Our research interests intersect the diverse fields of development, metabolism and cancer biology, by study of the Notch signaling pathway. The Notch family of transmembrane receptors has been traditionally thought to regulate normal development and then remain quiescent unless deregulated in cancer. Contrary to this notion, we demonstrated beneficial effects on insulin sensitivity through Notch inhibition in the adult animal, partially through its interaction with FoxO1, a transcription factor that mediates hormone-dependent hepatic glucose production (HGP). Mice with a liver-specific deletion of the Notch transcriptional effector, Rbp-Jκ (L-Rbpj mice) are protected from obesity-induced insulin resistance and demonstrate decreased HGP, likely due to direct transcriptional regulation of Glucose-6-phosphatase expression. Remarkably, L-Rbpj mice are additionally resistant to obesity-induced fatty liver, likely through decreased mTorc1-dependent de novo lipogenesis. These results establish Notch as a unique pharmacological target in liver, whose inhibition may prevent both aberrant obesity-induced glucose and lipid metabolism, by virtue of its ability to uncouple insulin and nutrient signaling at the molecular level.
We are currently investigating upstream signaling events leading to hepatocyte Notch activation in obesity, as well as whether this pathway may be a pharmacologically tractable means at ameliorating T2D and NAFLD. This point is critical – Notch inhibitors are in various stages of clinical development for cancer. We have shown that specific Notch inhibitors recapitulate the phenotype of L-Rbpj mice, suggesting that we may be able to repurpose these emerging therapeutics for the burgeoning crisis of obesity-related metabolic disease. Reciprocally, our surprising discovery that Notch inhibition allows manipulation of both insulin and nutrient signaling pathways may provide impetus to develop the next generation of Notch inhibitors.
Pajvani UB, Shawber CJ, Samuel VT, Birkenfeld AL, Shulman GI, Kitajewski J, Accili D. Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. 2011. Nature Medicine 17, 961-967. PMID: 21804540.
Pajvani UB, Qiang L, Kangsamaksin T, Kitajewski J, Ginsberg HN, Accili D. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. 2013. Nature Medicine 19, 1054-60. PMID: 23832089.
Valenti L, Mendoza RM, Rametta R, Maggioni M, Kitajewski C, Shawber CJ and Pajvani UB. Hepatic Notch signaling correlates with insulin resistance and non-alcoholic fatty liver disease. 2013. Diabetes 62, 4052-62. PMID: 23990360.