Editors' ChoiceMetabolic Syndrome

Mechanism of a Metabolic Shift in Monkeys

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Science Translational Medicine  13 Jan 2010:
Vol. 2, Issue 14, pp. 14ec4
DOI: 10.1126/scitranslmed.3000805

The metabolic syndrome (MetS) and its principal features—insulin resistance, visceral adiposity, abnormal blood lipid concentrations, and high blood pressure—have been linked to an adverse intrauterine environment. Both poor maternal nutrition and fetal glucocorticoid exposure have been proposed as etiological hypotheses of the developmental origins of cardiometabolic disease; however, the biological processes that link intrauterine insults to adverse metabolic programming are not yet understood. Now, Nyirenda et al. investigate the mechanistic effects of fetal glucocorticoid exposure on MetS in a nonhuman primate model.

Although MetS resembles a state of glucocorticoid excess, in most cases plasma cortisol levels in patients with MetS are not elevated. This finding suggests that these MetS patients display increased tissue sensitivity to glucocorticoid action in the major metabolic organs, as determined by the number of glucocorticoid receptors and the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyzes the generation of active cortisol from inert cortisone.

Studies of 11β-HSD1 expression in the major metabolic organs and its relation to the development of MetS have been limited because of differences in 11β-HSD1 gene regulation between humans and rodent models of MetS, underscoring the importance of using relevant animal models in the evaluation of human disease. Nyirenda et al. studied early-life antecedents of MetS and 11β-HSD1 expression in the common marmoset monkey. The authors showed that brief exposure of the fetus to glucocorticoids during late gestation led to permanent tissue-specific changes in 11β-HSD1 expression and MetS features (increased body weight, elevated fasting glucose concentrations, and a trend toward elevated fasting triglyceride concentrations) in the offspring without affecting glucocorticoid receptor expression. These observations suggest that long-term upregulation of 11β-HSD1 expression in metabolically active tissues may follow prenatal stress hormone exposure. Together with the fact that many individuals with MetS have increased 11β-HSD1 expression in their major metabolic organs, these data offer a new mechanism for the fetal origins of MetS and suggest that a deeper understanding of the molecular mechanisms that regulate 11β-HSD1 expression may pave the way to new therapies for this prevalent syndrome.

M. J. Nyirenda et al., Prenatal programming of metabolic syndrome in the common marmoset is associated with increased expression of 11β-hydroxysteroid dehydrogenase type 1. Diabetes 58, 2873–2879 (2009). [Abstract]

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