Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women.
Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue were studied.
Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11βHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11βHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months.
Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.
Excessive cortisol production in Cushing’s syndrome leads to visceral fat accumulation, dyslipidemia, hypertension and diabetes.1 This has suggested that hypercortisolism may be a link to metabolic dysregulation in obesity. However, circulating cortisol levels are lower than the normal in obesity,2 which may at least partly be due to an increased metabolic clearance rate of glucocorticoids.3, 4 Therefore increased systemic cortisol levels do not seem to explain the link between obesity and metabolic dysregulation. Importantly, cortisol levels can be regulated locally in tissues independently of blood cortisol concentrations.
The enzyme 11β hydroxysteroid dehydrogenase type 1 (11βHSD1) converts cortisone into cortisol and is expressed in several tissues ,for example, liver, adipose, brain and immune cells.5 Over-expression of adipose 11βHSD1 in transgenic mice leads to development of visceral adiposity, hyperlipidemia and insulin resistance,6 whereas mice with selective disruption of 11βHSD1 are resistant to high-fat diet-induced obesity.7 In obese humans, expression and activity of 11βHSD1 are increased in subcutaneous adipose tissue (SAT)8 and initial studies suggested decreased hepatic 11βHSD1 activity,8 but this has been contradicted by more recent studies.3 In obesity-associated type 2 diabetes 11βHSD1 activity is similarly increased in SAT and maintained in the liver leading to increased systemic extra-adrenal cortisol production.3, 9
Glucocorticoids are metabolized by 5α- and 5β-reductase in the liver and increased clearance rate of glucocorticoids, predominantly by 5α-reductase, has been suggested to be a primary change of glucocorticoid metabolism in obesity10 and associated with insulin resistance.11, 12 However this may represent a protective response since use of dual 5α-reductase inhibitors in men promotes insulin resistance,13 a phenotype recapitulated in rodents with genetic disruption of 5αR1.14
Short-term weight loss induced by calorie restriction is associated with decreased excretion of urinary glucocorticoid metabolites and decreased 5α-reduction of glucocorticoids but no change in systemic or hepatic 11βHSD1 activity.15, 16, 17 Initial studies achieving only 5–10% weight loss found unaltered,18 or increased16 11βHSD1 expression in SAT, but more recent data suggest that greater weight loss is associated with decreased expression and activity of 11βHSD1 in SAT.19, 20 Macronutrients may also alter local-tissue glucocorticoid metabolism independently of weight. For example, a single high-carbohydrate meal increased post-prandial extra-adrenal regeneration of cortisol by 11βHSD1, more so than a high-protein or high-fat meal.21 Furthermore, 4 weeks of a low-carbohydrate/high-fat diet decreased glucocorticoid clearance by 5α- and 5β-reduction, and increased systemic 11βHSD1 activity in obese men;22 thus reversing the abnormal glucocorticoid metabolism associated with obesity. The effects of long-term (>6 months) dietary interventions with different macronutrient composition on tissue-specific glucocorticoid metabolism are, however, unknown.
The use of a paleolithic-type diet (PD) is based on the hypothesis that humans are adapted to food that has been present throughout evolution. Advocates of this theory propose that the relatively recent changes in our diet with increased energy intake from grains, dairy products and refined fat and sugar has predisposed to the development of cardiovascular disease.23 Recent short-term studies suggest that a paleolithic diet with a high intake of fruits, berries, nuts, lean meat and fish lowers hepatic lipid content24 and improves glucose tolerance compared with a Mediterranean diet.25 The Nordic nutrition recommendations (NNR) is a conventional low-fat/high-fiber diet and the basis for general diet advice given in the Nordic countries.26 In a recent publication we reported that both a PD and a diet according to NNR ad libitum led to sustained weight loss over 24 months with a significantly greater reduction of weight after 6, 12 and 18 months in the PD group.27
We hypothesized that diet-induced weight loss chronically reverses the abnormal glucocorticoid metabolism observed in human obesity. Furthermore, we hypothesized that the PD would normalize glucocorticoid metabolism to a greater extent than the NNR diet. To test this, we investigated the effects of a 2-year dietary intervention, using either a modified PD or a diet according to NNR, on tissue-specific metabolism of glucocorticoids in overweight and obese postmenopausal women.
