Hormone and nutrient signaling coordinate various aspects of organismal physiology. Our lab focuses on the hormone insulin, which is a potent anabolic molecule that controls many metabolic processes. Importantly, abnormalities in insulin action underlie a host of metabolic diseases such as diabetes, obesity and cancer. Specifically, our lab is interested in the role that the PI3K-Akt-mTORC1 pathway plays in coordinating insulin’s cellular response. In recent years, we have focused on the role of insulin in controlling lipid and glucose metabolism We will continue to build upon these studies and through detailed mechanistic-based studies; we aim to define molecular mechanisms responsible for the cellular control of cell growth, lipid biosynthesis and export, and glucose metabolism. Please see below for a more detailed description of the current projects in the lab.
Regulation of glucose metabolism and Growth by skeletal muscle AKT signaling
Insulin resistance is considered to be the principal factor underlying several metabolic diseases including type II diabetes mellitus. However, despite decades of investigation, critical knowledge gap remains in the identification of the underlying organs and molecular mechanisms that are responsible for the initiation and propagation of insulin resistance. Since, skeletal muscle is the predominant site of insulin-mediated glucose uptake in the postprandial state, a reduction in the insulin signaling pathway of diabetic skeletal muscle is widely considered to be the primary cause of postprandial hyperglycemia. Importantly, reduction in the activity of the serine/threonine kinase AKT, which is central to insulin action, is observed in muscle from insulin-resistant mice and humans, suggesting the critical role of skeletal muscle AKT activity in glucose homeostasis and muscle function. This project aims to understand the direct requirement of skeletal muscle AKT signaling on systemic glucose metabolism and muscle physiology. Recently, we made the surprising discovery that while skeletal muscle AKT is required for muscle growth and function, it is not an obligate intermediate for insulin-stimulated glucose uptake in all conditions. Current experiments are underway to define the signaling pathways mediating this AKT-independent control of insulin sensitivity in muscle. Additionally, our laboratory is performing experiments to define the AKT-dependent signals controlling muscle growth, mitochondrial function, and exercise performance.
Control of hepatic phosphatidylcholine synthesis and VLDL-TAG secretion by mTORC1
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are recognized as leading causes of liver dysfunction worldwide. Currently, there are no FDA approved medical treatments for NAFLD and NASH. NAFLD pathogenesis is closely correlated with obesity, insulin resistance, and type 2 diabetes mellitus. In the liver, insulin regulates hepatic lipid homeostasis by increasing triacylglyceride (TAG) synthesis, suppressing fatty acid breakdown, and promoting TAG export via very low-density lipoproteins (VLDL). VLDL-TAG secretion from the liver is controlled by the biosynthesis of phosphatidylcholine (PC), the main phospholipid coating lipoproteins. Defects in PC synthesis lead to decreased VLDL-TAG secretion and ultimately, hepatic steatosis. Our lab recently demonstrated that downstream of insulin signaling, the mechanistic target of rapamycin complex 1 (mTORC1) controls VLDL-TAG secretion through regulating CCTα, the rate-limiting enzyme in PC synthesis. Current experiments in our laboratory aim to define the role of mTORC1 in phosphorylation of CCTα as a critical step in controlling CCTα activity, thus regulating hepatic PC synthesis and TAG export. Ongoing studies utilize in vivo systems to determine the role of mTORC1-dependent hepatic TAG metabolism in the initiation and progression of NAFLD/NASH.
Evaluating the role for glucokinase and its regulatory protein in regulating hepatic metabolism
Glucokinase (Gck) is a robust insulin-target gene and is the primary glucose-sensing enzyme in the liver. Gck is responsible for converting glucose into glucose-6-phosphate so it can be utilized by the liver either for energy or stored for later use. Gck drives hepatic glucose uptake when stimulated by insulin and glucose during feeding and is inactivated and sequestered in the nucleus by Glucokinase Regulatory Protein (GKRP). This regulatory mechanism helps the liver alter its glucose homeostasis to fit the needs of the rest of the body. In addition to their traditional roles in regulating hepatic glucose homeostasis, there is also growing evidence that both proteins contribute to lipid homeostasis as well. The use of Gck activating drugs to lower high blood glucose in diabetic patients often results in hyperlipidemia, hypercholesterolemia, or fatty liver. Likewise, GWAS studies identified several mutations in GKRP to be highly correlated with increased plasma triglyceride levels. Using sophisticated genetic mouse models, we are investigating the mechanisms by which Gck and GKRP regulate hepatic lipid and cholesterol metabolism.
Investigating the control of adipose tissue function by liver insulin signaling
Obesity correlates with an increase in metabolic disorders such as insulin resistance. It has been shown that during an obese or insulin-resistant state the adipose tissue becomes resistant to catecholamine response, causing a decrease in energy expenditure and promoting weight gain. Our lab has shown that insulin signaling in the liver via the AKT-FOXO1 axis is a key regulator of systemic insulin sensitivity and adipose tissue metabolism. Studies are underway to define the cell non-autonomous mechanism mediating liver-adipose tissue crosstalk and the regulation of fat metabolism.