Metabolic role of thioredoxin-interacting protein in facilitating the fasting response

Thioredoxin-interacting protein (Txnip) is a ubiquitously expressed protein whose well established function is to bind to thioredoxin, effectively inhibiting its ability to facilitate redox-mediated functions. Txnip has been characterized as a potent tumor suppressor and (through its association with thioredoxin) is involved in various cellular homeostatic functions that regulate cell growth, proliferation, and apoptosis. Recently, Txnip has emerged as an important player in metabolism. Here, we demonstrate that Txnip is essential for integrating signals that allow for an appropriate metabolic response to survive a fasting challenge. Using a mouse model harboring genetic disruption of the Txnip gene, we attempted to elucidate the role of Txnip in facilitating the fasting response where the body normally elicits a set of metabolic reactions to maintain energy homeostasis necessary for survival. We establish that loss of Txnip alone is sufficient to induce fasting hypoglycemia, hyperketonemia and hypertriglyceridemia. Furthermore, we show that Txnip ablation leads to attenuated mitochondrial oxidative phosphorylation of all major fuel substrate types (glucose, ketone bodies, and fatty acids) and enhances the propensity to utilize glucose in muscle tissues. Moreover, we establish that Txnip exerts its metabolic role in the fasting response in great part through the heart and skeletal muscles, as the phenotype of global Txnip knockout mice is closely recapitulated in the heart and skeletal muscle-specific knockout mice. Upon concentrating our efforts to understand the function of Txnip in the heart and skeletal muscle of fasting Txnip -/- mice, we observed hypoactivation of AMPK in the more oxidative muscle tissues (heart and soleus muscles) relative to their controls. We found that this phenomenon is a consequence of a low AMP:ATP ratio (high energy state) and is associated with increased muscle glycogen content. In this dissertation we demonstrate that Txnip is an essential player for facilitating the glucose-fatty acid cycle, which is an essential part of the fasting response. Because of the critical and influential role it plays in cellular energetics and house keeping functions, Txnip may be a potentially good target for therapeutic research into treating many of the metabolic maladies man faces today that include heart disease, cancer, and diabete