Our research centers on the mechanisms whereby hydrophobic lipid molecules regulate nutrient metabolism and energy homeostasis. We seek to identify new molecular targets that could be leveraged in the management of obesity and its common metabolic complications, including non-alcoholic fatty liver disease and type 2 diabetes.
Our interests include the role of steroidogenic acute regulatory transfer related (START) domain proteins in lipid and glucose metabolism. START domains bind hydrophobic ligands, including phospholipids, cholesterol and fatty acids. The laboratory has described novel roles for lipid-binding START domain proteins in metabolic control within the liver, as well as in whole body energy homeostasis.
We have demonstrated that the START domain protein StarD2, also know as phosphatidylcholine transfer protein (PC-TP) plays a critical role in governing hepatic insulin sensitivity. We have demonstrated that Pctp-/- mice are sensitized to hepatic insulin action, are relatively resistant to the development of type 2 diabetes and atherosclerosis, and exhibit more efficient brown fat-mediated thermogenesis. Milestones in this research have included cloning and characterization of the Pctp gene, expression of recombinant protein and detailed structure-function analyses, studies of cellar function, solving the crystal structure of PC-TP, identification of key PC-TP-interacting proteins and detailed phenotyping of Pctp-/- mice. We have shown the fatty acyl-CoA thioesterase superfamily member 2 (Them2) is an interacting partner of PC-TP and is activated upon binding PC-TP. We have further demonstrated that Them2 in turn plays a key role in regulating hepatic lipid and glucose metabolism, as well as energy homeostasis. Our studies suggest that a complex of Them2–PC-TP suppresses insulin signaling by reducing the activation of insulin receptor substrate 2 (IRS2), as well as by stabilizing the tuberous sclerosis 1 (TSC1)–TSC2 complex, which suppresses mTOR activity. We have gone on to identify small molecule inhibitors of PC-TP and to demonstrate their efficacy in a mouse model of type 2 diabetes. Our research suggests that PC-TP functions as a sensor of membrane phosphatidylcholine composition, which in turn regulates lipid and glucose metabolism.
In separate studies, we have demonstrated that StarD14 (synonym Them1), which is highly enriched in brown adipose tissue, plays a major role in regulating energy homeostasis. Mice lacking Them1 are highly resistant to diet-induced obesity, diabetes and inflammation. We have proposed that Them1 functions as a fatty acid sensor that controls energy expenditure in brown adipose tissue by limiting access of free fatty acids to mitochondria and by reducing thermogenic gene expression.
Most recently, we have begun to identify a key role for the gut microbiome in regulating thermogenesis and energy expenditure in mice. These studies are beginning to define how adaptations to varying ambient temperatures affect the microbiome composition, and how this in turn regulates body weight and nutrient metabolism.