Materials and Methods
Seventy overweight/obese (body mass index (BMI) >27 kg m-2) postmenopausal women were recruited by advertisement in newspapers and within Umeå University Hospital area. Exclusion criteria were as follows: a history of diabetes, current glucocorticoid treatment and those already maintaining a restricted diet. A postmenopausal state was defined as no menstrual periods during the last 12 months (for further details see Mellberg et al.27). We excluded 21 participants that did not complete measurements of either 24-hour urine samples, a cortisone conversion test or SAT biopsies at baseline, after 6 and 24 months, resulting in 49 participants for the final analysis. There were no significant differences between the 49 included and 21 excluded participants in weight, BMI, waist circumference, total body fat or homeostasis model assessment for insulin resistance (HOMA-IR) at baseline (data not shown). The ethical committee of Umeå University approved the study and all participants gave written informed consent before inclusion.
Participants were randomized to a PD27 or a diet according to NNR.26 The PD was based on foods such as lean meat, poultry, fish, eggs, fruits, berries and nuts. Dairy products, cereals, added sugar and salt were avoided. The PD aimed to provide 30 energy percent (E%) as protein, 30 E% as carbohydrates and 40 E% as fat with a high proportion of mono- and polyunsaturated fatty acids. The diet according to NNR aimed to provide 55–60 E% as carbohydrates, 25–30 E% as fat and 15 E% as protein, with emphasis on low-fat dairy and high-fiber products. Energy intake in both diets was ad libitum. During the 24 month study period, subjects attended 12 group sessions with a dietician to ensure compliance with their diet. Food diaries and nitrogen levels in 24-h urine samples were used at baseline, 6 and 24 months to measure food intake. For details regarding diet validation see.27
All measures and examinations were performed during a 3-week period at baseline, 6 and 24 months. Weight was measured to the nearest 0.1 kg in light clothing on a digital scale and height to the nearest 0.5 cm. BMI was calculated as the ratio of body weight to the square of height (kg m-2). Waist circumference was measured using a tape midway between the lowest rib and the iliac crest during gentle exhalation and hip circumference as the maximum circumference around the buttocks. Body composition was determined by dual energy X-ray absorptiometry (GE Medical Systems, Lunar Prodigy X-ray Tube Housing Assembly, Brand BX-1L, Model 8743, Madison, WI, USA). Blood pressure was measured after 5 min rest in the sitting position with an automated blood pressure meter (Boso-Medicus, Bosch, Jungingen, Germany).
Fasting plasma cortisol (Elecsys Cortisol kit, Roche Diagnostics, Branchburg, NJ, USA), glucose (Vitros GLU, Johnson & Johnson, New Brunswick, NJ, USA), and fasting serum insulin (Elecsys Insulin kit, Roche Diagnostics), cholesterol (Vitros CHOL, Johnson & Johnson), triglycerides (Vitros TRIG, Johnson & Johnson) and high-density lipoprotein (Vitros dHDL, Johnson & Johnson) were analyzed at the Department for Clinical Chemistry, Umeå University Hospital. Low-density lipoprotein was calculated as (serum cholesterol—serum high-density lipoprotein—serum triglycerides)/2.2. The HOMA-IR, ((fasting glucose × fasting insulin)/22.5) was used to estimate insulin resistance.
Urine was collected for 24 h and stored at −80 °C until analysis of glucocorticoid metabolites. A cortisone to cortisol conversion test was performed; at 2300 h the day before the test, participants took 1 mg dexamethasone orally (Dexamethason, Galepharm, Küssnacht, Germany) to suppress the hypothalamic pituitary adrenal axis. At 0800 h the following day, subjects attended the Clinical research center at Umeå University Hospital where fasting venous blood samples were drawn. Cortisone acetate (25 mg ) (Cortison, Nycomed Pharma, Asker, Norway) was given orally and blood sampled for the following 4 h during which plasma cortisol (Cobas E Cortisol regency kits, Cobas 6000, Roche Diagnostics) was analyzed. A needle biopsy of periumbilical SAT was taken under local anesthesia (Xylocain 10 mg ml-1, AstraZeneca, Södertälje, Sweden), washed in saline, immediately frozen in liquid nitrogen and then stored at −80 °C until analysis of transcript levels, this was not done in a fasted state. The urinary collection, the cortisone to cortisol conversion test and the SAT biopsy were performed on three separate, nonconsecutive days.
Urinary glucocorticoid metabolites
5α-Tetrahydrocortisol (5α-THF), 5β-tetrahydrocortisol (5β-THF), 5β-tetrahydrocortisone (THE), free cortisol and cortisone were analyzed in the 24-h urine samples using gas chromatography mass spectrometry. The ratios of these glucocorticoid metabolites were then used as indices of 11βHSD1, 5α-reductase and 5β-reductase activity as previously described.28
Real-time quantitative RT-PCR
Total RNA was extracted according to the manufacturer’s instructions from a maximum of 100 mg AT using the RNeasy lipid tissue mini kit (Qiagen Nordic, Qiagen House, West Sussex, UK). The RNA concentrations were measured on a ND-1000 Spectrophotometer (NanoDrop Technologies, Bancroft Building, Wilmington, DE, USA).
