Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice

摘要

Disruption of the growth hormone (GH) axis promotes longevity and delays aging. In contrast, GH over-expression may lead to accelerated aging and shorter life. Calorie restriction (CR) improves insulin sensitivity and may extend lifespan. Long-lived Ames dwarf (df/df) mice have additional extension of longevity when subjected to 30% CR. The aim of the study was to assess effects of CR or GH replacement therapy separately and as a combined (CR + GH) treatment in GH-deficient df/df and normal mice, on selected metabolic parameters (e.g., insulin, glucose, cholesterol), insulin signaling components (e.g., insulin receptor [IR] [5-subunit, phosphor-ylated form of IR [IR pYl 158], protein kinase C ? [p-PKCg/X] and mTOR [p-mTOR]), transcription factor p-CREB, and components of the mitogen-activated protein kinase (MAPK) signaling (p-ERKl/2, p-p38), responsible for cell proliferation, differentiation and survival. CR decreased plasma levels of insulin, glucose, cholesterol and lep-tin, and increased hepatic IR p>-subunit and IR pYl 158 levels as well as IR, IRS-1 and GLUT-2 gene expression compared to ad libitum feeding, showing a significant beneficial diet intervention effect. Moreover, hepatic protein levels of p-PKGJ/X, p-mTOR and p-p38 decreased, and p-CREB increased in CR mice. On the contrary, GH increased levels of glucose, cholesterol and leptin in plasma, and p-mTOR or p-p38 in livers, and decreased plasma adiponectin and hepatic IR (i-subunit compared to saline treatment. There were no GH effects on adiponectin in N mice. Moreover, GH replacement therapy did not affect IR, IRS-1 and GLUT-2 gene expression. GH treatment abolishes the beneficial effects of CR; it may suggest an important role of GH-IGF1 axis in mediating the CR action. Suppressed somatotrophic signaling seems to predominate over GH replacement therapy in the context of the examined parameters and signaling pathways.