The role of 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

Nisbet, Janelle Cherie (2012). The role of 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome PhD Thesis, Diamantina Institute, The University of Queensland.

       
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Author Nisbet, Janelle Cherie
Thesis Title The role of 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome
Formatted title The role of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome
School, Centre or Institute Diamantina Institute
Institution The University of Queensland
Publication date 2012
Thesis type PhD Thesis
Supervisor John Prins
David McIntyre
Jon Whitehead
Total pages 159
Total colour pages 5
Total black and white pages 154
Language eng
Subjects 060103 Cell Development, Proliferation and Death
060107 Enzymes
110306 Endocrinology
Formatted abstract Obesity is a major public health problem. Central or visceral obesity is associated with hypertension, dyslipidaemia, and insulin resistance. This clustering of abnormalities is known as the metabolic syndrome.

Both exogenous administration of glucocorticoids and the endocrine disease Cushing’s syndrome are associated with increased circulating glucocorticoid levels. This leads to a clinical phenotype of central obesity, insulin resistance, dyslipidaemia, and hypertension. The similarities between this and metabolic syndrome have stimulated considerable interest in the role of glucocorticoids in obesity and metabolic syndrome. Circulating cortisol levels are normal or low in obesity, and interest has thus focused on tissue cortisol levels. Tissue cortisol levels are regulated by the enzyme 11ß-hydroxysteroid dehydrogenase (11ß HSD). 11ß-HSD type 1, located within adipose tissue and the liver, catalyses the conversion of cortisone to cortisol, the biologically active form of glucocorticoid. The purpose of this research project was to further elucidate the role of 11ß-HSD type 1 in obesity and metabolic syndrome.

Biochemical and anthropometric were examined in a group of 109 individuals, ranging from lean through to morbidly obese. Lower circulating cortisol levels were found in those who were overweight and obese compared with those of normal body weight. Circulating cortisone levels were likewise reduced in the overweight and obese group. The cortisol: cortisone ratio was ascertained, and was not significantly different between groups.

The presence or absence of a candidate genetic polymorphism ins4436A in the HSD11B1 gene was determined in 106 individuals as a pilot study. Forty percent (42/106) of individuals were heterozygous and one individual was homozygous for this polymorphism. Overall, the ins4436A polymorphism was associated with higher morning cortisol levels and lower circulating DHEAS. After correcting for age, sex, and BMI, this polymorphism was significantly associated with fasting insulin and HOMA insulin resistance, as well as remaining significantly associated with DHEAS. We hypothesize that the ins4436A polymorphism, within intron 3 of the HSD11B1 gene, is located in a region associated with post-transcriptional regulation. The presence of this polymorphism may be up-regulating 11ß-HSD type 1 activity, leading to the higher tissue cortisol levels. Higher levels of cortisol produced in peripheral tissues will lead firstly to increased insulin resistance, and secondly to a reduction in adrenal stimulation, with consequent lower circulating adrenal androgens. 3 The depot-specific enzyme activity and gene expression of 11ß-HSD type 1 were determined in adipose tissue explants, and correlated with biochemical and anthropometric characteristics in a group of patients over a broad range of BMI. Overall, 11ß-HSD type 1 activity and expression were significantly greater in omental adipose tissue than subcutaneous adipose tissue. Furthermore, a negative correlation was demonstrated between omental 11ß-HSD type 1 enzyme activity and insulin resistance. Insulin may have a role in post-transcriptional regulation of 11ß HSD type 1, possibly to compensate for the potential deleterious metabolic effects of increased cortisol.

The glucocorticoid profile of normal individuals was examined. Morning cortisol, cortisone, and the cortisol: cortisone ratio were reproducible within individuals, but varied significantly between individuals. Cortisol displayed a diurnal rhythm whilst cortisone levels declined through the day in 4/8 individuals, and were variable over the 24 hours in the remaining 4 individuals. The cortisol: cortisone ratio declined through the day. The serum cortisol: cortisone ratio did not significantly correlate with the 24 hour urinary cortisol and cortisone metabolite (THF: THE) ratio, an accepted measure of global 11ß-HSD type 1 activity.

The role of 11ß-HSD type 1 was also examined in relation to the differentiation of Simpson-Golabi- Behmel Syndrome (SGBS) and primary human preadipocytes from both omental and subcutaneous adipose tissue depots. Primary human preadipocytes from both the omental and subcutaneous adipose tissue depots differentiated with cortisone displayed greater accumulation of lipid droplets both morphologically and when quantified with oil red-O staining. As well, cells differentiated with cortisone displayed greater G3PDH activity and had greater adiponectin gene expression. These findings were also true for SGBS cells, predominantly when differentiated with cortisone in the absence of dexamethasone. Thus 11ß-HSD type 1 is active in the production of intracellular cortisol throughout the differentiation of primary human preadipocytes. This reinforces a potential therapeutic role for targeted 11ß-HSD type 1 inhibitors in the management of obesity.

The findings presented in this thesis support a role for cortisol, generated intracellularly by the 11ß- HSD type 1 enzyme, in the pathogenesis of obesity, insulin resistance, and metabolic syndrome. Inhibition of the 11ß-HSD type 1 enzyme has become a target for pharmaceutical drug development and may prove useful in the management of obesity and metabolic syndrome.
Keyword 11beta-hydroxysteroid dehydrogenase type 1
Glucocorticoid
Adipose tissue
Obesity
Metabolic syndrome
Preadipocyte differentiation

 
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Created: Mon, 17 Sep 2012, 19:55:06 EST by Dr Janelle Nisbet on behalf of Scholarly Publishing and Digitisation Service