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The Maladaptive Notch Reactivation in Obesity-Induced Glucose Homeostasis

My post-doctoral training with Domenico Accili raised several interesting questions, specifically, the novel role of Notch in glucose metabolism. Notch is a highly conserved family of proteins critical for cell fate decision-making, but prior to our studies, less was known about Notch action in mature tissue. We showed that Notch signaling is present at low levels in normal physiologic conditions, but increases markedly in livers from diet-induced or genetic mouse models of obesity. To test the repercussions of this increased Notch signal, we generated mouse models lacking hepatocyte Notch signaling. These mice, when challenged with high-fat diet feeding, showed improved glucose tolerance due to reduced FoxO1 action on gluconeogenic promoters (Pajvani et al, Nature Medicine, 2011; Ozcan et al, Cell Metabolism, 2012). In euglycemic-hyperinsulinemic clamp studies in obese mice, we found that pharmacologic Notch inhibitor treatment improves hepatic insulin sensitivity with little effect on glucose disposal, confirmed by parallel studies in adipocyte-specific Notch loss-of-function mice (Sparling et al, Molecular Metabolism, 2015). These studies also revealed the unexpected role of Notch signaling to regulate β cell maturity and proliferation (Bartolome et al, Journal of Clinical Investigation, 2018); in sum, these data provide the groundwork to repurpose these agents to address the dual pathologies that characterize type 2 diabetes – insulin resistance and β cell dysfunction (Pajvani and Accili, Diabetologia, 2015).

  1. 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. Nature Medicine, 2011. DOI: 10.1038/nm.2378 | PubMed

  2. Sparling DP, Yu J, Kim K, Zhu C, Brachs S, Birkenfeld AL, Pajvani UB. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity. Molecular Metabolism, 2015. DOI: 10.1016/j.molmet.2015.11.006 | PubMed

  3. Pajvani UB, Accili D. The new biology of diabetes. Diabetologia, 2015. DOI: 10.1007/s00125-015-3722-5 | PubMed

  4. Bartolome A, Zhu C, Sussel L, Pajvani UB. Notch signaling dynamically regulates adult β cell proliferation and maturity. J Clin Invest., 2019. DOI: 10.1172/JCI98098 | PubMed