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

Abstract

PurposeDipeptidyl 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.MethodsObesity-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.ResultsThe 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.ConclusionTaken 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.

The MERS-CoV Receptor DPP4 as a Candidate Binding Target of the SARS-CoV-2 Spike

“…DPP4 is a serine protease that is abundantly distributed in human tissues, playing roles as a multifunctional protein (Aliyari Serej et al, 2017). Apart from the lower respiratory tract, kidney, liver, small iScience Article intestine, and prostate, DPP4 presents in the placenta, fibroblasts of lung and wounded skin, muscle, as well as central nervous systems (Aliyari Serej et al, 2017;Cheng et al, 2019;Cui et al, 2019;Song et al, 2019). Moreover, DPP4 is widely expressed on activated immune cells including CD4(+) and CD8(+) T cells, B cells, natural killer cells, dendritic cells, and macrophages (Shao et al, 2020;Song et al, 2019).…”

Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway

“…Liraglutide treatment could improve insulin sensitivity, accompanied with the reduced expression of the phosphorylated Acetyl-CoA carboxylase-2 and upregulation of long chain acyl CoA dehydrogenase (LCAD) ( Zhou et al, 2019 ). The administration of liraglutide could activate the expression and downstream signaling of GLP-1R ( Kushima et al, 2017 ; Cheng et al, 2019 ). GLP-1 receptor belongs to a class B G-protein-coupled receptor family that signals primarily through the stimulatory G protein Gs, and activates the protein kinase A (PKA), extracellular signal-regulated kinase (ERK)1/2 and phosphoinositol 3 kinase (PI3K)/protein kinase B (PKB) ( Thorens, 1992 ; Arnette et al, 2003 ; Briaud et al, 2003 ; Zhang et al, 2017 ).…”

“…AMPK signaling is also involved in liraglutide stimulated fatty degradation in both hepatic and adipose tissues ( He et al, 2016 ; He et al, 2020 ). DPP4 inhibitor, which could inhibit the degradation of endogenous GLP-1, can stimulate the activation of AMPK and fatty degeneration in adipocyte ( Cheng et al, 2019 ). In our current study, we confirmed the involvement of AMPK signaling in liraglutide stimulated fatty degradation.…”

Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis

“…In animal and cell IR models, DPP4 expression is inhibited by AMPK activation by JAK2/STAT3 signaling in adipocytes ( 90 ). It was subsequently reported that DPP4 inhibition or silencing can improve endothelial senescence by regulating AMPK/SIRT1/NRF2 in vivo and in vitro ( 91 ).…”