Peroxisome Proliferator-Activated Receptor γ (PPARγ)-Independent Specific Cytotoxicity against Immature Adipocytes Induced by PPARγ Antagonist T0070907

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) plays indispensable roles in adipogenesis, which is frequently impaired under pathological conditions such as non-alcoholic steatohepatitis (NASH). Thus, a potent PPARγ antagonist, T0070907 is known as a useful tool for understanding such pathological conditions, while T007097 was also suggested to have PPARγ-independent actions. In the present study, we found that T0070907 inhibited adipogenesis concomitantly with the induction of rapid apoptosis of immature adipocytes within 2 h, whereas another PPARγ antagonist, SR-202 did not show such cytotoxicity. However, T0070907 did not affect the viabilities of pre-adipocytes, mature adipocytes, and NIH-3T3 fibroblasts. The cytotoxic effect of T0070907 was not inhibited by GW1929, a PPARγ agonist, but was inhibited by α-tocopherol, which was previously shown to provide clinical benefit to NASH patients. Interestingly, treatment with high amounts of α-tocopherol alone slightly increased the cellular lipid content in mature adipocytes, but did not affect PPARγ-dependent luciferase reporter expression in COS-7 cells. Moreover, other lipophilic antioxidants, such as tocotrienols, tert-butylhydroquinone, and butylated hydroxyanisole, also inhibited T0070907-induced apoptosis like α-tocopherol. Consequently, it is suggested that T0070907 efficiently inhibits adipogenesis, not only via PPARγ-dependent manner, but also through the induction of apoptosis specifically against immature adipocytes via oxidative stress in a PPARγ-independent manner.

Recovery of Tendon Characteristics by Inhibition of Aberrant Differentiation of Tendon-Derived Stem Cells from Degenerative Tendinopathy

“…We found the optimal dose of each inhibitor-25 µM of AGA for Runx2 and 10 µM of T0070907 for PPARγ. Previous studies also used the same doses of inhibitors to observe aberrant differentiation [26,30,34,35], which was consistent with our results. Over 25 µM of AGA killed more than 50% of cells due to the cytotoxicity of this inhibitor.…”

“…In addition, Jeong et al [26] showed that AGA has an inhibitory effect on osteoblastic differentiation and inhibits the transcriptional activity of Runx2. The role of T0070907 in suppressing PPARγ activity has been demonstrated in many studies [27][28][29][30]. It has also been shown that T0070907 treatment has significant antitumor effects in various cancer cell types, and these effects are explained by the PPARγ pathway [31][32][33].…”

Effect of PPARG on AGEs‐induced AKT/MTOR signaling‐associated human chondrocytes autophagy

“…Based on previous experimental results, we first examined whether T0070907 (PPARG inhibitor) and pioglitazone (PPARG agonist) have cytotoxic effects on chondrocytes. Chondrocytes were treated with various doses of pioglitazone (1–50 µM) and T0070907 (10 µM) (Kawahara et al, ). Our results show that significant cytotoxicity was not detected after 24 h exposure (Figures A and B).…”

Skin aging: are adipocytes the next target?

“…Moreover, it is known that α-tocopherol can stimulate the expression of PPARγ and along with that lipid accumulation during adipogenic differentiation [51]. This PPARγ stimulation seems to be realized indirectly through inhibition of its antagonists [52]. Moreover, α-tocopherol can induce the expression of adiponectin, which is in line with its adipogenic effects [53].…”