Hepatic glucose production (HGP) provides temporary protection from hypoglycemia in the fasted state, and as such, is an adaptive physiologic mechanism to provide for glucose needs of organs that are unable to store sufficient energy in the form of glycogen (ie, brain). Nevertheless, excessive HGP is a pathologic hallmark ofthe insulin-resistant state encountered in patients with type 2 diabetes and leads to hyperglycemia. HGP is mediated by Forkhead Box-containing, sub-family O protein 1 (FoxOI)-induced transcription of the rate-limiting enzymes in glucose production, glucose-6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Previous work in our laboratory has demonstrated that FoxOI physically and functionally interacts with Rbp-Jk, the transcriptional effector of Notch receptor signalling, bridging nutrient availability (insulin/FoxOI) and differentiation pathways (Notch/Rbp-Jk) in a natural coupling. The role of the Notch family of transmembrane receptors in ligand-dependent cell-fate decisions during differentiation is well-established, but Notch signaling in developed liver is relatively uncharacterized. Our laboratory has shown that FoxOI is necessary for Notchi-mediated induction of differentiation, in a Rbp^Jk-dependent manner. We hypothesize that similar interactions regulate FoxOI dependent metabolic functions.
In Aim 1, we will generate FoxOI/Notchi double-heterozygous mice (F/N mice) in order to circumvent the embryonic lethality of homozygous mutation of either Foxol or Notchi. We hypothesize that F/N mice will demonstrate increased basal insulin sensitivity and resistance to diet-induced metabolic derangements, likely due to a relative inability to increase G6Pase and PEPCK expression.
In Aim2, we propose to elucidate the metabolic role of Notch signaling in adult liver tissue by generating a post-natal liver-specific knockout of Rbp-Jk, functionally ablating Notch-dependent transcription. Relevance: Understanding the mechanism of insulin resistance is critical to developing novel therapeutic options for the increasing numbers of patients who are at risk for the substantial health risks associated with type 2 diabetes. Through genetic manipulation ofthe Notch pathway in mice, we hope to provide evidence that inhibition of Notch signaling in liver can lead to improved glycemic control.
| Pajvani, Utpal B; Shawber, Carrie J; Samuel, Varman T et al. (2011) Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nat Med 17:961-7 |
