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Fetal origins of insulin resistance and obesity

  • Claire J. Stocker (a1), Jonathan R. S. Arch (a1) and Michael A. Cawthorne (a1)

Abstract

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The ‘thrifty phenotype’ hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11β-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

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Corresponding author

*Corresponding author: Dr C. J. Stocker, fax +44 1280 820135, email claire.stocker@buckingham.ac.uk

References

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