Maria J Pereira1, Jenny Palming2, Maria K Svensson2, Magnus Rizell3, Jan Dalenbäck4, Mårten Hammar5, Tove Fall6, Cherno O Sidibeh6, Per-Arne Svensson7, Jan W Eriksson8. 1. Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. 2. Department of Molecular and Clinical Medicine and Sahlgrenska University Hospital, Gothenburg, Sweden. 3. Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden. 4. Department of Surgery, Frölunda Specialist Hospital, Gothenburg, Sweden. 5. AstraZeneca R&D, Mölndal, Sweden. 6. Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 7. Department of Molecular and Clinical Medicine and Center for Cardiovascular and Metabolic Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 8. Department of Medical Sciences, Uppsala University, Uppsala, Sweden; AstraZeneca R&D, Mölndal, Sweden. Electronic address: jan.eriksson@medsci.uu.se.
Abstract
OBJECTIVE: To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance. MATERIALS/ METHODS: Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28-60 years; BMI: 20.7-30.6 kg/m²), was incubated with or without dexamethasone (0.003-3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting. RESULTS: FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples. CONCLUSIONS: Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance.
OBJECTIVE: To study effects of dexamethasone on gene expression in human adipose tissue aiming to identify potential novel mechanisms for glucocorticoid-induced insulin resistance. MATERIALS/ METHODS: Subcutaneous and omental adipose tissue, obtained from non-diabetic donors (10 M/15 F; age: 28-60 years; BMI: 20.7-30.6 kg/m²), was incubated with or without dexamethasone (0.003-3 μmol/L) for 24 h. Gene expression was assessed by microarray and real time-PCR and protein expression by immunoblotting. RESULTS:FKBP5 (FK506-binding protein 5) and CNR1 (cannabinoid receptor 1) were the most responsive genes to dexamethasone in both subcutaneous and omental adipose tissue (~7-fold). Dexamethasone increased FKBP5 gene and protein expression in a dose-dependent manner in both depots. The gene product, FKBP51 protein, was 10-fold higher in the omental than in the subcutaneous depot, whereas the mRNA levels were similar. Higher FKBP5 gene expression in omental adipose tissue was associated with reduced insulin effects on glucose uptake in both depots. Furthermore, FKBP5 gene expression in subcutaneous adipose tissue was positively correlated with serum insulin, HOMA-IR and subcutaneous adipocyte diameter and negatively with plasma HDL-cholesterol. FKBP5 SNPs were found to be associated with type 2 diabetes and diabetes-related phenotypes in large population-based samples. CONCLUSIONS:Dexamethasone exposure promotes expression of FKBP5 in adipose tissue, a gene that may be implicated in glucocorticoid-induced insulin resistance.
Authors: Lance A Stechschulte; Bin Qiu; Manya Warrier; Terry D Hinds; Man Zhang; Hao Gu; Yuxue Xu; Saja S Khuder; Lucia Russo; Sonia M Najjar; Beata Lecka-Czernik; Weidong Yong; Edwin R Sanchez Journal: Endocrinology Date: 2016-07-21 Impact factor: 4.736