Dipeptidyl Peptidase 4 Is a Novel Adipokine Potentially Linking Obesity to the Metabolic Syndrome

Abstract

OBJECTIVEComprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome.RESEARCH DESIGN AND METHODSHuman adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot-specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome.RESULTSFully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome.CONCLUSIONSDPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome.

Plasma dipeptidyl peptidase 4 activity correlates with body mass index and the plasma adiponectin concentration in healthy young people

“…The correlations between DPP4 activity and BMI (r = 0.24, p = 0.0017) and total cholesterol (r = 0.27, p = 0.0006) remained significant after adjusting for age and sex (Table 3), but not found to increase [9,10] and decrease [11][12][13] in patients with type-2 diabetes. Moreover, it has been reported that the degree of plasma DPP4 activity was significantly higher in obese subjects than in lean subjects [14,15]; however, the DPP4 hyperactivity in obese individuals did not seem to be affected by their degree of overweightedness [14]. Moreover, it has been reported that the degree of plasma DPP4 activity was affected by widely used anti-diabetic agents, such as metformin [16], and ageing [12].…”

“…Recently, Lamers et al reported that DPP4 is an adipokine that might be linked to obesity, and the serum DPP4 concentration is correlated with various clinical parameters such as age; BMI; the sizes of subcutaneous and visceral adipocytes; and the levels of insulin, adiponectin, and leptin in lean (n = 20) and morbidly obese (n =20) men [15]. Our data are consistent with those of previous studies and support the evidence obtained from obese and healthy young subjects.…”

The role of endothelial dysfunction driven by adipocitokines in the development and progression of microvascular complications in patients with type 1 and type 2 diabetes

“…In animal and cell culture studies adiponectin increased the bioavailability of NO directly, stimulating eNOS, and indirectly, by reducing the concentration of superoxide products (27)(28)(29). Sharma et al (2008) The results of recent experimental studies suggest an increased expression of DPP-4 in adipocytes of visceral fat and increased serum enzymes in patients with IR and T2DM (39,40). In vitro studies also suggest a possible link between DPP4 activity and renovascular protective effect (41,42).…”

Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity

“…However, the expression levels were not different among the control, OVX-HF, and Tene groups (Supplemental Figure 1, see section on supplementary data given at the end of this article). Since the secretion of DPP4 was more prominent in patients with metabolic syndrome than simple obese subjects (Lamers et al 2011), other metabolic factors might influence the secretion.…”

“…Recently, DPP4 has been shown to be secreted from adipose tissue in a tissue-volume-dependent manner, and serum DPP4 concentrations were positively correlated with an increased BMI, fat volume, and insulin concentration in humans (Lamers et al 2011). Because visceral fat accumulation is a notable phenotype of postmenopause, we measured the expression of DPP4 in the perigonadal fat of the mice.…”