Abstract
Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and inactivation by 5α- and 5β-reductases. A low carbohydrate diet increases hepatic 11β-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum ‘Western’ diet (37% fat, n = 36) for 22 weeks, then randomised to continue this diet (n = 12) or to switch to either a low carbohydrate (n = 12) or a moderate carbohydrate (n = 12) diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12) throughout. The low and moderate carbohydrate diets decreased hepatic 11β-HSD1 mRNA compared with the Western diet (both 0.7±0.0 vs 0.9±0.1 AU; p<0.01), but did not alter 11β-HSD1 in adipose tissue. 5α-Reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11β-HSD1 activity (1.6±0.1 vs 2.8±0.1 nmol/mcg protein/hr; p<0.001) and increased 5α-reductase and 5β-reductase mRNAs (1.9±0.3 vs 1.0±0.2 and 1.6±0.1 vs 1.0±0.1 AU respectively; p<0.01) in the liver, and reduced 11β-HSD1 mRNA and activity (both p<0.01) in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue), a low carbohydrate diet does not increase hepatic 11β-HSD1 in obese rats as occurs in humans.
Highlights
Glucocorticoids are potent regulators of energy metabolism
We recently examined the effects of dietary composition during weight loss in obese humans, and found that a high fat-low carbohydrate diet increased whole body 11bHSD1 activity and decreased 5a- and 5b-reductase activities compared with a moderate fat-moderate carbohydrate diet, with no effect on subcutaneous adipose tissue 11b-HSD1 [20]
After 22 weeks, obese rats were randomised to 3 further sub-groups (n = 12 each): one group remained on the Western diet; a second was placed on a ketogenic high fat-low carbohydrate diet (CHO 7%, protein 37%, fat 56%); while a third was commenced on a moderate fat-moderate carbohydrate diet (CHO 27%, protein 37%, fat 36%)
Summary
Glucocorticoids are potent regulators of energy metabolism. In addition to production by the adrenal glands, tissue glucocorticoid levels are regulated by several enzymes, 11bhydroxysteroid dehydrogenase type 1 (11b-HSD1). 11b-HSD1 functions in vivo to regenerate cortisol from inactive cortisone (corticosterone from inactive 11-dehydrocorticosterone in rodents) and is highly expressed in the liver and adipose tissue [1]. Control of tissue glucocorticoids is dysregulated in human obesity, with decreased cortisol levels in the liver secondary to reduced 11b-HSD1 activity [3,4] and increased 5a- and 5b-reductase activity [5,6]. In obese Zucker rats, 5a- and 5b-reductase activities are increased and 11b-HSD1 is decreased in the liver, while 11b-HSD1 is increased in adipose tissue [10,11]. The mechanism of these tissue-specific changes in glucocorticoid metabolism is unknown, but may reflect abnormal dietary intake in obesity
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