Obesity Cortisol Metabolism

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Cortisol is subjected to metabolic transformations in the periphery, which are of importance for the impact of cortisol on peripheral target tissues. This area is reviewed in the chapter by Walker and Seckl (Chapter 18), where detailed references can be found, and is only discussed here in relation to the central perturbations of HPA axis activity, reviewed in the preceding section.

There are two main systems regulating cortisol metabolism. One is the 5a reductases which transfer cortisol to tetrahydrocortisone, which is an essentially inactive metabolite excreted in the urine. The other system is the 11^-hydroxysteroid dehyd-

rogenases (HSD), which consist of the HSD1, converting cortisone to Cortisol, and the HSD2, converting Cortisol to cortisone. In humans cortisone is a much less powerful glucocorticoid than cortisol.

There is evidence for an increased activity in obesity of 5a-reductase and HSD2, which inactivates cortisol. This would be expected to result in less active occupancy of the central glucocorticoid receptors (GR) which regulate cortisol secretion by a negative feedback mechanism (9), and an elevated cortisol secretion would be the expected outcome. In a recent study cortisol measurements have been adjusted for the body mass index (BMI), in an attempt to examine cortisol secretion without the influence of adipose tissue inactivation. This resulted in a visualization of elevated cortisol secretion in obesity (24). Consequently peripheral inactivation of cortisol might explain the elevated cortisol secretion in obesity.

It is, however, apparently not possible to explain why cortisol secretion is particularly elevated in centrally localized obesity, since an elevated cortisol secretion along this mechanism would be expected to be dependent on total mass of adipose tissue irrespective of its localization. Furthermore, if cortisol is rapidly inactivated in the peripheray, this would not be expected to result in peripheral consequences of hypercortisolism, as seen in central obesity.

Local elevations of the HSD1, which has been reported to occur in visceral fat depots, might have local effects but it seems difficult to imagine that a secretion of cortisol from visceral fat would have systemic effects, due to the small mass of this tissue. Cortisol from such elevated secretion would presumably also be inactivated peripherally. It is also difficult to understand the relationships, if any, between mechanisms, working on the regulatory centres of the HPA axis, described in the preceding section, and peripheral metabolism of cortisol. It might be considered that the peripheral enzymes involved in cortisol metabolism are secondarily modified by obesity-related factors such as cotisol itself, insulin and other hormone secretions which are abnormal.

These peripheral conversions of cortisol add to the complexity of this field, but are clearly important for the understanding of the problems involved. Parallel studies of both the central and peripheral mechanisms, regulating the net concentration of circulating glucocorticoids and their interaction with peripheral target tissues, would be needed to understand potential interactions and the resulting outcome.

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