Dysregulation of DPP4 Is Associated with the AMPK/JAK2/STAT3 Pathway in Adipocytes Under Insulin Resistance Status and Liraglutide Intervention

Abstract

Purpose: Dipeptidyl peptidase 4 (DPP4) is one of the newly identified adipokines, which acts as paracrine in adipose tissue and as endocrine hormones in the liver, muscles and central nervous system. Expression of DPP4 was significantly upregulated in obese patients upon insulin resistance (IR) conditions, but the mechanism underlying the dysregulation of DPP4 remains unclear. This study aimed to investigate the DPP4 expression in adipose tissue and adipocytes under IR conditions or with liraglutide intervention, and explore the potential molecular mechanisms.

Methods: Obesity-associated IR animal and cell models were, respectively, constructed by using high-fat diet and palmitic acid (PA) stimulation. Expression of DPP4 in adipose tissues and adipocytes was estimated by quantitative real-time RT-PCR and Western-blot. Effects of the AMPK/JAK2/STAT3 pathway on DPP4 were examined by regulating the activity of AMPK and the JAK2/STAT signaling. The therapeutic efficacy of liraglutide in the IR models was evaluated, and its regulatory effects on DPP4 expression and the underlying molecular mechanisms were explored.

Results: The expression of DPP4 was markedly upregulated in both the animal and cell IR models. In the adipocyte, DPP4 expression was found to be suppressed by the activation of AMPK, and this inhibition effect was mediated by the JAK2/STAT3 signaling. Moreover, liraglutide could alleviate the obesity-induced IR, and led to the downregulation of DPP4 in IR animal and cell models. Liraglutide intervention resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling in the adipocytes.

Conclusion: Taken together, the expression of DPP4 is upregulated in adipose tissues and adipocytes upon IR conditions, but is reduced after liraglutide intervention. The dysregulation of DPP4 in the adipocytes may be performed by the AMPK/JAK2/STAT3 pathway.

Keywords: AMPK; DPP4; JAK2/STAT3; adipocyte; insulin resistance; liraglutide; obesity.

Figure 1

Expression of DPP4 in adipose tissues and adipocytes under IR conditions. (A, B) The mRNA and protein expression levels of DPP4 were increased in the IR rats compared with the normal controls. (C, D) The mRNA and protein expression levels of DPP4 were increased in the IR cells compared with the controls. *P < 0.05, **P < 0.01.

Figure 2

Effect of the AMPK/JAK2/STAT3 pathway on the expression of DPP4 in adipocytes. (A) Western blot results for DPP4 and proteins in the JAK2/STAT3 signaling pathway. (B) Activity of the JAK2/STAT3 signaling pathway in adipocytes under IR conditions, and its activity was inhibited by CPT and was promoted by COL. (C) DPP4 expression was suppressed by deactivation of the JAK2/STAT3 signaling pathway, and was enhanced by activation of the JAK2/STAT3 signaling pathway. (D) Western blot results for DPP4 and proteins in the AMPK/JAK2/STAT3 pathway. (E) AMPK was deactivated in adipocytes under IR status, and the activation of AMPK led to the suppression of the JAK2/STAT3 signaling pathway. (F) The decreased expression of DPP4 induced by activation of AMPK was rescued by the activation of the JAK2/STAT3 signaling pathway. *P < 0.05 compared with the NC group; ^#P < 0.05 compared with the PA group; ^&P < 0.05 compared with the MET group.

Figure 3

Therapeutic efficacy of liraglutide against obesity-associated IR. (A) The impaired glucose tolerance was significantly improved by liraglutide. (B) The decreased insulin sensitivity in IR animals was increased following the treatment of liraglutide. (C) AUCs for OGTT and IPITT significantly decreased after liraglutide treatment. (D) The increased HOMA-IR in IR animals was reduced by liraglutide. (E) The insulin-stimulated glucose uptake ability was improved by the treatment of liraglutide. *P < 0.05, **P < 0.01.

Figure 4

Liraglutide treatment reduced the expression of DPP4 in IR animal and cell models. (A) DPP4 expression was decreased by liraglutide in adipose tissues under IR conditions. (B) Liraglutide intervention in adipocytes led to decreased DPP4 expression. *P < 0.05.

Figure 5

Liraglutide regulated the activity of AMPK and the JAK2/STAT3 signaling pathway. (A) Western blot results for activity of AMPK and the JAK2/STAT3 signaling pathway. (B) Liraglutide intervention in adipocytes resulted in the activation of AMPK and deactivation of the JAK2/STAT3 signaling pathway. *P < 0.05.