Two micrograms of RNA was reverse transcribed using TaqMan Reverse Transcription Reagents (Roche Molecular Systems, Inc). Relative quantification real-time PCR was carried out using an ABI Prism 7000 Sequence Detection System or 7900HF Fast Real-time PCR (Applied Biosystems, Foster City, CA, USA) according to the manufacturer’s instructions using Universal PCR Master Mix 2X (Roche Molecular Systems, Inc.) and TaqMan Gene expression assays for target gene 11βHSD1 (assay no. Hs00194153_m1) and the endogenous control low-density lipoprotein receptor-related protein 10 (LRP10) (assay no. Hs01047362_m1)(Applied Biosystems). All reactions were performed in duplicates. Data were normalized against LRP10 and the comparative CT method (ΔΔ Ct) used for relative quantification of gene expression.
Distribution of the data was analyzed with the Kolmogorov–Smirnov test. Plasma glucose, HOMA-IR, total urinary glucocorticoid excretion and area under the curve (AUC) for plasma cortisol levels after orally taken cortisone had skewed distributions and were logarithmically transformed, and achieved normal distribution, before statistical analysis. The data are presented as means with s.d. A mixed-design analysis of variance was used to evaluate main effects of diet, time and diet × time interactions on study variables. Percental changes in total urinary glucocorticoid excretion, 5α-THF/5β-THF, 5α-THF/Cortisol, (5α-THF/5β-THF)/THE and AUC for plasma cortisol levels after orally taken cortisone between baseline and 24 months were calculated and presented as mean. Correlations between percental changes in total urinary glucocorticoid excretion, 5α-THF/5β-THF, (5α-THF+5β-THF)/THE, AUC for plasma cortisol levels after oral cortisone and 11βHSD1 mRNA in SAT to percental changes in BMI and HOMA-IR between baseline to 6 and baseline to 24 months were analyzed with Pearson correlations. A two-sided P-value of <0.05 was considered significant. All analyzes were performed using SPSS version 21 (SPSS Inc. Chicago, IL, USA).
Anthropometric and biochemical measurements
The results from the full diet intervention have been published separately.27 There were no baseline differences between diet groups. Both groups lost weight and decreased BMI, waist circumference and body fat throughout the study (Table 1, time effect P<0.001 for all). At 6 months the PD group had a greater reduction of weight, BMI (diet × time effect P⩽0.001) and body fat (diet × time effect P⩽0.01) than the NNR group. However, at 24 months, there were no significant differences in anthropometric measurements between the groups. Fasting serum insulin and HOMA-IR decreased at 6 months (time effect P<0.01) but was unaltered after 24 months (with respect to baseline). Systolic and diastolic blood pressure decreased at 6 months (time effect P<0.001), but had increased to baseline levels after 24 months. Fasting serum cholesterol decreased after 6 months (time effect P<0.001) but was unaltered at 24 months compared with baseline. Fasting serum triglycerides, and low-density lipoprotein decreased throughout the intervention (time effect 6 months P<0.001, 24 months P<0.01) whereas high-density lipoprotein increased after 24 months (time effect P<0.001). There were no group differences in blood pressure, fasting serum insulin, HOMA-IR or blood lipids. Morning plasma cortisol levels increased at 6 and 24 months in both diet groups (Table 1, time effect, P<0.05).
Twenty-six participants in the PD group and 17 participants in the NNR group provided 24-hour urine samples at baseline, 6 and 24 months. By 24 months, there were significant changes in the urinary glucocorticoid metabolites compared with baseline, these changes occurred predominantly between 6 and 24 months (Table 2). Between baseline and 24 months, total excretion of glucocorticoid metabolites in 24-hour urine increased 12% in the PD group and 19% in the NNR group, which was primarily due to increased excretion of 5α-THF. Similarly, the 5α-THF/5β-THF ratio increased by 54% in the PD group and 42% in the NNR group, 5α-THF/Cortisol increased by 95% in the PD group and 52% in the NNR group and (5α-THF+5β-THF)/THE increased by 36% in the PD group and 18% in the NNR group. All these effects were significant over time (time effect, P<0.001), but not different between the diet groups.
