Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition

Gelernter-Yaniv, Liat; Feng, Ningping; Sebring, Nancy G.; Hochberg, Zèev; Yanovski, Jack A.

doi:10.1038/sj.ijo.0802327

Cited by 52 publications

(36 citation statements)

References 21 publications

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“…19 There is also one study that has reported a positive association of the ins4436A SNP in the HSD11B1 gene with body mass index (BMI) and insulin resistance in obese children. 20 Thus, the objective of the current study was to evaluate whether the unstudied variations in the HSD11B1 gene are associated with obesity and features of metabolic syndrome in a cohort of Spanish children.…”

Section: Introductionmentioning

confidence: 99%

A gene variant of 11β-hydroxysteroid dehydrogenase type 1 is associated with obesity in children

et al. 2012

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BACKGROUND:The 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) enzyme catalyses the regeneration of active cortisol from inert cortisone and plays a critical role in tissue-specific corticosteroid reactions; therefore, 11b-HSD1 is a key molecule associated with the development of obesity. Despite evidence for its role in obesity, no genetic polymorphisms have been significantly associated with the disease per se. OBJECTIVE: The aim of this study was to evaluate whether HSD11B1 gene variants, which have never been studied before, are associated with obesity and its related traits, as well as its relation to biomarkers of inflammation, liver damage and cardiovascular disease in a cohort of Spanish children. DESIGN: We performed a prospective case --control study. SUBJECTS: A total of 534 children were examined and classified as being obese (n ¼ 292) or normal weight (n ¼ 242). Anthropometric and biochemical measurements related to obesity, including inflammation, liver damage and cardiovascular disease, were determined. Genomic DNA was extracted and 10 HSD11B1 gene single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS: A novel SNP, rs3753519, was strongly associated with obesity and this SNP was the only statistically significant HSD11B1 gene SNP remaining after a Bonferroni correction (odds ratio ¼ 1.97 for allelic effect, 95% confidence interval 1.23--3.16; P ¼ 0.004 and Bonferroni corrected P ¼ 0.046). In addition, this SNP was significantly and positively associated with increased body mass index (BMI), BMI z-score, weight, waist circumference, plasma g-glutamyl transpeptidase and plasma active plasminogen activator inhibitor 1. The SNP was negatively associated with plasma adiponectin and cortisol after adjusting for sex and age. None of the inflammation biomarkers tested were associated with the risk allele. CONCLUSION: These data, which link an HSD11B1 genotype with both disease prevalence and its related phenotypes, strongly support a role for the rs3753519 polymorphism in the pathogenesis of pediatric-onset obesity.

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Section: Introductionmentioning

confidence: 99%

A gene variant of 11β-hydroxysteroid dehydrogenase type 1 is associated with obesity in children

et al. 2012

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“…Several studies have shown that 11␤HSD1 activity and expression in subcutaneous adipose tissue (SCAT) are positively correlated with obesity and insulin resistance in both men and women (11)(12)(13)(14)(15)(16)(17). In addition, polymorphic variability at the 11␤HSD1 locus is associated with increased waist-to-hip ratio in adults (18) and with body composition and insulin resistance in children (19).…”

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confidence: 99%

Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity

et al. 2005

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Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11␤-hydroxysteroid dehydrogenases (11␤HSDs). 11␤HSD1 activates GCs, while 11␤HSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11␤HSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocytespecific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11␤HSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11␤HSD2). Transgenic mice have increased 11␤HSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor ␥, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.

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“…Increased concentrations of 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1), the enzyme that catalyzes the local reactivation of circulating inert cortisone (11-dehydrocortisosterone in rodents) to cortisol (corticosterone) have been found in adipose tissue of obese patients (3)(4)(5)(6) and are closely related to adipose tissue accumulation and features of insulin resistance (5,6). Polymorphic variability at the 11␤-HSD-1 locus is associated with greater BMI, waist circumference, waistto-hip ratio, and insulin resistance in children (7) and with increased waist-to-hip ratio in adults (8). Transgenic mice with adipocyte-targeted 11␤-HSD-1 overexpression developed a visceral obesity that was exaggerated by a high-fat diet (9).…”

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confidence: 99%

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

et al. 2008

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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 (11␤-hydroxysteroid dehydrogenase type 1 [11␤-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 dietinduced 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 dietinduced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11␤-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 highfat 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 11␤-HSD-1 inhibitors. Diabetes 57:669-677, 2008

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Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition

Cited by 52 publications

References 21 publications

A gene variant of 11β-hydroxysteroid dehydrogenase type 1 is associated with obesity in children

A gene variant of 11β-hydroxysteroid dehydrogenase type 1 is associated with obesity in children

Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity

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

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