FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes

Abstract

Purpose: Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1.

Methods: Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 non-diabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes.

Results: FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake.

Conclusions: FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.

Keywords: Adipose tissue; FKBP51; Glucocorticoids; Insulin resistance; SAFit1; Type 2 diabetes.

Fig. 1

FKBP5 gene expression is higher in SAT from male subjects compared to SAT from female subjects a. FKBP5 gene expression levels in SAT do not differ between non-obese and obese subjects b. There was a tendency of higher FKBP5 gene expression in SAT from T2D subjects compared to non-diabetic subjects c. n = 20, each group. ND non-diabetic, NS not significant

Fig. 2

FKBP5 expression during human preadipocyte differentiation into adipocyte. FKBP51 gene a and protein b expression levels in human preadipocytes before starting differentiation (pre-differentiation) and at days 7 and 14 after inducing differentiation into adipocytes without or with cortisol (0.01 and 0.1 µM) in the differentiation media (n = 5). Differentiation rate at days 7 and 14 of differentiation (n = 3), measured by image quantification of adipocyte lipids stained with Oil Red O, and normalised by cell number c. ^#p < 0.05, between different days; *p < 0.05, **p < 0.01 between different treatments. Data were log(x + 1) transformed

Fig. 3

FKBP51 protein expression levels were 20-fold elevated in preadipocytes differentiated into adipocytes ex vivo following 24 h incubation with dexamethasone (0.3 µM) (n = 4) a. Incubation for 24 h with dexamethasone reduced basal glucose uptake in preadipocytes differentiated into adipocytes ex vivo by 51% (n = 4) b. Data were log(x + 1) transformed

Fig. 4

SAFit1 dose-response curve for adipocyte glucose uptake obtained from adipose tissue treated for 24 h with dexamethasone (0.3 µM) and with different concentrations of SAFit1 (100–10,000 nM) (n = 7–19) a and SAFit1 dose-response curve for adipocyte glucose uptake with higher percent inhibitory effect of dexamethasone on glucose uptake (50th percentile and above, n = 3–10), compared with control (no dexamethasone treatment), after 24 h of incubation b. For reference, the basal glucose uptake in all subjects was 38.0 femtoliter/cell/s (control). Values are percentage relative to basal dexamethasone. Dexa Dexamethasone, SAT subcutaneous adipose tissue. ^&p < 0.05, Dexa + SAFit1 (500 nM) treated vs Dexa treated; ^§p < 0.05, Dexa + SAFit1 (2000 nM) treated vs Dexa treated; ^#p < 0.05, Dexa + SAFit1 (10,000 nM) treated vs Dexa treated