Systemic Hypoxia Increases the Expression of DPP4 in Preadipocytes of Healthy Human Participants

Abstract

Dipeptidyl peptidase 4 (DPP4) is a transmembrane glycoprotein involved in protein degradation. Due to its action on incretins, which increase insulin secretion, DPP4 is considered a therapeutic target for type 2 diabetes. Here we have studied the role of single and combined effects of hypoxia and inactivity on the expression of DPP4 in human adipose tissue of 12 adult normal-weight males. Fat biopsies were obtained at baseline and after each of three experimental campaigns. The results revealed that in isolated human preadipocytes the expression of DPP4 was significantly increased by exposure of participants to hypoxia. Physical inactivity per se had no apparent effect on the DPP4 expression. It is concluded that DPP4 may be a marker to monitor indirectly tissue hypoxia, as occurs in obese subjects.

Key words

dipeptidyl peptidase 4 - adipose differentiation - hypoxia - stemness

• References

• 1 Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?. Trends Pharmacol Sci 2009; 30: 600-607 10.1016/j.tips.2009.08.003
• 2 Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab 2007; 21: 517-533 10.1016/j.beem.2007.07.005
• 3 Hosogai N, Fukuhara A, Oshima K. et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901-911 10.2337/db06-0911
• 4 Rausch ME, Weisberg S, Vardhana P. et al. Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 2008; 32: 451-463 10.1038/sj.ijo.0803744
• 5 Regazzetti C, Peraldi P, Grémeaux T. et al. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 2009; 58: 95-103 10.2337/db08-0457
• 6 Trayhurn P. Hypoxia and adipocyte physiology: Implications for adipose tissue dysfunction in obesity. Annu Rev Nutr 2014; 34: 207-236 10.1146/annurev-nutr-071812-161156
• 7 Lamers D, Famulla S, Wronkowitz N. et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011; 60: 1917-1925 10.2337/db10-1707
• 8 Zilleßen P, Celner J, Kretschmann A. et al. Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes. Sci Rep 2016; 6: 23074 10.1038/srep23074
• 9 Debevec T, McDonnell AC, Macdonald IA. et al. Whole body and regional body composition changes following 10-day hypoxic confinement and unloading-inactivity. Appl Physiol Nutr Metab 2014; 39: 386-395 10.1139/apnm-2013-0278
• 10 Hauner H, Entenmann G, Wabitsch M. et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J Clin Invest 1989; 84: 1663-1670 10.1172/JCI114345
• 11 Smas CM, Sul HS. Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 1993; 73: 725-734
• 12 Maxwell P, Salnikow K. HIF-1: An oxygen and metal responsive transcription factor. Cancer Biol Ther 2004; 3: 29-35
• 13 Semenza GL. Surviving ischemia: Adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 2000; 106: 809-812 10.1172/JCI11223
• 14 Wang B, Wood IS, Trayhurn P. Hypoxia induces leptin gene expression and secretion in human preadipocytes: Differential effects of hypoxia on adipokine expression by preadipocytes. J Endocrinol 2008; 198: 127-134 10.1677/JOE-08-0156
• 15 Goossens GH, Bizzarri A, Venteclef N. et al. Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. Circulation 2011; 124: 67-76 10.1161/CIRCULATIONAHA.111.027813
• 16 Ban J, Ruthenborg R, Cho K. et al. Regulation of obesity and insulin resistance by hypoxia-inducible factors. Hypoxia 2014; 2: 171-183 10.2147/HP.S68771
• 17 Halberg N, Khan T, Trujillo ME. et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29: 4467-4483 10.1128/MCB.00192-09
• 18 Dang DT, Chun SY, Burkitt K. et al. Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res 2008; 68: 1872-1880 10.1158/0008-5472.CAN-07-1589
• 19 Chowdhury HH, Velebit J, Radić N. et al. Hypoxia Alters the Expression of Dipeptidyl Peptidase 4 and Induces Developmental Remodeling of Human Preadipocytes. J Diabetes Res 2016; 2016: 7481470 10.1155/2016/7481470