This Article Full Text Full Text (PDF) All Versions of this Article: 146/2/851    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Al-Regaiey, K. A. Articles by Bartke, A. Search for Related Content PubMed PubMed Citation Articles by Al-Regaiey, K. A. Articles by Bartke, A.

Long-Lived Growth Hormone Receptor Knockout Mice: Interaction of Reduced Insulin-Like Growth Factor I/Insulin Signaling and Caloric Restriction

Departments of Physiology and Internal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois 62794

Address all correspondence and requests for reprints to: Dr. Andrzej Bartke, 801 North Rutledge, P.O. Box 19628, Springfield, Illinois 62794-9628. E-mail: abartke{at}siumed.edu.

Reduced IGF-I/insulin signaling and caloric restriction (CR) are known to extend the life span and delay age-related diseases. To address the interaction of these two interventions, we subjected normal (N) and long-lived GH receptor knockout (GHRKO) mice to CR for 20 months starting at weaning. We also used bovine GH transgenic (bGH Tg) mice, which overexpress GH and are short-lived and insulin resistant, for comparison. Circulating insulin and IGF-I levels were reduced by CR in N animals, whereas GHRKO animals exhibited very low insulin and undetectable IGF-I. Consistently, hepatic Akt phosphorylation was reduced by CR and was very low in GHRKO mice. bGH Tg mice exhibited increased active Akt. The forkhead box O1 (Foxo1) transcription factor was additively increased by CR and GHRKO at the mRNA level. However, Foxo1 protein levels were only elevated in GHRKO mice. The coactivator peroxisome proliferator-activated receptor- coactivator 1 was increased at both gene and protein levels in GHRKO mice. N-CR and GHRKO mice also exhibited increased phosphorylated cAMP response element-binding protein and active p38 compared with the N ad libitum-fed mice, and the levels of these proteins were greatly diminished in bGH Tg mice. The protein levels of the deacetylase sirtuin 1 (SIRT1) were elevated in the two CR groups and, unexpectedly, also in bGH Tg mice. These results suggest a major role for the Akt/Foxo1 pathway in the regulation of longevity in rodents. An activated gluconeogenic pathway and increased fat metabolism may be involved in mediating the effects of reduced somatotropic and insulin signaling on longevity. These results also add to the evidence that targeted disruption of the GH receptor/GH-binding protein gene and CR act via overlapping, but distinct, mechanisms.

This article has been cited by other articles:

				Z. Wang, M. M. Masternak, K. A. Al-Regaiey, and A. Bartke Adipocytokines and the Regulation of Lipid Metabolism in Growth Hormone Transgenic and Calorie-Restricted Mice Endocrinology, June 1, 2007; 148(6): 2845 - 2853. [Abstract] [Full Text] [PDF]

				H. LIANG, Y. BAI, Y. LI, A. RICHARDSON, and W. F. WARD PGC-1{alpha}-Induced Mitochondrial Alterations in 3T3 Fibroblast Cells Ann. N.Y. Acad. Sci., April 1, 2007; 1100(1): 264 - 279. [Abstract] [Full Text] [PDF]

				K. A. Al-Regaiey, M. M. Masternak, M. S. Bonkowski, J. A. Panici, J. J. Kopchick, and A. Bartke Effects of Caloric Restriction and Growth Hormone Resistance on Insulin-Related Intermediates in the Skeletal Muscle J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2007; 62(1): 18 - 26. [Abstract] [Full Text] [PDF]

				H. Yamaza, T. Komatsu, K. To, H. Toyama, T. Chiba, Y. Higami, and I. Shimokawa Involvement of Insulin-Like Growth Factor-1 in the Effect of Caloric Restriction: Regulation of Plasma Adiponectin and Leptin J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2007; 62(1): 27 - 33. [Abstract] [Full Text] [PDF]

				Q. F. Collins, Y. Xiong, E. G. Lupo Jr., H.-Y. Liu, and W. Cao p38 Mitogen-activated Protein Kinase Mediates Free Fatty Acid-induced Gluconeogenesis in Hepatocytes J. Biol. Chem., August 25, 2006; 281(34): 24336 - 24344. [Abstract] [Full Text] [PDF]

				K. J. Nadeau, L. B. Ehlers, L. E. Aguirre, R. L. Moore, K. N. Jew, H. K. Ortmeyer, B. C. Hansen, J. E. B. Reusch, and B. Draznin Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E90 - E98. [Abstract] [Full Text] [PDF]

				M. S. Bonkowski, J. S. Rocha, M. M. Masternak, K. A. Al Regaiey, and A. Bartke From the Cover: Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction PNAS, May 16, 2006; 103(20): 7901 - 7905. [Abstract] [Full Text] [PDF]

				E. Egecioglu, M. Bjursell, A. Ljungberg, S. L. Dickson, J. J. Kopchick, G. Bergstrom, L. Svensson, J. Oscarsson, J. Tornell, and M. Bohlooly-Y Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E317 - E325. [Abstract] [Full Text] [PDF]

				J. C. Corton and H. M. Brown-Borg Peroxisome Proliferator-Activated Receptor {gamma} Coactivator 1 in Caloric Restriction and Other Models of Longevity J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1494 - 1509. [Abstract] [Full Text] [PDF]

				M. M. Masternak, K. A. Al-Regaiey, M. M. Del Rosario Lim, V. Jimenez-Ortega, J. A. Panici, M. S. Bonkowski, J. J. Kopchick, and A. Bartke Effects of Caloric Restriction and Growth Hormone Resistance on the Expression Level of Peroxisome Proliferator-Activated Receptors Superfamily in Liver of Normal and Long-Lived Growth Hormone Receptor/Binding Protein Knockout Mice J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2005; 60(11): 1394 - 1398. [Abstract] [Full Text] [PDF]

				M. M. Masternak, K. A. Al-Regaiey, M. M. Del Rosario Lim, M. S. Bonkowski, J. A. Panici, G. K. Przybylski, and A. Bartke Caloric Restriction Results in Decreased Expression of Peroxisome Proliferator-Activated Receptor Superfamily in Muscle of Normal and Long-Lived Growth Hormone Receptor/Binding Protein Knockout Mice J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2005; 60(10): 1238 - 1245. [Abstract] [Full Text] [PDF]

				A. Bartke Minireview: Role of the Growth Hormone/Insulin-Like Growth Factor System in Mammalian Aging Endocrinology, September 1, 2005; 146(9): 3718 - 3723. [Abstract] [Full Text] [PDF]