The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11<i>β</i>-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis.
Hence, 11beta-HSD1 acts at the interface of inflammation and obesity and represents an efficient integrator and effector of local inflammatory and metabolic state.
Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration.
Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.
Extensive data have been obtained in mice with transgenic over-expression of 11beta-HSD1 in liver and adipocytes, targeted deletion of 11beta-HSD1, and using novel selective 11beta-HSD1 inhibitors; these data support the use of 11beta-HSD1 inhibitors to lower intracellular glucocorticoid levels and treat both obesity and its metabolic complications.
As 11beta-HSD1 expression in lean women was found to be significantly lower than in lean males, the up-regulation associated with obesity may be relatively more devastating in women than in men, and may help explain the higher relative risk of cardiovascular disease in women suffering from the metabolic syndrome.
Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity.
Increasing 11beta-HSD1 and leptin mRNA in SC with increasing BMI SDS could suggest that the risk of metabolic consequences of obesity may be established early in life.
Our objective was to investigate a functional polymorphism in HSD11B1 (T-->G in the third intron rs12086634, which associates with lower 11beta-HSD1 activity) in PCOS with and without obesity.
Our data show the involvement of 11beta-HSD1 enzyme invisceral obesity, which is more evident in severely obese patients than in Cushing's syndrome patients.
'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.Conversely, 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma).
Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
We confirmed that adipocyte 11beta-HSD1 mRNA concentrations were associated with adiposity, and showed that genetic variations in the HSD11B1 gene were associated with Type 2 diabetes mellitus, plasma insulin concentrations and insulin action, independent of obesity.
'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome.
However, weak associations between HSD11B1 genotype, increased 11beta-HSD1 activity, and W:H ratio suggest that polymorphic variability at the HSD11B1 locus may influence susceptibility to central obesity through enhanced 11beta-HSD1 activity (E to F conversion) in visceral adipose tissue.
The main results of our study are the exclusion of a common association of 11beta-HSD1 mutations to obesity and the identification of two novel allelic variants for the gene 11beta-HSD1 in the Italian population, not previously described in any database.