Growth Hormone (GH) is a diabetogenic molecule, i.e., it inhibits insulin action resulting in insulin resistance and diabetes. The diabetogenic effect of GH can be seen in GH transgenic mice that express relatively high levels of GH. These animals also possess high levels of insulin like growth factor one (IGF-1) and insulin, are insulin resistant and have short life spans. In humans, patients with acromegaly possess elevated levels of GH and IGF-1, are typically insulin resistance and many will develop diabetes. Thus, elevated levels of GH in both mice and humans results in insulin resistance. Conversely, mice were developed in our laboratory that lack the GH receptor (GHR/BP-/- mice) and therefore GH action. These mice are dwarf, possess low levels of IGF-1 and insulin, are extremely insulin sensitive and have an extended life span. Furthermore, disruption of the insulin or IGF-1 signaling system also leads to extended life spans in worms, yeast, flies, and other mouse lines with reduced GH/IGF-1 signaling. Thus, one would predict that increasing insulin sensitivity through repression of GH/IGF-1 signaling will result in animals with increased life span. Three insulin and GH sensitive .tissues are the liver, white adipose tissue (WAT) and muscle. By increasing insulin sensitivity in these tissues, one may increase the animal's life span. We hypothesize that the life span extension seen in the GHR/BP-/- mouse is due to decreased GHaction and consequent increased insulin sensitivity in insulin responsive tissues. To test this hypothesis, we will selectively disrupt the GHR gene in liver, WAT, and muscle to determine their individual contributions to overall insulin sensitivity and longevity. We expect to find improved insulin sensitivity in the three tissue- specific gene disrupted mouse lines, which, in turn, will increase longevity. Once the three mouse lines are generated, we will also assess a variety of growth, endocrine, physiological and metabolic parameters. Collectively, this data will help establish the importance of individual tissues on overall insulin sensitivity as a contributing factor to increased life span. Also, the data will help advance the understanding of molecular and cellular changes that underlie the aging process. Finally, the results may lead to interventions to extend life or delay the onset of age-related diseases and/or disabilities.
The absence of GH action has been shown to improve insulin sensitivity and increase life span. Removal of GH action in liver, fat, and muscle, as outlined in this proposal will help identify organs that are important for improved insulin sensitivity and life extension.
|Gesing, Adam; Wang, Feiya; List, Edward O et al. (2015) Expression of apoptosis-related genes in liver-specific growth hormone receptor gene-disrupted mice is sex dependent. J Gerontol A Biol Sci Med Sci 70:44-52|
|Li, Weiquan; Miller, Richard A (2015) Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J Gerontol A Biol Sci Med Sci 70:263-72|
|Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61|
|Tran, Duc; Bergholz, Johann; Zhang, Haibo et al. (2014) Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence. Aging Cell 13:669-78|
|Kopchick, John J; List, Edward O; Kelder, Bruce et al. (2014) Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications. Mol Cell Endocrinol 386:34-45|
|Jara, Adam; Benner, Chance M; Sim, Don et al. (2014) Elevated systolic blood pressure in male GH transgenic mice is age dependent. Endocrinology 155:975-86|
|Schneider, Augusto; Zhi, Xu; Bartke, Andrzej et al. (2014) Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries. Age (Dordr) 36:9701|
|Wiesenborn, Denise S; Ayala, Julio E; King, Emily et al. (2014) Insulin sensitivity in long-living Ames dwarf mice. Age (Dordr) 36:9709|
|Berryman, Darlene E; Lubbers, Ellen R; Magon, Vishakha et al. (2014) A dwarf mouse model with decreased GH/IGF-1 activity that does not experience life-span extension: potential impact of increased adiposity, leptin, and insulin with advancing age. J Gerontol A Biol Sci Med Sci 69:131-41|
|Hong, S Lee; Longo, Kenneth A; Gosney, Elahu et al. (2014) Increased metabolic flexibility and complexity in a long-lived growth hormone insensitive mouse model. J Gerontol A Biol Sci Med Sci 69:274-81|
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