GH and IGF1: roles in energy metabolism of long-living GH mutant mice - PubMed (original) (raw)

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GH and IGF1: roles in energy metabolism of long-living GH mutant mice

Holly M Brown-Borg et al. J Gerontol A Biol Sci Med Sci. 2012 Jun.

Abstract

Of the multiple theories to explain exceptional longevity, the most robust of these has centered on the reduction of three anabolic protein hormones, growth hormone (GH), insulin-like growth factor, and insulin. GH mutant mice live 50% longer and exhibit significant differences in several aspects of energy metabolism as compared with wild-type mice. Mitochondrial metabolism is upregulated in the absence of GH, whereas in GH transgenic mice and dwarf mice treated with GH, multiple aspects of these pathways are suppressed. Core body temperature is markedly lower in dwarf mice, yet whole-body metabolism, as measured by indirect calorimetry, is surprisingly higher in Ames dwarf and Ghr-/- mice compared with normal controls. Elevated adiponectin, a key antiinflammatory cytokine, is also very likely to contribute to longevity in these mice. Thus, several important components related to energy metabolism are altered in GH mutant mice, and these differences are likely critical in aging processes and life-span extension.

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Figures

Figure 1.

Figure 1.

Body and liver weights and complex enzyme activities in liver tissue from Ames dwarf mice following a short-term 7-day treatment with growth hormone (GH; 25 μg porcine GH per injection × two injections per day for 7 days). Top left: Body weight change (g); top right: Liver weights (g); bottom left: Liver complex II + III activity (ng/min × mg protein) in 12-month-old Ames mice; and bottom right: Liver complex IV activity (nmol/min × mg protein) in 12-month-old Ames mice. Details of enzyme assays described in (24). Values represent means ± SEM, n = 7–8 mice per treatment.

Figure 2.

Figure 2.

Gene expression of complex enzymes in 3-month-old male liver tissue from GH transgenic and wild-type control mice. Primer pairs and real-time reverse transcription-PCR conditions described in (24). Values represent means ± SEM, n = 6–7 mice per genotype.

Figure 3.

Figure 3.

Liver protein levels of complexes I, II, and V in 3- and 12-month-old male tissue from growth hormone transgenic and wild-type control mice. Protein extraction and immunoblotting assays and antibodies are described in (24). Values represent means ± SEM, n = 7–8 mice per age per genotype.

Figure 4.

Figure 4.

Body weight change (g) and liver complex II + III activity (nmol/min × mg) in Ames dwarf mice following short-term treatment with thyroxine or saline. Details of complex II + III activity assay described in (24). Values represent means ± SEM, n = 6–8 mice per treatment.

Figure 5.

Figure 5.

Interactions of pathways mediating effects of growth hormone (GH) on metabolism and inflammation. GH inhibits adiponectin, peroxisome proliferator-activated receptor γ, PPARα, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and thus promotes inflammation, insulin resistance, and reduced oxidation of fatty acids. Suppression of GH signaling in long-lived mutants removes these inhibitory effects and thus reduces inflammation and promotes insulin sensitivity and fatty acid oxidation. (This diagram is greatly simplified and is not intended to present all pathways and mediators involved).

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