Dipeptidyl Peptidase-4 Regulation of SDF-1/CXCR4 Axis: Implications for Cardiovascular Disease

Zhong, Jixin; Rajagopalan, Sanjay

Serves as an adipokine mediating obesity-induced metabolic syndrome (9) Adipose tissue macrophage and dendritic cells Enhances T cell inflammation and obesity-induced insulin resistance (12) T cells Promotes T cell activation by providing co-stimulatory signaling (17, 18) Endothelial cells Regulates endothelial function and vascular tone (19, 20) Epithelial cells Expressed in the epithelial cells in the kidney, lung, and GI tract. Mediates MERS-CoV infection in the lung (21), kidney fibrosis (22) , diabetic nephropathy (23), intestinal growth (24) Hepatocytes Involved in lipogenesis (25) and liver damage (26) as monocytes differentiate into antigen-presenting cells as well as during T cell activation (12, 13) . DPP4 is expressed at high levels in kidney, spleen, lung, pancreas, and prostate (14) . Mice lacking the gene encoding DPP4 are refractory to the development of obesity and hyperinsulinemia and demonstrate improved post-prandial glucose control (15, 16) . Mice deleted for Dpp4 are fertile and appear healthy. Only slight decrease of body weight in Dpp4 −/− mice was observed compared to wild types. They have normal fasting blood glucose level, but shows reduced glycemic excursion after an oral glucose challenge (16) . Increased intact insulinotropic form of GLP-1 and circulating insulin were seen in Dpp4 −/− mice after oral glucose stimulation (16) . Pair feeding and indirect calorimetry studies indicate that reduced food intake and increased energy expenditure accounted for the resistance to high fat diet-induced obesity in the Dpp4 −/− mice. Ablation/ deletion of DPP4 is associated with improved metabolic control with improved insulin sensitivity, reduced pancreatic islet hypertrophy, and protection against streptozotocin-induced loss of β cell mass and hyperglycemia (15) . Pharmacological inhibition of DPP4 enzymatic activity improves glucose tolerance in wildtype but not in Dpp4 −/− mice. Interestingly, DPP4 inhibitor's also improve glucose tolerance in Glp1r −/− mice, indicating that DPP4 contributes to blood glucose regulation by controlling the activity of GLP-1 as well as additional substrates (16) .