Deletion, But Not Antagonism, of the Mouse Growth Hormone Receptor Results in Severely Decreased Body Weights, Insulin, and Insulin-Like Growth Factor I Levels and Increased Life Span

Abstract

GH participates in growth, metabolism, and cellular differentiation. To study these roles, we previously generated two different dwarf mouse lines, one expressing a GH antagonist (GHA) and the other having a disrupted GH receptor and binding protein gene (GHR -/-). In this study we compared the two dwarf lines in the same genetic background (C57BL/6J). One of the most striking differences between the mouse lines was their weight gain profile after weaning. The weights of the GHA dwarfs gradually approached controls over time, but the weights of the GHR -/- dwarfs remained low throughout the analysis period. Additionally, fasting insulin and glucose levels were reduced in the GHR -/- mice but normal in the GHA mice. IGF-I and IGF binding protein 3 (IGFBP-3) levels were significantly reduced, but by different degrees, in both mouse lines, but IGFBP-1 and -4 levels were reduced and IGFBP-2 levels increased in GHR -/- mice but unaltered in GHA mice. Finally, life span was significantly extended for the GHR -/- mice but remained unchanged for GHA dwarfs. These results suggest that the degree of blockade of GH signaling can lead to dramatically different phenotypes.

Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans

“…Overexpression of dFOXO, a homolog of DAF-16, has also been shown to increase lifespan in flies (Giannakou et al 2004;Hwangbo et al 2004). Fat-specific insulin receptor knockout (KO) mice have an increased lifespan (Bluher et al 2003), as do both growth hormone receptordeficient and IGF receptor KO mice (Coschigano et al 2003;Holzenberger et al 2003).…”

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice

“…Litter crowding improved glucose homeostasis in male GHR-KO mice Compared to normal animals, GHR-KO mice typically have improved glucose metabolism with very low insulin levels and increased insulin sensitivity (Coschigano et al 2003). Because litter crowding is essentially a mild early-life calorie restriction, it was of interest to see if the glucose metabolism in these mice was altered.…”

“…Mice with growth hormone (GH) resistance produced by targeted disruption of the GH receptor/ binding protein gene (GHR/GHBP-KO, hereafter referred to as GHR-KO mice) (Zhou et al 1997) are characterized by normal prenatal growth, major retardation of postnatal growth and adult body size, and a major extension of longevity (Coschigano et al 2003). These animals thrive under a standard feeding regimen, but as adults fail to benefit from a regimen of calorie restriction (CR) that significantly extends longevity of their normal siblings Bonkowski et al 2006).…”

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

“…In laboratory animals, growth inhibition by targeted mutation of the growth hormone or insulin‐like growth factor receptors (GHR, IGF1R) is known to significantly increase lifespan (Coschigano et al ., 2003; Holzenberger et al ., 2003), suggesting that higher growth activities may be at the expense of lifespan; this raises the question of whether smaller body dimensions might result in a healthier condition (Bartke, 2012). In addition, in worms and insects, long‐lived mutants with impaired insulin/IGF‐signaling frequently represent dwarf individuals (Kenyon, 2005).…”

“…In fact, female Ghr knockout mice in a C57BL/6 background have been demonstrated to have a 21% increased lifespan in comparison with wild‐type mice (Coschigano et al ., 2003). In a different genetic background, Ghr −/− mice were able to reach an age of almost 5 years, which represents a quantum leap of lifespan extension and is unmatched by other long‐lived mouse models (Junnila et al ., 2013).…”