Ethyl Gallate Dual-Targeting PTPN6 and PPARγ Shows Anti-Diabetic and Anti-Obese Effects

Abstract

The emergence of the high correlation between type 2 diabetes and obesity with complicated conditions has led to the coinage of the term “diabesity”. AMP-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPARγ) antagonists have shown therapeutic activity for diabesity, respectively. Hence, the discovery of compounds that activate AMPK as well as antagonize PPARγ may lead to the discovery of novel therapeutic agents for diabesity. In this study, the knockdown of PTPN6 activated AMPK and suppressed adipogenesis in 3T3-L1 cells. By screening a library of 1033 natural products against PTPN6, we found ethyl gallate to be the most selective inhibitor of PTPN6 (Ki = 3.4 μM). Subsequent assay identified ethyl gallate as the best PPARγ antagonist (IC50 = 5.4 μM) among the hit compounds inhibiting PTPN6. Ethyl gallate upregulated glucose uptake and downregulated adipogenesis in 3T3-L1 cells as anticipated. These results strongly suggest that ethyl gallate, which targets both PTPN6 and PPARγ, is a potent therapeutic candidate to combat diabesity.

Bioinformatics gene analysis of potential biomarkers and therapeutic targets of osteoarthritis associated myelodysplastic syndrome

“…Non-receptor-type protein tyrosine phosphatase 6 (PTPN6), expressed mainly in hematopoietic stem cells, regulates receptor tyrosine kinases by binding to target proteins and dephosphorylating tyrosine substrates ( Ahn et al, 2022 ; Luo et al, 2022 ). The m6A methyltransferase METTL14 promotes proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells in steroid-associated femoral head necrosis by upregulating m6A levels of PTPN6 and activating the Wnt signaling pathway ( Cheng C. et al, 2021 ).…”

Identifying the mechanisms and molecular targets of Hongjingtian injection on treatment of TGFβ1-induced HK-2 cells: coupling network pharmacology with experimental verification

“…Cui et al ( 17 ) demonstrated that EG suppresses proliferation and invasion in human breast cancer cells by modulating the PI3K/Akt pathway, and inhibit downstream targets such as NF-κB p-65, Bcl-2/Bax . Ahn et al ( 18 ) proposed that EG targeting PTPN6 and PPARγ exerts an anti-diabetes effect. Crispo et al ( 19 ) suggested that EG protects PC12 cells against oxidative stress induction through the Nrf2 pathway.…”

Exploring the Anti-Diabetic Potential of Quercetagitrin through Dual Inhibition of PTPN6 and PTPN9

“…The purification and expression techniques for PTPN6 and PTPN9 have previously been outlined in literature [ 7 , 13 , 15 ]. Escherichia coli Rosetta (DE3) cells were utilized to express recombinant plasmids encoding PTPN6 and PTPN9, supplied by Merck KGaA, Germany.…”

“…The cell viability assay was conducted following the full differentiation of C2C12 myoblasts as previously described [ 15 , 16 ]. Upon achieving complete differentiation, cells were subjected to a 16 h starvation period in low-glucose DMEM (11885084, Gibco BRL, Middlesex, UK).…”

“…Glucose absorption was assessed using the protocol previously outlined in the literature [ 7 , 15 ]. Briefly, well-differentiated C2C12 myoblasts underwent a 16 h starvation phase in low-glucose DMEM (11885084, Gibco BRL, Middlesex, UK) to deplete essential nutrients.…”