Konstantinos Manolopoulos1, Hafwen Thornhill2, Jennifer Thomas2, Wiebke Arlt3, Jeremy Tomlinson4. 1. Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK. Electronic address: k.manolopoulos@bham.ac.uk. 2. Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 3. Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK. 4. Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Abstract
BACKGROUND: An apple-shaped fat distribution is associated with an adverse cardiometabolic phenotype. Hypercortisolaemia (Cushing's syndrome) is characterised by abdominal fat accumulation and gluteofemoral fat loss. The mechanisms underpinning this redistribution of fat mass are unknown. Since adipose tissue blood flow (ATBF) is an important determinant of lipolytic rate in vivo, we hypothesised that hypercortisolaemia might lead to differential abdominal and femoral ATBF. METHODS:Six healthy male volunteers (median age 25 years [IQR 20-50], median body-mass index 27·0 kg/m(2) [24·4-29·1]) were recruited. Abdominal and femoral ATBF were studied in vivo by use of the radioactive xenon washout technique after a hydrocortisone infusion (2 mg/kg per min for 16 h) or saline (control). Infusions were given in a randomised double-blind manner. On each of 2 study days ATBF was studied in the fasting state and after a 75 g glucose drink. FINDINGS: Under control conditions, there was no difference between fasting or postprandial abdominal and femoral ATBF. Hypercortisolaemia increased fasting femoral ATBF (time-averaged area under the curve, from a median of 1·6 mL/min per 100 g tissue [IQR 1·2-4·4] to 4·3 [2·7-5·9], Wilcoxon signed rank test p=0·08), increased postprandial femoral ATBF (2·4 [1·6-4·0] to 6·9 [3·4-8·7], p=0·046), increased abdominal fasting ATBF (2·2 [1·8-6·2] to 3·0 [1·7-7·5], p=0·465), and increased abdominal postprandial ATBF (3·5 [1·9-4·2] to 4·7 [2·1-9·0], p=0·225). Total ATBF time-averaged area under the curve response to hypercortisolaemia showed a strong negative correlation with waist to hip ratio (Spearman's r abdomen -0·986, p<0·0001; femoral -0·928, p=0·008). INTERPRETATION: We showed that hypercortisolaemia increases ATBF, most strikingly in the gluteofemoral depot, an effect further augmented in the postprandial state. This finding might point to depot specificity of glucocorticoid responses and insulin interactions. Depot-specific responses might lead to differential fatty acid fluxes in the abdominal and gluteofemoral depot, resulting in the fat distribution changes associated with Cushing's syndrome. FUNDING: Society for Endocrinology, Wellcome Trust Institutional Strategic Support Fund.
RCT Entities:
BACKGROUND: An apple-shaped fat distribution is associated with an adverse cardiometabolic phenotype. Hypercortisolaemia (Cushing's syndrome) is characterised by abdominal fat accumulation and gluteofemoral fat loss. The mechanisms underpinning this redistribution of fat mass are unknown. Since adipose tissue blood flow (ATBF) is an important determinant of lipolytic rate in vivo, we hypothesised that hypercortisolaemia might lead to differential abdominal and femoral ATBF. METHODS: Six healthy male volunteers (median age 25 years [IQR 20-50], median body-mass index 27·0 kg/m(2) [24·4-29·1]) were recruited. Abdominal and femoral ATBF were studied in vivo by use of the radioactive xenon washout technique after a hydrocortisone infusion (2 mg/kg per min for 16 h) or saline (control). Infusions were given in a randomised double-blind manner. On each of 2 study days ATBF was studied in the fasting state and after a 75 g glucose drink. FINDINGS: Under control conditions, there was no difference between fasting or postprandial abdominal and femoral ATBF. Hypercortisolaemia increased fasting femoral ATBF (time-averaged area under the curve, from a median of 1·6 mL/min per 100 g tissue [IQR 1·2-4·4] to 4·3 [2·7-5·9], Wilcoxon signed rank test p=0·08), increased postprandial femoral ATBF (2·4 [1·6-4·0] to 6·9 [3·4-8·7], p=0·046), increased abdominal fasting ATBF (2·2 [1·8-6·2] to 3·0 [1·7-7·5], p=0·465), and increased abdominal postprandial ATBF (3·5 [1·9-4·2] to 4·7 [2·1-9·0], p=0·225). Total ATBF time-averaged area under the curve response to hypercortisolaemia showed a strong negative correlation with waist to hip ratio (Spearman's r abdomen -0·986, p<0·0001; femoral -0·928, p=0·008). INTERPRETATION: We showed that hypercortisolaemia increases ATBF, most strikingly in the gluteofemoral depot, an effect further augmented in the postprandial state. This finding might point to depot specificity of glucocorticoid responses and insulin interactions. Depot-specific responses might lead to differential fatty acid fluxes in the abdominal and gluteofemoral depot, resulting in the fat distribution changes associated with Cushing's syndrome. FUNDING: Society for Endocrinology, Wellcome Trust Institutional Strategic Support Fund.