Endothelin-1 stimulates preadipocyte growth via the PKC, STAT3, AMPK, c-JUN, ERK, sphingosine kinase, and sphingomyelinase pathways

An-Ci Siao, Yen-Yue Lin, Li-Jane Shih, Yi-Wei Tsuei, Chih-Pin Chuu, Yow-Chii Kuo, Yung-Hsi Kao
American Journal of Physiology. Cell Physiology 2020 August 5
Endothelin (ET)-1 regulates adipogenesis and the endocrine activity of fat cells. However, relatively little is known about the ET-1 signaling pathway in preadipocyte growth. We used 3T3-L1 preadipocytes to investigate the signaling pathways involved in ET-1 modulation of preadipocyte proliferation. As indicated by an increased number of cells and greater incorporation of BrdU, the stimulation of preadipocyte growth by ET-1 depends on concentration and timing. The concentration of ET-1 that increased preadipocyte number by 50-70% was approximately 100 nM for approximately 24-48 h of treatment. ET-1 signaling time-dependently stimulated phosphorylation of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins, but not AKT, JNK, or p38 MAPK. Treatment with an ETA R antagonist, such as BQ610, but not ETB R antagonist BQ788, blocked the ET-1-induced increase in cell proliferation and phosphorylated levels of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins. In addition, pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), JAK2/STAT-3 (AG490), AMPK (Compound C), or PKC (Ro318220) prevented the ET-1-induced increase in cell proliferation and reduced the ET-1-stimulated phosphorylation of ERK1/2, c-JUN, STAT-3, AMPK, and PKCα/β. Moreover, SphK antagonist suppressed ET-1-induced cell proliferation and ERK, c-JUN, STAT3, AMPK, and PKC phosphorylation, and SMase2 antagonist suppressed ET-1-induced cell proliferation. However, neither p38 MAPK antagonist nor CerS inhibitor altered the effect of ET-1. The results indicate that ETA R, JAK2/STAT3, ERK1/2, JNK/c-JUN, AMPK, PKC, SphK, and SMase2, but not ETB R, p38 MAPK, or CerS, are necessary for the ET-1 stimulation of preadipocyte proliferation.

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