| Popis: |
Rapamycin is an immunosuppressant and anticancer drug that extends lifespan in model organisms including mice, but side effects including metabolic disruption may limit its wide-scale use for diseases of aging. We have previously found that many side effects of rapamycin may be mediated by “off-target” disruption of the mechanistic target of rapamycin complex 2 (mTORC2), and that deletion of Rictor, an essential protein component of mTORC2, specifically in the liver results in hepatic insulin resistance, disrupted glucose homeostasis and decreased male, but not female, lifespan. Here, we investigated the interaction of sex hormones and hepatic mTORC2 with respect to metabolic health and lifespan. We gonadectomized pre-pubertal male and female mice in which Rictor is specifically deleted in the liver and their wild-type littermates. Ovariectomy impaired glucose and pyruvate tolerance, while castration had no effect on glucose homeostasis. Deletion of Rictor strongly impaired glucose and pyruvate tolerance in male mice, regardless of surgery treatment. Intriguingly, Rictor deletion impaired glucose and pyruvate tolerance in female mice undergoing sham surgery, but had no further effect on ovariectomized mice. These results suggest that female, but not male, sex hormones are required for mTORC2 modulation of hepatic insulin signaling and glucose homeostasis. We will also present the results of our ongoing lifespan study investigating the interaction of sex hormones and hepatic Rictor expression on longevity. |
