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.
|Fang, Yimin; Hill, Cristal M; Darcy, Justin et al. (2018) Effects of rapamycin on growth hormone receptor knockout mice. Proc Natl Acad Sci U S A 115:E1495-E1503|
|Householder, Lara A; Comisford, Ross; Duran-Ortiz, Silvana et al. (2018) Increased fibrosis: A novel means by which GH influences white adipose tissue function. Growth Horm IGF Res 39:45-53|
|Nelson, Caroline N; List, Edward O; Ieremia, Makerita et al. (2018) Growth hormone activated STAT5 is required for induction of beige fat in vivo. Growth Horm IGF Res 42-43:40-51|
|Duran-Ortiz, Silvana; Noboa, Vanessa; Kopchick, John J (2018) Disruption of the GH receptor gene in adult mice and in insulin sensitive tissues. Growth Horm IGF Res 38:3-7|
|Schneider, Augusto; Matkovich, Scot J; Saccon, Tatiana et al. (2017) Ovarian transcriptome associated with reproductive senescence in the long-living Ames dwarf mice. Mol Cell Endocrinol 439:328-336|
|Dominick, Graham; Bowman, Jacqueline; Li, Xinna et al. (2017) mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell 16:52-60|
|Bartke, Andrzej; Darcy, Justin (2017) GH and ageing: Pitfalls and new insights. Best Pract Res Clin Endocrinol Metab 31:113-125|
|Bennis, Mohammed T; Schneider, Augusto; Victoria, Berta et al. (2017) The role of transplanted visceral fat from the long-lived growth hormone receptor knockout mice on insulin signaling. Geroscience 39:51-59|
|Saccon, Tatiana D; Moreira, Fabiana; Cruz, Luis A et al. (2017) Ovarian aging and the activation of the primordial follicle reserve in the long-lived Ames dwarf and the short-lived bGH transgenic mice. Mol Cell Endocrinol 455:23-32|
|Hascup, Kevin N; Lynn, Mary K; Fitzgerald, Patrick J et al. (2017) Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging. J Gerontol A Biol Sci Med Sci 72:329-337|
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