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

Fangxiao Cheng,1 Geheng Yuan,1 Jiao He,2 Yimin Shao,1 Junqing Zhang,1 Xiaohui Guo1 1Department of Endocrinology, Peking University First Hospital, Beijing 100034, People’s Republic of China; 2Department of Endocrinology, Baoding First Central Hospital, Baoding 071000, Hebei Province, People’s Republic of ChinaCorrespondence: Geheng Yuan; Xiaohui GuoDepartment of Endocrinology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, People’s Republic of ChinaTel|Fax +86 010 83575103Email 139197109@qq.com; bdyyguoxiaohui@sina.comPurpose: 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: obesity, adipocyte, DPP4, AMPK, JAK2/STAT3, liraglutide, insulin resistance