Thrombospondin 1 as a novel biological marker of obesity and metabolic syndrome

Abstract

Context: Thrombospondin 1 (THBS1 or TSP-1) is an adipose-derived matricellular protein, which has recently been highlighted as a potential mediator of insulin resistance and adipose inflammation in obesity.

Objective: In this study, we aimed to determine the clinical significance of THBS1 as a novel biological marker of visceral obesity, metabolic syndrome, and diabetes.

Methods: The THBS1 mRNA level was quantified with real-time PCR in human adipose tissues obtained from 16 non-obese subjects. The relationships between serum THBS1 level and obesity/diabetes traits as well as the diagnostic components of metabolic syndrome were assessed in 164 normal-weight or overweight/obese subjects (78 males and 86 females; mean age, 50.4; mean BMI, 29.8) with analysis of covariance (ANCOVA) and regression analyses.

Results: THBS1 was predominantly expressed in visceral adipose tissues relative to subcutaneous adipose tissues (P<0.001). The visceral THBS1 expression was positively associated with the body mass index (BMI; γs=0.54, P=0.033). ANCOVA demonstrated that the THBS1 level is associated with abdominal obesity (P<0.001), hyperglycemia (P=0.02), and hypertension (P=0.04). Multivariable regression analysis suggested an association between serum THBS1 and fasting plasma glucose levels. The associations between serum THBS1 levels and obesity/diabetes traits were found preferentially in women (BMI, γs=0.30, P=0.05; FPG, γs=0.26, P=0.016). Subanalyses demonstrated that the association with obesity traits was predominantly found in premenopausal women (BMI, γs=0.41, P=0.007), whereas the association with diabetes traits was predominant in postmenopausal women (HbA1c, γs=0.38, P=0.01). During medical weight reduction treatment, the change in the serum THBS1 level was associated with the change in BMI and HbA1c in pre- and postmenopausal women, respectively.

Conclusions: Serum THBS1 is a useful biological marker of obesity and metabolic syndrome in Japanese subjects, particularly in women. THBS1 may act as a critical circulating factor that couples obesity with metabolic syndrome and diabetes in humans.

Keywords: Biological marker; Diabetes; Metabolic syndrome; Obesity; Thrombospondin 1.

Fig. 1

(A, B) The expression levels of THBS1 (A) and IL-6 (B) in human adipose tissues were quantified with real-time PCR. Data are expressed relative to the 36B4 gene used as an internal control for normalization. Horizontal bars represent median values. SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue. The Wilcoxon signed-rank test was used to compare the difference in gene expression between SAT and VAT. (C, D) Correlations between THBS1 expression levels and obesity traits. Spearman’s rank correlation coefficient (γ_s) was used to determine the association of THBS1 expression with BMI in SAT (C) or VAT (D). *P < 0.05 (statistically significant).

Fig. 2

Box and whisker plots of circulating THBS1 levels. Study subjects (A, females, n = 86; B, males, n = 78; C, premenopausal females, n = 42; D, postmenopausal females, n = 44) were divided into four groups based on BMI: group 1, BMI <25; group 2, 25 ≤ BMI <30; group 3, 30 ≤ BMI <35; group 4, 35 ≤ BMI. A, females, n = 86 (group 1 = 15; group 2 = 22; group 3 = 28; group 4 = 21). (B) Males, n = 78 (group 1 = 28; group 2 = 25; group 3 = 15; group 4 = 10). (C) Premenopausal females, n = 42 (group 1 = 9; group 2 = 7; group 3 = 14; group 4 = 12). (D) Postmenopausal females, n = 44 (group 1 = 6; group 2 = 15; group 3 = 14; group 4 = 9). The horizontal line within the box indicates the median, and boundaries of the box represent the 25th and 75th percentile. Groups were compared by the Mann–Whitney U test with Bonferroni correction. *P < 0.05.