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Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet–Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood

From INSERM U626, Marseille, France, and the Faculté de Médecine, Aix-Marseille Université, Marseille, France

Address correspondence and reprint requests to Michel Grino, MD, PhD, INSERM U626, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France. E-mail: michel.grino{at}gmail.com

Key Words: 11β-HSD-1, 11β-hydroxysteroid dehydrogenase type 1 • AUC, area under the curve • C/EBPs, CCAAT/enhancer-binding proteins • CHF, control high-fat diet • CLF, control low-fat diet • EAT, epididymal adipose tissue • FFA, free fatty acid • GR, glucocorticoid receptor • IL, interleukin • MAT, mesenteric adipose tissue • PAI, plasminogen activator inhibitor • PHF, programmed high-fat diet • PLF, programmed low-fat diet • PPAR, peroxisome proliferator–activated receptor • TNF, tumor necrosis factor • TNF-R1, TNF receptor 1

OBJECTIVE—Alterations of the perinatal environment, which lead to increased prevalence of the metabolic syndrome in adulthood, program an upregulation of systemic and/or adipose tissue glucocorticoid metabolism (11β-hydroxysteroid dehydrogenase type 1 [11β-HSD-1]-induced corticosterone reactivation). We hypothesized that postnatal programming could modulate high-fat diet–induced adipose tissue dysregulation in adulthood.

RESEARCH DESIGN AND METHODS—We compared the effects of chronic (since weaning) high- or low-fat diet in postnatally normofed (control) or overfed (programmed) rats.

RESULTS—Postnatal programming accentuated high-fat diet–induced overweight, insulin resistance, glucose intolerance, and decrease in circulating and epididymal adipose tissue adiponectin. Neither manipulation altered liver function. Postnatal programming or high-fat diet increased systemic corticosterone production, which was not further modified when both manipulations were associated. Postnatal programming suppressed high-fat diet–induced decrease in mesenteric adipose tissue (MAT) glucocorticoid sensitivity and triggered high-fat diet–induced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11β-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-, TNF-receptor 1, interleukin (IL)-6, resistin, and plasminogen activator inhibitor-1 mRNAs were not changed by high-fat feeding in control rats and showed a large increase in programmed animals, with this effect further enhanced by high-fat diet for TNF- and IL-6.

CONCLUSIONS—Our data show for the first time that postnatal manipulation programs high-fat diet–induced upregulation of MAT glucocorticoid exposure, sensitivity, and inflammatory status and therefore reveal the pivotal role of the environment during the perinatal period on the development of diet-induced adipose tissue dysregulation in adulthood. They also urge the need for clinical trials with specific 11β-HSD-1 inhibitors.

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