Join us   Log in   pharmaspire@isfcp.org  

PHARMASPIRE - Volume 13, Issue 4 , October - December, 2021

Pages: 202-206
Print Article   Download XML  Download PDF

Pathological role of dipeptidyl peptidase (DPP) -4 in liver and ameliorative effects of dpp-4 inhibitors

Author: Divya Sharma, Gaaminepreet Singh

Category: Pharmaceutics

Abstract:

Dipeptidyl peptidase 4 (DPP4) is the target of the gliptins, a recent class of oral ant diabetics. DPP4 (also called cluster of differentiation 26) was previously characterized in immune cells but also has important metabolic functions which are not yet fully understood. Thus, we investigated the function of DPP4 in human white preadipocytes and adipocytes. We found that both cell types express DPP4 in high amounts; DPP4 release markedly increased during differentiation. In preadipocytes, lentiviral DPP4 knockdown caused significant changes in gene expression as determined by wholegenome DNA-array analysis. Metabolic genes were increased, forexample, PDK4 18- fold and PPARγC1α (=PGC1α) 6-fold, and proliferation elated genes were decreased (e.g. FGF7 5-fold). These effects, contributing to differentiation, were not inhibited by the PPARγ antagonist T0070907. Vice versa, the PPARγ agonist pioglitazone induced a different set of genes (mainly FABP4). DPP4 knockdown also affected growth factor signaling and, accordingly, retarded preadipocyte proliferation. In particular, basal and insulin-induced ERK activation (but not Akt activation) was markedly diminished (by around 60%). This indicates that DPP4 knockdown contributes to adipocyte maturation by mimicking growth factor withdrawal, an early step in fat cell differentiation. In mature adipocytes, DPP4 becomes liberated so that adipose tissue may constitute a relevant source of circulating DPP4.

Keywords: Dipeptidyl peptidase 4, adipocytes, pre-adipocytes, hepatocyte, adipokine

References:

  1. Zilleßen P, Celner J, Kretschmann A, Pfeifer A, Racké K, Mayer P. Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre) adipocytes. Sci Rep 2016;6:23074.
  2. Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, et al. Adipose dipeptidyl peptidase-4 and obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 2013;36:4083-90.
  3. Silva WS Jr., Souza MD, Nogueira Neto JF, Bouskela E, Kraemer-Aguiar LG. Dipeptidyl peptidase 4 activity is related to body composition, measures of adiposity, and insulin resistance in subjects with excessive adiposity and different degrees of glucose tolerance. J Diabetes Res 2019;2019:5238013.
  4. Takeda K, Sawazaki H, Takahashi H, Yeh YS, Jheng HF, Nomura W, et al. The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin enhances brown adipose tissue function, thereby preventing obesity in mice. FEBS Open Bio 2018;8:1782-93.
  5. Omolekulo TE, Michael OS, Olatunji LA. Dipeptidyl peptidase-4 inhibition protects the liver of insulin-resistant female rats against triglyceride accumulation by suppressing uric acid. Biomed Pharmacother 2019;110:869-77.
  6. James WP. WHO recognition of the global obesity epidemic. Int J Obesity 2008;32:S120-6.
  7. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Investig 2005;115:1111-9.
  8. Breitling R. Robust signaling networks of the adipose secretome. Trends Endocrinol Metab 2009;20:1-7.
  9. Sell H, Dietze-Schroeder D, Eckel J. The adipocyte-myocyte axis in insulin resistance. Trends Endocrinol Metab 2006;17:416-22.
  10. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011;60:1917-25.
  11. Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci 2009;30:600-7.
  12. Deacon CF, Carr RD, Holst JJ. DPP-4 inhibitor therapy: New directions in the treatment of Type 2 diabetes. Front Biosci 2008;13:1780-94.
  13. Bluher M, Bashan N, Shai I, Harman-Boehm I, Tarnovscki T, Avinaoch E, et al. Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body Insulin sensitivity. J Clin Endocrinol Metab 2009;94:2507-15.
  14. Matteucci EL, Giampietro OT. Dipeptidyl peptidase-4 (CD26): Knowing the function before inhibiting the enzyme. Curr Med Chem 2009;16:2943-51.
  15. Hol JJ. On the physiology of GIP and GLP-1. Horm Metab Res 2004;36:747-54.
  16. Silva Júnior WS, Godoy-Matos AF, Kraemer-Aguiar LG. Dipeptidyl peptidase 4: A new link between diabetes mellitus and atherosclerosis? BioMed Res Int 2015;2015:816164.
  17. Lamers D, Famulla S, Wronkowitz N, Hartwig S, Lehr S, Ouwens DM, et al. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 2011;60:1917-25.
  18. Neidert LE, Mobley CB, Kephart WC, Roberts MD, Kluess HA. The serine protease, dipeptidyl peptidase IV as a myokine: Dietary protein and exercise mimetics as a stimulus for transcription and release. Physiol Rep 2016;4:e12827.
  19. Sell H, Blüher M, Klöting N, Schlich R, Willems M, Ruppe F, et al. Adipose dipeptidyl peptidase-4 and obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 2013;36:4083-90.
  20. Raschke S, Eckel J. Adipo-myokines: Two sides of the same coin-mediators of inflammation and mediators of exercise. Mediat Inflamm 2013;2013:320724.
  21. Selvin E, Parrinello CM. Age-related differences in glycaemic control in diabetes. Diabetologia 2013;56:2549-51.
  22. Lindsay JR, Duffy NA, McKillop AM, Ardill J, O’Harte FP, Flatt PR, et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabetic Med 2005;22:654-7.
  23. Snijder MB, Nicolaou M, Van Valkengoed IG, Brewster LM, Stronks K. Newly proposed body adiposity index (bai) by Bergman et al. Is not strongly related to cardiovascular health risk. Obesity 2012;20:1138.
  24. de Oliveira Siciliano P, Godoy-Matos AF, Braga LD, Carvalho JD, do Amaral Corrêa JO. DPP4 activity is related to body weight and central fat in postmenopausal women. Diabetes Metab Synd Clin Res Rev 2019;13:3031-4.
  25. Ho-Pham LT, Nguyen UD, Nguyen TV. Association between lean mass, fat mass, and bone mineral density: A meta-analysis. J Clin Endocrinol Metab 2014;99:30-8.