title: Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice.
abstract: 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] β-subunit, phosphorylated form of IR [IR pY1158], protein kinase C ζ/λ [p-PKCζ/λ] and mTOR [p-mTOR]), transcription factor p-CREB, and components of the mitogen-activated protein kinase (MAPK) signaling (p-ERK1/2, p-p38), responsible for cell proliferation, differentiation and survival. CR decreased plasma levels of insulin, glucose, cholesterol and leptin, and increased hepatic IR β-subunit and IR pY1158 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-PKCζ/λ, 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 β-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.
authors.affiliation: Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, 801 N Rutledge St., Room 4389, Springfield, IL, 62794, USA.|Department of Oncological Endocrinology, Medical University of Lodz, Zeligowski St., No 7/9, 90-752 Lodz, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Gesing
authors.affiliation: Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, 801 N Rutledge St., Room 4389, Springfield, IL, 62794, USA.|Department of Physiology, College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia.
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Al-Regaiey
authors.affiliation: Department of Internal Medicine, Geriatrics Research, Southern Illinois University School of Medicine, 801 N Rutledge St., Room 4389, Springfield, IL, 62794, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.affiliation: College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL, 32827, USA.
authors.forename: Michal M
authors.initials: MM
authors.lastname: Masternak
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D031204:Caloric Restriction; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004393:Dwarfism, Pituitary / Q000097:blood / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation; D005838:Genotype; D013006:Growth Hormone / Q000097:blood / Q000172:deficiency / Q000494:pharmacology*; D020249:Hormone Replacement Therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008136:Longevity / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D015415:Biomarkers; D013006:Growth Hormone
keywords: Ames dwarf mice; Calorie restriction; Growth hormone; MAPK signaling; Metabolism; Transcription factors