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Altered hepatic insulin signalling in male offspring of obese mice

Published online by Cambridge University Press:  18 May 2010

M. S. Martin-Gronert ,
D. S. Fernandez-Twinn ,
L. Poston  and
S. E. Ozanne
M. S. Martin-Gronert*
Affiliation:
Addenbrooke’s Hospital, Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
D. S. Fernandez-Twinn
Affiliation:
Addenbrooke’s Hospital, Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
L. Poston
Affiliation:
Division of Reproduction and Endocrinology, St Thomas’s Hospital, King’s College London, London, UK
S. E. Ozanne
Affiliation:
Addenbrooke’s Hospital, Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
*
Address for correspondence: M. S. Martin-Gronert, Addenbrooke’s Hospital, Hills Road, Institute of Metabolic Science, Level 4, Box 289, University of Cambridge Metabolic Research Laboratories, Cambridge CB2 OQQ, UK. (Email [email protected])
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Abstract

Individuals exposed in utero to maternal obesity have increased risk of developing type 2 diabetes mellitus and obesity in adulthood. The molecular mechanisms underlying this association are unknown. We have therefore used a murine model of maternal obesity, in which the offspring of obese dams develop hyperinsulinaemia by 3 months of age indicative of insulin resistance. Here, we investigate the effects of maternal diet-induced obesity on the expression/phosphorylation of key hepatic insulin signalling proteins and the expression of anti-oxidant enzymes in male offspring. At 3 months of age, offspring of obese dams had decreased levels of insulin receptor substrate (IRS) 1 (P < 0.01), whereas the ratio of phosphorylated IRS1 Ser307 to total IRS1 was significantly increased (P < 0.001), suggesting that it was less active. Protein expression of the PI3K p85α subunit was decreased (P < 0.01) and there was a tendency for phosphorylation of Akt at Ser473 to be reduced (P = 0.08) in the offspring of obese dams. protein kinase Cζ (P < 0.001) and glycogen synthase kinase 3β (P < 0.05) levels were increased in these animals in comparison with controls. Maternal obesity also resulted in increased phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182 (P < 0.01) and raised c-Jun N-terminal kinase 1 expression (P < 0.5) in the offspring. The expression of antioxidant enzymes was also affected by maternal obesity with CuZnSOD (P < 0.001) and glutathione reductase (P < 0.05) being increased, whereas glutathione peroxidase 1 was reduced (P < 0.05) in the offspring. We conclude that maternal obesity leads to alterations in hepatic insulin signalling protein expression and phosphorylation. These molecular changes may contribute to the development of insulin resistance.

Keywords

antioxidant enzymesinsulin resistancematernal obesity
Type
Original Articles
Information
Journal of Developmental Origins of Health and Disease , Volume 1 , Issue 3 , June 2010 , pp. 184 - 191
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2010

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Footnotes

a

These authors contributed equally.

