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Male and Female Sex Hormones Modulate the Effects of Hepatic Rictor Deletion on Glucose Metabolism and Lifespan
Author(s) -
Apelo Sebastian I Arriola,
Pumper Cassidy P,
Morrison Mark T,
Meyer Emma J,
Cummings Nicole E,
Lin Amy,
Baar Emma L,
Lamming Dudley W
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.645.22
Subject(s) - endocrinology , medicine , glucose homeostasis , mtorc2 , biology , hormone , homeostasis , carbohydrate metabolism , impaired glucose tolerance , insulin , castration , insulin resistance , pi3k/akt/mtor pathway , mtorc1 , signal transduction , microbiology and biotechnology
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 (LRKO) 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. As expected, we observe that intact LRKO male mice die at a faster rate than wild type male mice; however, castrated LRKO mice die at similar rate than castrated wild type mice. These results suggest that female sex hormones are required for mTORC2 modulation of hepatic insulin signaling and glucose homeostasis, and that testosterone sensitizes male mice to loss of hepatic Rictor on lifespan. Support or Funding Information This work was supported by the National Institute on Aging at the National Institutes of Health (R00 AG041765 to D.W.L.); American Federation for Aging Research (A15057 to D.W.L.); the UW‐Madison School of Medicine and Public Health; and the UW‐Madison Department of Medicine. S.I.A.A is supported by a fellowship from the American Diabetes Association (1‐16‐PMF‐001). This work was supported using facilities and resources at the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government.