Targeting Notch to Prevent Insulin Resistance

Science Signaling  23 Aug 2011:
Vol. 4, Issue 187, pp. ec230
DOI: 10.1126/scisignal.4187ec230

Given the association between insulin resistance and type 2 diabetes, a better understanding of the mechanism(s) by which insulin resistance occurs would help in the development of relevant therapeutics. Members of the Forkhead box–containing (FoxO) family of transcription factors mediate the effects of insulin by stimulating the production of enzymes that generate glucose in the liver. Proteins of the Notch family, which are involved in cell-fate decisions, are cell-surface receptors that activate the transcription factor Rbp-Jκ, which leads to the expression of Notch target genes. Noting that Rbp-Jκ and FoxO1 interact during cellular differentiation, Pajvani et al. studied metabolic function in hepatocytes from mice that were haploinsufficient in both Foxo1 and Notch1. These mice on various diets had lower concentrations of serum glucose and insulin than did wild-type (WT) and Foxo1+/– mice, indicating that they had greater insulin sensitivity. Mice deficient in Rbpj (which encodes Rbp-Jκ) in the liver exhibited lower serum insulin concentrations and greater glucose tolerance when on a high-fat diet than did control mice. The expression of constitutively active Notch1 (N1-IC) in mouse hepatocytes that expressed constitutively active Foxo1 (Foxo1-ADA) increased the production of glucose-6-phosphatase (encoded by G6pc) relative to that in cells expressing Foxo1-ADA alone, which led to increased glucose release into the culture medium. Chromatin immunoprecipitation studies showed that Rbp-Jκ bound to the G6pc promoter. Mice with N1-IC expressed in the liver had increased serum glucose and insulin concentrations compared with those in control mice. Finally, treatment of mice with an inhibitor of γ-secretase, which prevents Notch1 activation, resulted in reduced G6pc expression, reduced serum glucose concentrations, and increased glucose tolerance compared with those in control mice. Together, these data suggest that Notch functions in metabolism and that its inhibition might be beneficial in the treatment of diabetes.

U. B. Pajvani, C. J. Shawber, V. T. Samuel, A. L. Birkenfeld, G. I. Shulman, J. Kitajewski, D. Accili, Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat. Med. 17, 961–967 (2011). [PubMed]