Cortisol Metabolism After Weight Loss
Cortisol Metabolism After Weight Loss
Objective Increased glucocorticoid metabolite excretion and enhanced expression and activity of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue are closely correlated with obesity and its detrimental consequences. Weight loss ameliorates the latter. The aim of this study was to explore whether increased glucocorticoid exposure in obesity is improved with substantial weight loss and thus is a consequence rather than a cause of obesity.
Design and patients A prospective cohort study in 31 women.
Measurements 11β-HSD type 1 expression and activity, urinary glucocorticoid metabolite excretion, body composition including regional adipose tissue depots and insulin resistance by HOMA-IR before and 2 years after gastric bypass surgery.
Results After weight loss, excretion of cortisol and cortisone metabolites decreased. Both cortisol and cortisone metabolite excretion correlated with central obesity, where the intraabdominal fat depot showed the strongest association. Cortisol metabolites correlated with 11β-HSD type 1 activity in abdominal subcutaneous adipose tissue. The ratio of cortisol to cortisone metabolites [(5α-tetrahydrocortisol (5αTHF) + tetrahydrocortisol (THF) + α-cortol)/(tetrahydrocortisone (THE) + α-cortolone)] and the ratio of 5α-THF/THF both decreased after stable weight loss, reflecting a downregulation of the net activities of 11β-HSD type 1 and 5α-reductase.
Conclusion Long-term weight loss in women is not only followed by reduced glucocorticoid production, but also favourably decreases the global and tissue-specific activity of the cortisol-activating enzyme 11 β-HSD type 1, possibly contributing to the health benefits of bariatric surgery.
The similarities between obesity and Cushing's syndrome are well recognized, but circulating cortisol levels are not elevated in obesity. There is increasing evidence that altered prereceptor cortisol metabolism is of importance for the development of the harmful components of the metabolic syndrome including obesity. The most important enzyme responsible for the reversible activation of cortisol, 11β-hydroxysteroid dehydrogenase, has been extensively explored with its isoforms, type 1 and 2, being differently expressed in different organs, i.e. glucocorticoid action is tissue specific. Obesity and other components of the metabolic syndrome are linked to increased adipose tissue 11β-HSD type 1 expression and activity, but whether this upregulation is enough for a systemic hypercortisolism in obese individuals, facilitating the development of the metabolic syndrome, is not well understood.
Obesity is associated with increased glucocorticoid production, and although men excrete more glucocorticoid metabolites than women, this correlation is not sex specific. Correlations between glucocorticoid secretion and other components of the metabolic syndrome, i.e. insulin sensitivity, hypertension and HDL cholesterol, have also been seen in cross-sectional studies.
Total glucocorticoid production in man can be estimated by analysing the sum of glucocorticoid metabolites in a 24-h urinary sample. The relative excretion of cortisol to cortisone metabolites [(5α-THF + THF + α-cortol)/(THE + α-cortolone)] reflects the global activity of 11β-HSD type 1, and although a technique with isotopically labelled cortisol is more accurate, GC-MS measurement of urinary glucocorticoid metabolites provides a useful tool for evaluating overall 11β-HSD activity, as does the ratio of 5α-THF to THF for estimating the activity of 5α-reductase.
Comprehensive studies have shown that measurement of urinary free cortisol and cortisone provides the best estimate of 11β-HSD type 2 activity. This enzyme is mainly expressed in kidney, protecting the mineral corticoid receptor against excessive cortisol levels.
Recently, increased cortisol excretion has been shown to predict cardiovascular mortality, reviving the hypothesis of the harmful action of excessive cortisol as a mediator of the atherosclerotic process, and possibly a marker for negative stress. The best way to evaluate the cause and consequence of increased cortisol exposure in the natural history of obesity would of course be to follow a cohort from the nonobese to the obese state, but because this is difficult to achieve in human studies, models of weight loss could be an interesting alternative, especially with emphasis on 11β-HSD type 1.
Weight loss and glucocorticoid production have only been studied in short time term series and, not to our knowledge, separately in women. Earlier studies were based on low calorie diets as means of weight loss, with a maximum follow-up time of approximately 4 months. Glucocorticoid production decreased in three of four studies, but a short period of starvation (6 days) induced increased cortisol secretion. The long-term effect of weight loss is not known. Gastric bypass surgery has become the most common surgical technique to achieve lasting weight loss, owing to relatively few postoperative problems and good results. Several studies have shown a rapid weight loss during the first postoperative year, with a weight stabilization after approximately 1–2 years. Treatment of obesity with bariatric surgery decreases comorbidity and mortality.
Here, we report a study of a group of obese women, before and 2 years after bariatric surgery, analysing glucocorticoid production including urinary metabolites, exploring the net changes in 11β-HSD type 1 activity and its correlations with obesity and weight loss, with the hypothesis that weight loss is followed by a decreased local as well as overall 11β-HSD type 1 activity.
