There is a pressing need for new therapeutic strategies for addressing the epidemic of obesity and its co-morbidities. Therefore, our lab aims to understand the molecular underpinnings of metabolic and cardiovascular disease and to identify new therapeutic targets for these highly prevalent diseases. We have developed and use a combination of mouse modeling, molecular biology, biochemical and genomic approaches to achieve this goal. One of our primary discovery platforms is mouse models of bariatric surgery. Bariatric surgery is defined as a surgical manipulation of the gut that is performed with the goal of body weight loss. However, bariatric surgery also produces cardiovascular and metabolic benefits that are independent of weight loss. Compelling work from our lab using mouse models of bariatric surgery has identified several new and exciting pathways that may prove useful in treating cardiometabolic disease. Specifically, our work in mouse bariatric models has led us to identify a new pathway regulating pancreatic islet function and a new pathway regulating bile acid metabolism that form two of the primary areas of research in our laboratory. These lines of research are described in further detail below:
Pancreatic islets are clusters of hormone-producing cells that orchestrate blood glucose regulation. Insulin is produced by islet beta cells and functions to decrease blood glucose. Glucagon is produced by islet alpha cells and functions to directly counter insulin action and increase blood glucose (Figure 1). While type 2 diabetes is classically thought to be due to a deficiency in insulin action, insulin-based therapeutics fail to cure this disease. Instead, we and others propose that glucagon excess is a key driver of type 2 diabetes, making it a compelling target for treatment. Using our mouse bariatric model, we have discovered a way to turn off production of the pro-diabetic hormone, glucagon, while simultaneously turning on an anti-diabetic hormone, glucagon-like peptide-1 (GLP-1), providing a potential therapeutic target that will bypass issues previously encountered with targeting glucagon action. Current studies are focused on using in vivo and in vitro techniques alongside untargeted proteomics, metabolomics and transcriptomics to define the physiology and biochemical mediators of this new pathway.
2. Bile Acid Metabolism
Bile acids are key regulators of metabolic homeostasis, and thus attractive therapeutic targets. Bile acids are synthesized in the liver and then metabolized by the gut microbiome (Figure 2). Our ongoing work seeks to define bile acid metabolic regulation in both of these compartments to enable targeting bile acids for the treatment of type 2 diabetes and cardiovascular disease.
Hepatic bile acid metabolism: We identified the bile acid receptor, TGR5, as a contributor to the glucoregulatory benefits of bariatric surgery. These studies used our mouse bariatric model to reveal a role for TGR5 in regulating gene expression to improve hepatic bile acid metabolism. Ongoing work aims to define the transcriptional and post-transcriptional regulation of the expression of genes involved in hepatic bile acid metabolism by TGR5.
Gut microbial bile acid metabolism: In parallel, we are performing studies investigating the mechanisms driving the metabolic benefits of dietary fiber (resistant starch) supplementation. Dietary resistant starch supplementation mimics many of the benefits of bariatric surgery which has prompted us to investigate the mechanisms by which dietary resistant starch supplementation improves glucose regulation as a complementary approach to our mouse bariatric modeling work. In particular, we are using dietary resistant starch supplementation as a model with which to understand gut microbial bile acid metabolism.