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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
Issue number3

King's Authors


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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