Our Work
Overview:
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.
Current Projects:
Improving functional and metabolic outcomes of weight loss via blockade of ActRII
The development of GLP-1 receptor agonists (GLP-1RAs) for weight loss is a breakthrough in pharmacological intervention for obesity. GLP-1RAs induce significant reductions in body weight through suppressing appetite and food intake, and this weight loss is driven by loss of both fat and lean mass. Skeletal muscle mediates whole-body glucose homeostasis and is necessary for skeletomuscular function. These reductions in muscle mass are a particular point of concern for aged individuals who are already prone to age-related muscle loss. Low muscle mass is also an independent risk factor for mortality driven by cardiovascular disease, especially in individuals with obesity. A novel treatment strategy that protects against loss of lean mass could improve the longevity of weight loss and offer metabolic and functional benefits. TGFβ-like ligands such as myostatin and activin A are negative regulators of skeletal muscle mass which signal via the activin type II receptors A and B (ActRII) to stimulate atrophy. Pharmacological inhibition of ActRII not only significantly increases muscle mass but also reduces fat mass and improves insulin sensitivity in both obese mice and humans, suggesting that both muscle and adipose tissue homeostasis are affected by this pathway—although whether effects in each tissue are cell-autonomous or if there is interplay between the two is unclear. We have recently demonstrated that obese mice treated with both an anti-ActRII antibody and GLP-1RA semaglutide experienced no loss of lean mass during weight loss, while losing additional fat mass compared to treatment with semaglutide alone. Current work in the lab is focused on defining the cell-specific effects of ActRII blockade in adipose and skeletal muscle and how this pathway modulates nutrient utilization by these tissues.
Regulation of Muscle Growth and Metabolism
Skeletal muscle plays many important functions in the body including whole body movement, mediating glucose metabolism and insulin action, and is responsible for a large proportion of the body's total energy expenditure. Thus, maintaining proper skeletal muscle mass, function, and metabolism is important across the lifespan and has implications for several different diseases. The main goals of my research are to identify Akt-dependent and Akt-independent regulators of muscle hypertrophy and identify therapeutic strategies to preserve muscle mass and function with pharmacological weight loss.
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.