UC Berkeley

Glucocorticoids (GC) are steroid hormones that exert necessary metabolic adaptation under stress, such as fasting/starvation, for the survival of mammals. To maintain blood glucose level during stress GC suppress insulin actions to promote hepatic gluconeogenesis and inhibit glucose utilization in muscle and adipose tissues. Chronic and/or excess GC exposure, however, leads to various metabolic disorders such as insulin resistance, dyslipidemia. Notably, the molecular mechanisms of GC- induced metabolic disorders are largely unclear. In this dissertation, we focus on two GC primary target genes: Angptl4 and Pik3r1 to study their roles in GC induced physiological/metabolic changes and insulin resistance in vivo.

In Chapter I, we identified a Glucocorticoids-Angiopoietin-like 4- ceramide axis as a mechanism for GC induced hepatic insulin resistance. Under Dex treatment, wild type mice developed hepatic insulin resistance with high hepatic ceramide level, increased expression of several ceramide synthesis associated genes, and increased PP2A and PKCζ activity. However, all these observations can be reversed by Angptl4 depletion in Angptl4 null mice.

In Chapter II, we found that Pik3r1 plays roles in the process to recruit PKA toward lipid droplet for Plin1 phosphorylation. Therefore, Pik3r1 knockout does not impair the activation of cytosolic HSL and PKA, but does impair the phosphorylation of Plin1 on lipid droplet. Therefore, less phosphor-HSL (the activated HSL) can be recruited to lipid droplet to mediate lipolysis. As a consequence, under Dex treatment, with less lipolysis, the adipose tissues specific Pik3r1 knockout (AKO) mice shown reduced fatty liver and dyslipidemia compared to wild type mice.

In Chapter III, we found that the expression of Pik3r1 is regulated by GC in skeletal muscle in vivo. In the molecular level, the GC induced Pik3r1 expression is mediated by p300 induced histone H3 and H4 acetylation. In the physiological level, the Pik3r1 expression in muscle is important for GC induced insulin resistance. Therefore, muscle specific Pik3r1 knockout (MKO) mice show improved glucose tolerance under Dex treatment. This result is consistent with the findings in vitro using C2C12 myotubes.

In total, this dissertation demonstrated that Angptl4 and Pik3r1 are two important genes mediating GC-induced metabolic disorders including insulin resistance, fatty liver and dyslipidemia.