My lab is focused on uncoupling obesity from the resultant metabolic complications. Our work intersects fields of development, metabolism and cancer biology by study of the Notch signaling pathway. Prior to my lab’s work, Notch had been thought to regulate normal development and then remain quiescent unless deregulated in cancer. Contrary to this notion, my lab discovered that hepatocyte Notch activity is increased in diet-induced and various genetic mouse models of obesity. To validate these mouse findings, we conducted cross-sectional and longitudinal studies in patients undergoing paired liver biopsies as part of routine clinical care or randomized control trials, which revealed positive correlations between hepatic Notch activity and markers of insulin resistance and hepatic triglyceride content, but independent and strongest associations with biochemical and pathologic markers of Non-Alcoholic Steatohepatitis (NASH). Our subsequent work in genetically engineered mouse models determined that Notch is causal to these phenotypes, which has led us to develop a range of Notch inhibitors that are in preclinical testing for application to NASH-induced liver fibrosis.

While conducting these studies, we performed a global survey of tissues from Notch reporter mice, and detected ongoing Notch activity in a small subset of pancreatic β cells; this result was non-intuitive, as unlike liver, β cells are not considered proliferative/regenerative. Even more intriguingly, β cell Notch activity was specifically increased in obese mice. To query the repercussions of this unexpected β cell Notch activity, we created inducible, β cell-specific Notch loss-of-function mice, indistinguishable from Cre- controls when fed normal chow, but protected from obesity-induced glucose intolerance. Conversely, Notch gain-of-function mice or forced Notch expression in human islets result in impaired β cell function.

Overall, my lab’s work have prompted re-evaluation of the role and therapeutic potential of developmental pathways in obesity-induced pathophysiology.