatment or antagonism of hepatic UGT1A1 lowers blood pressure and reverses dietary obesity-induced hepatic steatosis and hepatic insulin resistance. Aim 2 will test the hypothesis that moderate hyperbilirubinemia lowers blood pressure and reverses hepatic steatosis and insulin resistance via activation of PPARa. Aim 3 will test the hypothesis that that specific loss of hepatic bilirubin generation enhances hepatic steatosis and insulin resistance through a GSK3b mediated pathway that decreases PPARa activity. Findings of these studies will have profound implications on development of moderate hyperbilirubinemia as a novel therapy for treatment of obesity-induced cardiometabolic disease. These studies will also determine the novel role of bilirubin as a nuclear hormone receptor signaling molecule and the role of this mechanism in protection against obesity-induced cardiometabolic diseases such as hypertension, NAFLD and type II diabetes.
Obesity is a major risk factor for hypertension and chronic kidney disease. In experimental studies of obesity, weight gain is associated with increased renal sodium reabsorption and elevated blood pressure. One potential mechanism by which obesity may contribute to renal dysfunction and hypertension is through compressive effects of fat in and around the kidneys. This perirenal and renal sinus fat may compress the loops of Henle in the renal medulla and increase renal medullary fractional sodium reabsorption. This increase in sodium reabsorption would increase oxygen consumption and decrease tissue oxygen levels which can be assessed with non-contrasted blood oxygen level dependent (BOLD) magnetic resonance (MR) using a furosemide stimulus.
Early, pre-clinical renal injury is difficult to assess, particularly renal medullary injury and dysfunction. We will evaluate a comprehensive MR strategy to determine if surgical weight loss after bariatric surgery (vertical sleeve gastrectomy) improves subclinical renal medullary injury and dysfunction using several non-contrasted MR techniques including renal perfusion (arterial spin labeling and phase contrast MR), renal tissue oxygenation response to a furosemide stimulus (BOLD MR), and renal fibrosis (native T1 mapping). We will specifically evaluate if perirenal and renal sinus fat volumes (and subsequent reductions in volumes measured with MR) are associated with MR-derived measures of altered renal medullary function and renal fibrosis using these techniques. We will also assess whether reductions in specific fat depots after vertical sleeve gastrectomy are independently associated with improvement in measures of subclinical renal dysfunction beyond other traditional measures of adiposity. We will also determine relationships of perirenal and renal sinus fat (and subsequent reductions after bariatric surgery) and markers of sympathetic nervous activity, renin-angiotensin-aldosterone system activity and inflammation to provide further mechanistic insights into the link between perinephric fat and renal dysfunction. To achieve these aims, we will perform a comprehensive MR-imaging exam in 50 obese hypertensive and 50 obese non-hypertensive participants before and 1 and 2 years after vertical sleeve gastrectomy.