Metabolic Health with Obesity: A Novel Role for Cholesteryl Ester Transfer Protein

Abstract

Obesity is an increasingly prevalent condition that increases risk factors for type-2 diabetes and heart disease. Weight loss reverses the complications of obesity. Long-term maintenance of weight loss, however, is difficult. Mechanisms that improve metabolic health in obese people are therefore attractive targets for study. In my dissertation work, I have identified a novel role for Cholesteryl Ester Transfer Protein (CETP) to protect female mice against insulin resistance and exercise intolerance caused by obesity. CETP is a lipid transfer protein that shuttles lipids between lipoproteins, culminating in delivery of cholesterol esters to the liver for secretion as bile. Bile acids are known to have insulin-sensitizing effects. Mice naturally lack CETP expression. I discovered that female mice transgenic for CETP were protected from high fat diet-induced insulin resistance. This effect was modest in males. In female mice I found activation of bile acid signaling pathways in liver and muscle as well as increased glucose rate of disappearance and increased muscle glycolysis. These results suggest that CETP can ameliorate insulin resistance associated with obesity in female mice by promoting muscle glucose utilization. Based on the observations of improved muscle function in the CETP mice, I hypothesized that CETP could improve exercise capacity by increasing muscle oxidative metabolism. While there is no difference in exercise capacity between lean, chow fed CETP-expressing mice and their non-transgenic littermates, CETP-expressing female mice are protected against the decline in exercise capacity caused by obesity. This improvement in exercise capacity corresponded with increased mitochondrial oxidative capacity. My dissertation work has demonstrated a novel role for CETP to promote metabolic health in obese animals potentially through its effect on bile acid signaling to muscle. I propose that targeting bile acid signaling pathways could promote metabolic health in obese people. The sexual dimorphism observed adds to the growing body of evidence that CETP likely has a positive impact on metabolism in females. Further understanding the role of CETP and bile acid signaling will help to provide new strategies for promoting metabolic health in obese people.