References

1. Chu, SY, Kim, SY, Bish, CL. Prepregnancy obesity prevalence in the United States, 2004–2005. Matern Child Health J. 2009; 13, 614–620.CrossRefGoogle ScholarPubMed
2. Heslehurst, N, Rankin, J, Wilkinson, JR, Summerbell, CD. A nationally representative study of maternal obesity in England, UK: trends in incidence and demographic inequalities in 619 323 births, 1989–2007. Int J Obes (Lond). 2010; 34, 420–428.Google Scholar
3. Boney, CM, Verma, A, Tucker, R, Vohr, BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005; 115, e290–e296.CrossRefGoogle ScholarPubMed
4. Nelson, SM, Matthews, P, Poston, L. Maternal metabolism and obesity: modifiable determinants of pregnancy outcome. Hum Reprod Update. 2010; 16, 255–275.Google Scholar
5. Henderson, L, Gregory, J, Irving, K, Swan, G. The National Diet and Nutrition survey: Adults aged 19 and 64 Years. Vol. 2: Energy Protein Carbohydrate Fat and Alcohol Intake. 2003. The Stationary Office, London.Google Scholar
6. Samuelsson, AM, Matthews, PA, Argenton, M, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension. 2008; 51, 383–392.CrossRefGoogle ScholarPubMed
7. Shelley, P, Martin-Gronert, MS, Rowlerson, A, et al. Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice. Am J Physiol Regul Integr Comp Physiol. 2009; 297, R675–R681.CrossRefGoogle ScholarPubMed
8. Oben, J, Mouralidarane, A, Samuelsson, AM, et al. Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatology (in press).Google Scholar
9. Bruce, KD, Cagampang, FR, Argenton, M, et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology. 2009; 50, 1796–1808.CrossRefGoogle ScholarPubMed
10. Meshkani, R, Adeli, K. Hepatic insulin resistance, metabolic syndrome a cardiovascular disease. Clin Biochem. 2009; 42, 1331–1346.CrossRefGoogle ScholarPubMed
11. Standaert, ML, Sajan, MP, Miura, A, et al. Insulin-induced activation of atypical protein kinase C, but not protein kinase B, is maintained in diabetic (ob/ob and Goto-Kakizaki) liver. J Biol Chem. 2004; 279, 24929–24934.CrossRefGoogle ScholarPubMed
12. Hirosumi, J, Tuncman, G, Chang, L, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002; 420, 333–336.CrossRefGoogle ScholarPubMed
13. Li, S-Y, Liu, Y, Sigmon, VK, McCort, A, Ren, J. High-fat diet enhances visceral advanced glycation end products, nuclear O-Glc-Nac modification, p38 mitogenactivated protein kinase activation and apoptosis. Diabetes, Obes, Metab. 2005; 7, 448–454.CrossRefGoogle ScholarPubMed
14. Gum, RJ, Gaede, LL, Heindel, MA, et al. Antisense protein tyrosine phosphatase 1B reverses activation of p38 mitogen-activated protein kinase in liver of ob/ob mice. Mol Endocrinol. 2003; 17, 1131–1143.CrossRefGoogle ScholarPubMed
15. Zheng, Y, Zhang, W, Pendleton, E, et al. Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6K activities in the liver of obese Zucker rats. J Endocrinol. 2009; 203, 337–347.CrossRefGoogle ScholarPubMed
16. van Gaal, LF, Zhang, A, Steijaert, MM, Deleeuw, IH. Human obesity: from lipid abnormalities to lipid oxidation. Int J Obes. 1995; 9, 21–26.Google Scholar
17. Evans, JL, Goldfine, ID, Maddux, BA, Grodsky, GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev. 2002; 23, 599–622.CrossRefGoogle ScholarPubMed
18. Milagro, FI, Campión, J, Martínez, JA. Weight gain induced by high-fat feeding involves increased liver oxidative stress. Obesity. 2006; 14, 1118–1123.CrossRefGoogle ScholarPubMed
19. Kumashiro, N, Tamura, Y, Uchida, T, et al. Impact of oxidative stress and peroxisome proliferator-activated receptor gamma coactivator-1alpha in hepatic insulin resistance. Diabetes. 2008; 57, 2083–2091.CrossRefGoogle ScholarPubMed
20. Kubota, N, Kubota, T, Itoh, S, et al. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab. 2008; 8, 49–64.CrossRefGoogle ScholarPubMed
21. Kerouz, NJ, Horsch, D, Pons, S, Kahn, CR. Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest. 1997; 100, 3164–3172.CrossRefGoogle ScholarPubMed
22. Gual, P, Le Marchand-Brustel, Y, Tanti, JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie. 2005; 87, 99–109.CrossRefGoogle ScholarPubMed
23. Werner, ED, Lee, J, Hansen, L, Yuan, M, Shoelson, SE. Insulin resistance due to phosphorylation of insulin receptor substrate 1 at serine 302. J Biol Chem. 2004; 279, 35298–35305.CrossRefGoogle ScholarPubMed
24. Morino, K, Petersen, KF, Dufour, S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005; 115, 3587–3593.CrossRefGoogle ScholarPubMed
25. Considine, RV, Nyce, MR, Allen, LE, et al. Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia. J Clin Invest. 1995; 95, 2938–2944.CrossRefGoogle Scholar
26. Farese, RV, Sajan, MP, Standaert, ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005; 230, 593–605.CrossRefGoogle ScholarPubMed
27. Buckley, AJ, Keserü, B, Briody, J, et al. Altered body composition and metabolism in the male offspring of high fat-fed rats. Metabolism. 2005; 54, 500–507.CrossRefGoogle ScholarPubMed
28. Guo, S, Copps, KD, Dong, X, et al. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol. 2009; 29, 5070–5083.CrossRefGoogle Scholar
29. Kohjima, M, Higuchi, N, Kato, M, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008; 21, 507–511.Google Scholar
30. Eldar-Finkelman, H, Schreyer, SA, Shinohara, MM, LeBoeuf, RC, Krebs, EG. Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes. 1999; 48, 1662–1666.CrossRefGoogle ScholarPubMed
31. Cusi, K, Maezono, K, Osman, A, et al. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000; 105, 311–320.CrossRefGoogle ScholarPubMed
32. Aguirre, V, Uchida, T, Yenush, L, Davis, R, White, MF. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J Biol Chem. 2000; 275, 9047–9054.CrossRefGoogle Scholar
33. Singh, R, Wang, Y, Xiang, Y, et al. Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology. 2009; 49, 87–96.CrossRefGoogle ScholarPubMed
34. Tan, Y, Rouse, J, Zhang, A, et al. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 1996; 15, 4629–4642.CrossRefGoogle Scholar
35. Solomon, SS, Odunusi, O, Carrigan, D, et al. TNF-alpha Inhibits Insulin Action in Liver and Adipose Tissue: A Model of Metabolic Syndrome. Horm Metab Res. (in press).Google Scholar
36. Hotamisligil, G. The role of TNFα and TNF receptors in obesity and insulin resistance. J Intern Med. 1999; 425, 621–625.CrossRefGoogle Scholar
37. Matsuzawa-Nagata, N, Takamura, T, Ando, H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism. 2008; 57, 1071–1077.CrossRefGoogle ScholarPubMed
38. Videla, LA, Rodrigo, R, Orellana, M, et al. Oxidative stress-related parameters in the liver of nonalcoholic fatty liver disease patients. Clin Sci (London). 2004; 106, 261–268.CrossRefGoogle Scholar
39. Urakawa, H, Katsuki, A, Sumida, Y, et al. Oxidative stress is associated with adiposity and insulin resistance in men. J Clin Endocrinol Metab. 2003; 88, 4673–4686.CrossRefGoogle ScholarPubMed
40. Cheng, W, Fu, XY, Porres, JM, Ross, DA, Lei, XG. Selenium-dependent cellular glutathione peroxidase protects mice against a pro-oxidant-induced oxidation of NADPH, NADH, lipids and protein. FASEB J. 1999; 13, 1467–1475.CrossRefGoogle ScholarPubMed
41. Kinalski, M, Sledziewski, A, Telejko, B, Zarzycki, W, Kinalska, I. Lipid peroxidation and scavenging enzyme activity in streptozotocin-induced diabetes. Acta Diabetol. 2000; 37, 179–183.CrossRefGoogle ScholarPubMed