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Programming of Rat Muscle and Fat Metabolism by in Utero Overexposure to Glucocorticoids

Endocrinology Unit, Departments of Medical Sciences (M.E.C., B.R.W., J.R.S.), and Clinical Neuroscience (P.A.T.K.), University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, United Kingdom

Address all correspondence and requests for reprints to: Professor Jonathan R. Seckl, Endocrinology Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, United Kingdom. E-mail: j.seckl{at}ed.ac.uk.

In utero overexposure to glucocorticoids may explain the association between low birth weight and subsequent development of the metabolic syndrome. We previously showed that prenatal dexamethasone (dex) exposure in the rat lowers birth weight and programs adult fasting and postprandial hyperglycemia, associated with increased hepatic gluconeogenesis driven by elevated liver glucocorticoid receptor (GR) expression. This study aimed to determine whether prenatal dex (100 µg/kg per day from embryonic d 15 to embryonic d 21) programs adult GR expression in skeletal muscle and/or adipose tissue and whether this contributes to altered peripheral glucose uptake or metabolism. In utero dex-exposed rats remained lighter until 6 months of age, despite some early catch-up growth. Adults had smaller epididymal fat pads, with a relative increase in muscle size. Although glycogen storage was reduced in quadriceps, 2-deoxyglucose uptake into extensor digitorum longus muscle was increased by 32% (P < 0.05), whereas uptake in other muscles and adipose beds was unaffected by prenatal dex. GR mRNA was not different in most muscles but selectively reduced in soleus (by 23%, P < 0.05). However, GR mRNA was markedly increased specifically in retroperitoneal fat (by 50%, P < 0.02). This was accompanied by a shift from peroxisomal proliferator-activated receptor 1 to 2 expression and a reduction in lipoprotein lipase mRNA (by 28%, P < 0.02). Adipose leptin, uncoupling protein-3 and resistin mRNAs, muscle GLUT-4, and circulating lipids were not affected by prenatal dex. These data suggest that hyperglycemia in 6-month-old rats exposed to dexamethasone in utero is not due to attenuated peripheral glucose disposal. However, increased GR and attenuated fatty acid uptake specifically in visceral adipose are consistent with insulin resistance in this crucial metabolic depot and could indirectly contribute to increased hepatic glucose output.

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