11βHSD1 in subcutaneous adipose tissue and liver
Biopsies of SAT were performed in 26 participants in the PD group and 21 participants in the NNR group at baseline, 6 and 24 months (Figure 1). Gene expression decreased over 24 months (time effect, P<0.05) without any differences between groups.
Twenty-five participants in the PD group and 19 in the NNR group completed the cortisone conversion test at baseline, 6 and 24 months (Figure 2). AUC for plasma cortisol levels after orally taken cortisone increased significantly by 13% in the PD group and 9% in the NNR group at 6 months (time effect, P<0.05), but after 24 months it was unaltered versus baseline in both diet groups. Notably, plasma cortisol levels in the first hour after intake of oral cortisone acetate did not differ significantly between baseline, 6 and 24 month measurements; differences in AUC were thus attributable to later time points between 1 and 4 h after dosing. There were no significant differences between the diet groups.
Associations between changes in glucocorticoid metabolism, BMI and insulin resistance
Decreased expression of 11βHSD1 mRNA in SAT correlated with a reduction in BMI between baseline and 6 (r=0.38, P=0.009) as well as 24 months (r=0.33, P=0.022). Increased AUC for plasma cortisol levels after orally taken cortisone correlated with decreased BMI between baseline and 24 (r=−0.368, P=0.014) but not 6 months (r=−0.155, P=0.32). There were no significant associations between changes in the urinary glucocorticoid excretion and changes in BMI or HOMA-IR at either 6 or 24 months.
Our 2-year ad libitum dietary interventions with a significant weight loss in obese postmenopausal women, caused an increased excretion of 5α-reduced glucocorticoid metabolites and decreased expression of 11βHSD1 in SAT. There were no significant differences between the PD and NNR diets regarding glucocorticoid metabolism.
The tissue-specific effects on the key enzyme in glucocorticoid activation, 11βHSD1, are of considerable interest. Earlier weight-loss studies have reported unchanged,18, 22 increased16 and decreased19, 20 expression of this enzyme in SAT. These studies differ in weight-loss method, amount of weight loss, duration and localization of sampled adipose tissue, which complicates the interpretation of data. In line with our results, chronic weight loss after dietary intervention and gastric bypass has been associated with decreased SAT expression of 11βHSD1.19, 20 Importantly, the diets in our study were ad libitum and caused a significant but relatively slow weight loss compared with previous studies on gastric bypass20 and very-low calorie diets.19 Thus, weight loss achieved by ad libitum diet changes appears to be sufficient to lower 11βHSD1 expression in SAT.
This reduction in adipose tissue 11βHSD1 can be of clinical importance. Studies in humans have estimated that if cortisol production in whole-body SAT equals that of abdominal SAT, it may contribute to as much as 15% of the total systemic cortisol production.4 Increased regeneration of cortisone to cortisol in SAT among obese subjects may therefore have both local and systemic metabolic effects.
Our second major finding was the increased 5α-reduction of glucocorticoids after weight loss. Previous studies suggest that 5α-reduction of glucocorticoids is increased in obesity,11 associated with insulin resistance12 and that short-term weight loss leads to decreased 5α-reduction of glucocorticoids.15, 17 However, recent papers have shown that transgenic mice with loss of 5α-reductase type 1 develop hepatic steatosis and insulin resistance14 and inhibition of 5α-reductase with dutasteride causes insulin resistance in men.13 Therefore, we suggest that the increased 5α-reduction of glucocorticoids between 6 and 24 months may reflect a long-term protective adaptation to lower intrahepatic cortisol levels thereby counteracting metabolic dysregulation.
