Location: Children's Nutrition Research Center
Project Number: 3092-51000-064-02-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Sep 30, 2020
Objective 1: Use animal and cell culture models to investigate the interaction of various phospholipid species with the LRH-1 nuclear receptor, and determine the potential metabolic benefits to insulin resistance in obesity. Subobjective 1A: Combine biochemical and functional studies to identify specific endogenous PC species as LRH-1 agonist ligands. Subobjective 1B: Develop functional tests of the activity of endogenous LRH-1 agonists in mouse models of insulin resistance and diabetes. Objective 2: Use transgenic mice with liver specific knockout of the liver receptor homolog LRH-1 nuclear receptor to critically test its role as the potential mediator of the metabolic benefits of phosphatidylcholine agonist ligands in obesity. Confirmation of possible benefits will be through clinical trials in obese human subjects with insulin resistance. Subobjective 2A: Test the ability of both endogenous LRH-1 agonists and laurate supplementation to improve metabolic status in mouse models of obesity and insulin resistance. These studies will use both genetic loss of LRH-1 function in the liver and replacement of mouse LRH-1 with human LRH-1 to confirm the LRH-1 dependence of the beneficial effects of phospholipid or laurate supplementation. Subobjective 2B: Define optimal strategies for anti-diabetic effects of LRH-1 activation in mouse models and validate a therapeutic strategy appropriate for use in human studies. Objective 3: Study the role of circadian disruption induced selective leptin resistance in activation of the paraventricular nucleus-sympathetic axis. Subobjective 3A: Define the role of the chronic circadian disruption in sympathetic dysfunction. Subobjective 3B: Define the role of central clock dysfunction in obesity-related essential hypertension. Subobjective 3C: Define the role of the SCN clock in controlling the PVN-SNS axis. Objective 4: Define the role of circadian disruption induced selective leptin resistance in liver metabolic disorders and hepatocellular carcinoma risk. Subobjective 4A: Define the role of circadian dysfunction induced hepatic leptin resistance in NAFLD. Subobjective 4B: Define the role of circadian dysfunction induced hepatic leptin resistance in liver fibrosis. Subobjective 4C: Define the role of SNS circadian dysfunction in hepatic leptin resistance.
Obesity-related non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level world-wide. NAFLD is closely associated with obesity-related comorbidities, such as type 2 diabetes, and has also recently emerged as a direct driver of hepatocellular carcinoma (HCC). However, the mechanisms that induce NAFLD and link it to pathologic outcomes are poorly understood, and there are no approved medical treatments for NAFLD. We have reported that activation of the nuclear receptor LRH-1 by an exogenous non-natural phosphatidylcholine (PC) species, dilauroyl PC (DLPC), reduces liver fat accumulation and NAFLD-associated insulin resistance, and also that chronic circadian disruption induces leptin resistance, NAFLD, and HCC independent of other risk factors. We will study the role of endogenous PCs in the prevention and treatment of NAFLD and insulin resistance, and test the hypothesis that beneficial effects of these natural PCs are due to LRH-1 activation. We will also define the mechanism of circadian dysfunction-induced selective leptin resistance, and the role of sympathetic overdrive in NAFLD and NAFLD-associated liver fibrosis, which progresses to cirrhosis at advanced stages to promote liver failure and hepatocarcinogenesis. Our studies will lead to conceptual advances in our understanding of obesity-related NAFLD, type 2 diabetes, and HCC, and the development of novel therapeutic strategies for the prevention and treatment of NAFLD and its associated diseases.