The Herman laboratory uses a systems biology approach to understand molecular mechanisms underlying the metabolic syndrome - a constellation of pathologies including obesity; insulin resistance; impaired glucose metabolism; non-alcoholic fatty liver disease; and dyslipidemia, which predispose to the development of diabetes and cardiovascular disease.
Our general approach is to investigate how cells in key metabolic tissues like liver and adipose tissue sense nutrients and hormonal signals and how these diverse signals are integrated into coherent genomic responses. By delineating control mechanisms regulating key metabolic gene expression programs, we seek to gain insight into both normal and pathophysiological states contributing to metabolic disease. Much of our current work focuses on a key carbohydrate sensing transcription factor, carbohydrate-responsive element binding protein (ChREBP) which coordinates genomic responses to cellular hexose-phosphate levels to regulate glucose and lipid homeostasis. Specific projects include the following:
- Function of distinct ChREBP isoforms: We recently discovered the existence of distinct ChREBP isoforms including the novel, potent ChREBP-beta isoform (1). We have developed new mouse models so that we can assess the tissue-specific functions of distinct ChREBP isoforms in vivo.
- The role of ChREBP in fructose-induced metabolic disease: We recently demonstrated that ChREBP plays a key role in hepatic fructose metabolism and that ChREBP mediates fructose-induced hepatic insulin resistance in parallel with fructose-induced lipogenesis (2). Ongoing studies are focused on defining which of ChREBP’s transcriptional targets are critical for ChREBP’s pleiotropic metabolic effects.
- Identification and study of nutrient-induced hepatokines in humans and animal models: Based on our studies of hepatic nutrient sensing mechanisms, we and others have identified the pleiotropic metabolic hormone FGF21 as a ChREBP transcriptional target and have established a “fructose tolerance test” by showing that fructose ingestion acutely and robustly stimulates FGF21 secretion in human subjects (3). This is the first known hormonal response selective for fructose ingestion and the only know means to easily assess an individual’s acute metabolic response to fructose ingestion. Ongoing studies include identification of additional nutrient-induced hepatokines.