Abstract and Introduction
Abstract
Objective Increased glucocorticoid metabolite excretion and enhanced expression and activity of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue are closely correlated with obesity and its detrimental consequences. Weight loss ameliorates the latter. The aim of this study was to explore whether increased glucocorticoid exposure in obesity is improved with substantial weight loss and thus is a consequence rather than a cause of obesity.
Design and patients A prospective cohort study in 31 women.
Measurements 11β-HSD type 1 expression and activity, urinary glucocorticoid metabolite excretion, body composition including regional adipose tissue depots and insulin resistance by HOMA-IR before and 2 years after gastric bypass surgery.
Results After weight loss, excretion of cortisol and cortisone metabolites decreased. Both cortisol and cortisone metabolite excretion correlated with central obesity, where the intraabdominal fat depot showed the strongest association. Cortisol metabolites correlated with 11β-HSD type 1 activity in abdominal subcutaneous adipose tissue. The ratio of cortisol to cortisone metabolites [(5α-tetrahydrocortisol (5αTHF) + tetrahydrocortisol (THF) + α-cortol)/(tetrahydrocortisone (THE) + α-cortolone)] and the ratio of 5α-THF/THF both decreased after stable weight loss, reflecting a downregulation of the net activities of 11β-HSD type 1 and 5α-reductase.
Conclusion Long-term weight loss in women is not only followed by reduced glucocorticoid production, but also favourably decreases the global and tissue-specific activity of the cortisol-activating enzyme 11 β-HSD type 1, possibly contributing to the health benefits of bariatric surgery.
Introduction
The similarities between obesity and Cushing's syndrome are well recognized, but circulating cortisol levels are not elevated in obesity. There is increasing evidence that altered prereceptor cortisol metabolism is of importance for the development of the harmful components of the metabolic syndrome including obesity. The most important enzyme responsible for the reversible activation of cortisol, 11β-hydroxysteroid dehydrogenase, has been extensively explored with its isoforms, type 1 and 2, being differently expressed in different organs, i.e. glucocorticoid action is tissue specific. Obesity and other components of the metabolic syndrome are linked to increased adipose tissue 11β-HSD type 1 expression and activity, but whether this upregulation is enough for a systemic hypercortisolism in obese individuals, facilitating the development of the metabolic syndrome, is not well understood.
Obesity is associated with increased glucocorticoid production, and although men excrete more glucocorticoid metabolites than women, this correlation is not sex specific. Correlations between glucocorticoid secretion and other components of the metabolic syndrome, i.e. insulin sensitivity, hypertension and HDL cholesterol, have also been seen in cross-sectional studies.
Total glucocorticoid production in man can be estimated by analysing the sum of glucocorticoid metabolites in a 24-h urinary sample. The relative excretion of cortisol to cortisone metabolites [(5α-THF + THF + α-cortol)/(THE + α-cortolone)] reflects the global activity of 11β-HSD type 1, and although a technique with isotopically labelled cortisol is more accurate, GC-MS measurement of urinary glucocorticoid metabolites provides a useful tool for evaluating overall 11β-HSD activity, as does the ratio of 5α-THF to THF for estimating the activity of 5α-reductase.
Comprehensive studies have shown that measurement of urinary free cortisol and cortisone provides the best estimate of 11β-HSD type 2 activity. This enzyme is mainly expressed in kidney, protecting the mineral corticoid receptor against excessive cortisol levels.
Recently, increased cortisol excretion has been shown to predict cardiovascular mortality, reviving the hypothesis of the harmful action of excessive cortisol as a mediator of the atherosclerotic process, and possibly a marker for negative stress. The best way to evaluate the cause and consequence of increased cortisol exposure in the natural history of obesity would of course be to follow a cohort from the nonobese to the obese state, but because this is difficult to achieve in human studies, models of weight loss could be an interesting alternative, especially with emphasis on 11β-HSD type 1.
Weight loss and glucocorticoid production have only been studied in short time term series and, not to our knowledge, separately in women. Earlier studies were based on low calorie diets as means of weight loss, with a maximum follow-up time of approximately 4 months. Glucocorticoid production decreased in three of four studies, but a short period of starvation (6 days) induced increased cortisol secretion. The long-term effect of weight loss is not known. Gastric bypass surgery has become the most common surgical technique to achieve lasting weight loss, owing to relatively few postoperative problems and good results. Several studies have shown a rapid weight loss during the first postoperative year, with a weight stabilization after approximately 1–2 years. Treatment of obesity with bariatric surgery decreases comorbidity and mortality.
Here, we report a study of a group of obese women, before and 2 years after bariatric surgery, analysing glucocorticoid production including urinary metabolites, exploring the net changes in 11β-HSD type 1 activity and its correlations with obesity and weight loss, with the hypothesis that weight loss is followed by a decreased local as well as overall 11β-HSD type 1 activity.
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