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Dipeptidyl Peptidase 4 Is a Novel Adipokine Potentially Linking Obesity to the Metabolic Syndrome
Study Questions:
Is dipeptidyl peptidase 4 (DPP4), a novel adipokine associated with the metabolic syndrome?
Methods:
DPP4 is a transmembrane glycoprotein that cleaves N-terminal dipeptides from a variety of substrates, including growth factors and hormones, neuropeptides, and chemokines. Two substrates of DPP4, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are released from the intestinal mucosa and are responsible for approximately 60% of postprandial insulin secretion. Subjects comprised two study groups; one with 20 obese males and 20 lean controls and one with 19 obese females and 10 leans females. Criteria for the metabolic syndrome were based on the Adult Treatment Panel III definitions as follows: a fasting glucose >110 mg/dl or diagnosis of type 2 diabetes; blood pressure >135/85 mm Hg; serum triglycerides >150 mg/dl; high-density lipoprotein cholesterol <40 mg/dl for men and <50 mg/dl for women; and abdominal obesity characterized by a waist >102 cm for men and >88 cm for women. Subjects with a risk score of ≥3 are qualified as having the metabolic syndrome. 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. Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling.
Results:
Fully 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. Using adipose tissue explants from lean and obese subjects, a twofold increase in DPP4 release, which was strongly correlated with adipocyte volume and parameters of the metabolic syndrome, was observed. After weight reduction, DPP4 release was decreased to the lean level. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome.
Conclusions:
The investigators concluded that DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, DPP4 may be involved in linking adipose tissue and the metabolic syndrome.
Perspective:
This is an interesting study, which demonstrates an important aspect of glucose control related to the adipokine DPP4. Potential pharmacologic interventions that target this adipokine may have significant clinical impact in the future.
Keywords: Metabolic Syndrome, Obesity, Abdominal, Insulin, Adipokines, Dipeptidyl Peptidase 4, Chemokines, Adipocytes
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