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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 msm32@cam.ac.uk)
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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.

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