WSF-7 Inhibits Obesity-Mediated PPARγ Phosphorylation and Improves Insulin Sensitivity in 3T3-L1 Adipocytes

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ), the molecular target for antidiabetic thiazolidinediones (TZDs), is a master regulator of preadipocyte differentiation and lipid metabolism. The adverse side effects of TZDs, arising from their potent agonistic activity, can be minimized by PPARγ partial agonists or PPARγ non-agonists without loss of insulin sensitization. In this study, we reported that WSF-7, a synthetic chemical derived from natural monoterpene α-pinene, is a partial PPARγ agonist. We found that WSF-7 binds directly to PPARγ. Activation of PPARγ by WSF-7 promotes adipogenesis, adiponectin oligomerization and insulin-induced glucose uptake. WSF-7 also inhibits obesity-mediated PPARγ phosphorylation at serine (Ser)273 and improves insulin sensitivity of 3T3-L1 adipocytes. Our study suggested that WSF-7 activates PPARγ transcription by a mechanism different from that of rosiglitazone or luteolin. Therefore, WSF-7 might be a potential therapeutic drug to treat type 2 diabetes.

Terpene-Containing Analogues of Glitazars as Potential Therapeutic Agents for Metabolic Syndrome

“…The choice of monoterpenoids for derivatization was also made based on the literature data on the hypoglycemic and hypolipidemic activity of the terpene derivatives. Derivatives of both bicyclic and acyclic monoterpenoids ( Figure 12 ) are known to be partial PPAR agonists and also have hypoglycemic and hepatoprotective activity [ 11 , 12 , 13 , 14 ].…”

The role of peroxisome proliferator‐activated receptor γ in lipid metabolism and inflammation in atherosclerosis

“…For example, S26948 reduced LDL and VLDL in the blood of ob/ob male C57BL/6 mice and reduced atherosclerotic lesions (Carmona et al, 2007). WSF‐7 upregulates PPARγ responsive genes, such as adiponectin and glucose transporter (Glut)4, inhibits obesity‐induced phosphorylation of PPARγ at Ser273, and enhances insulin sensitivity in 3T3‐L1 adipocytes (Zhang et al, 2020). Lobeglitazone inhibits VSMC proliferation and migration, reduces vascular cell adhesion, reduces NF‐κB p65 translocation, and improves circulating factors associated with atherosclerosis (Lim et al, 2015; Song et al, 2021).…”

The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators

“…In fact, partial PPARγ agonist is different from the classic TZDs, with rosiglitazone as the “full agonist.” It is generally believed that 20–60% of rosiglitazone efficacy is a partial activator ( Table 1 ), such as GQ-177 ( Silva et al, 2016 ), S 26948 ( Carmona et al, 2007 ), WSF-7 ( Zhang et al, 2020 ) lobeglitazone ( Lim et al, 2015 ), and INT131 ( Xie et al, 2017 ). LDLr –/– mice treated with GQ-177 can significant decrease the VLDL, LDL fractions and increase mean HDL, Glut4 levels, increased the expression of apoA1, CD36, ABCA1, SR-B1, and ABCG5 in hepatic, contrary to rosiglitazone, GQ-177 did not affect fat accumulation and bone mineral density ( Silva et al, 2016 ).…”

“…S26948 improves lipid parameters (LDLs, VLDL) and reduces atherosclerotic lesions in ob/ob male C57BL/6 mice ( Carmona et al, 2007 ). WSF-7 upregulated PPARγ-responsive genes, such as adiponectin and Glut4, inhibits PPARγ phosphorylation at Ser273 by obesity and enhances insulin sensitivity in 3T3-L1 Adipocytes ( Zhang et al, 2020 ). Lobeglitazone inhibits the VSMCs proliferation and migration, reduces the vascular cells adhesion, NF-kB p65 translocation, and improves circulating factors related to atherosclerosis, then reduced neointimal formation significantly in balloon injury rat carotid arteries in ApoE –/– mice ( Lim et al, 2015 ; Song et al, 2021 ).…”