The factors mediating the changes in glucocorticoid metabolism are unclear, but insulin is a potential candidate which can drive the diet-induced regulation of glucocorticoid metabolism, including 11βHSD1 and 5α-reductase activity.29 Acute hyperinsulinemia increases systemic 11βHSD1 activity30 and decreases adipose 11βHSD1 activity in lean but not obese men 31 in vivo. In line with this, systemic 11βHSD1 activity is increased after a high-carbohydrate meal, and these changes are associated with higher insulin secretion.21 However, chronic reductions in insulin levels by low carbohydrate intake for 4 weeks was associated with increased systemic 11βHSD1 activity, probably because of increased 11βHSD1 activity in the liver.22 In our study, we did not find an association between changes in insulin sensitivity and 11βHSD1. Importantly, our participants had normal glucose tolerance at baseline and therefore more sensitive methods to study insulin effects may have been needed to reveal an association. This is in line with previous studies, in which adipose 11βHSD1 expression did not correlate with fasting serum insulin levels19, 20 but did correlate with insulin sensitivity measured during an intravenous glucose tolerance test.19 Interestingly, reduced BMI was significantly associated with decreased expression of 11βHSD1 in SAT. This suggests that other factors than insulin such as decreased inflammation in adipose tissue may link weight loss to 11βHSD1 in SAT.32
Previous studies have linked insulin resistance with high 5α-reductase activity,8, 11 and improved insulin sensitivity by weight loss15, 17 or treatment with glitazones33 reduces 5α-reductase activity in both rodents and men. In this study, neither changes in HOMA-IR or BMI correlated with changes in 5α-THF/5β-THF and do not seem to explain the altered 5α-reductase activity. Notably, morning plasma cortisol levels increased during the intervention. This can reflect a normalized diurnal cortisol secretion due to weight loss since obesity is associated with lower morning plasma cortisol levels.2 Increased cortisol levels may also have caused an increased metabolic clearance via 5α-reductase, although in Cushing’s syndrome 5β- rather than 5α-reductase activity is increased.34
The ratio of (5α-THF+5β-THF)/THE, reflecting systemic 11βHSD1 activity, increased throughout the intervention. Since the liver is the major site of 11βHSD1 activity4, 35, 36 a concomitant increase in conversion of orally taken cortisone to plasma cortisol could be expected. Although the AUC response for plasma cortisol after orally taken cortisone increased at 6 but not 24 months there were no significant effects on the initial rate of appearance of plasma cortisol, considered to be a better estimate of hepatic 11βHSD1 activity. The increased 5α-THF/5β-THF and 5α-THF/cortisol ratios between 6–24 months indicate that 5α-reduction of glucocorticoids increased in relation to 5β-reduction of glucocorticoids. This will inevitably increase the (5α-THF+5β-THF)/THE ratio as well which may thus be a consequence of increased 5α-reductase activity rather than systemic 11βHSD1 activity.
We did not find any major difference between diets on glucocorticoid metabolism. However, at odds with self-reported protein intake, 24-hour urinary nitrogen levels were not higher in the PD group compared with the NNR group at any time point indicating that the actual intake of protein was similar in both diet groups.27 Despite these limited differences in macronutrient composition the PD group lost more weight and fat mass the first 6 months, which may at least partially relate to a higher intake of mono- and polyunsaturated fatty acids in the PD group.27 Future studies are therefore of interest to analyse the associations between specific micro- and macronutrients and glucocorticoid metabolism.
Importantly, our study has, to the best of our knowledge, the longest duration in which effects of dietary interventions on glucocorticoid metabolism have been reported. We consider this a major strength since diet recommendations are given on a long-term basis. Drawbacks of the study are the fact that we used analysis of urinary glucocorticoids as indirect measures of 11βHSD1 and A-ring reductase activities and can only describe the balance of these different enzymes. Although we did not analyze 11βHSD1 protein levels in adipose tissue, previous studies have shown good correlation between 11βHSD1 mRNA and protein levels in SAT.37 Recent data propose that 11βHSD1 may not be one-directional converting cortisone to cortisol in vivo as previously thought.38 Future studies using deuterated cortisone and cortisol tracers38 are needed in order to estimate the direction of activity of 11βHSD1 in SAT in vivo after dietary interventions. Insulin sensitivity was estimated by HOMA-IR; more sensitive measures such as euglycemic hyperinsulinemic clamps would probably have increased the possibility to find associations between GC metabolism and both peripheral and hepatic insulin sensitivity.
In summary, this study suggests weight loss during a two-year diet intervention in obese postmenopausal women influences local-tissue GC metabolism; this may lead to improved metabolic regulation. The increased 5α-reductase activity throughout the intervention is a novel finding and the long-term consequences of this change are unclear.
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We thank all of the participants for taking part in this study. We also thank Susanne Sandberg, Inger Arnesjö and Marie Eriksson, Umeå University and the staff of the Wellcome Trust Clinical Research Facility Mass Spectrometry Core, University of Edinburgh. This study was supported by grants from The Swedish Council for Working Life and Social Research (2006-0699 and 2010-0398), the Swedish Research Council (K2011-12237-15-6), the Swedish Heart and Lung Foundation, the County Council of Västerbotten, and Umeå University, Sweden, the British Heart Foundation and the Wellcome Trust.
Clinical trials number: NCT00692536.
BRW is an inventor on relevant patents owned by the University of Edinburgh. AS, KS, CM, MR, RHS, CL, BL, RA and TO have nothing to disclose.
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Stomby, A., Simonyte, K., Mellberg, C. et al. Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women. Int J Obes 39, 814–819 (2015). https://doi.org/10.1038/ijo.2014.188
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