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Altered hepatic insulin signalling in male offspring of obese mice

Research output: Contribution to journalArticle

M. S. Martin-Gronert, D. S. Fernandez-Twinn, L. Poston, S. E. Ozanne

Original languageEnglish
Pages (from-to)184 - 191
Number of pages8
JournalJournal of Developmental Origins of Health and Disease
Volume1
Issue number3
DOIs
Published2010

King's Authors

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 p85 alpha 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 C zeta (P <0.001) and glycogen synthase kinase 3 beta (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.

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