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

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 bromodeoxyuridine (BrdU), the stimulation of preadipocyte growth by ET-1 depends on concentration and timing. The concentration of ET-1 that increased preadipocyte number by 51-67% was ~100 nM for ~24-48 h of treatment. ET-1 signaling time dependently stimulated phosphorylation of ERK, c-JUN, AMPK, and proteins but not AKT, JNK, or p38 MAPK. Treatment with an ET_AR antagonist, such as BQ610, but not ET_BR antagonist BQ788, blocked the ET-1-induced increase in cell proliferation and phosphorylated levels of ERK, c-JUN, duanyu18133, AMPK, and duanyu1531α/βII proteins. In addition, pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), (AG490), AMPK (compound C), or (Ro318220) prevented the ET-1-induced increase in cell proliferation and reduced the ET-1-stimulated phosphorylation of ERK1/2, c-JUN, duanyu18133, AMPK, and Moreover, the SphK antagonist suppressed ET-1-induced cell proliferation and ERK, c-JUN, duanyu18133, AMPK, and duanyu1531 phosphorylation, and the SMase2 antagonist suppressed ET-1-induced cell proliferation. However, neither the p38 MAPK antagonist nor the CerS inhibitor altered the effect of ET-1. The results indicate that ET_AR, ERK1/2, JNK/c-JUN, AMPK, SphK, and SMase2, but not ET_BR, p38 MAPK, or CerS, are necessary for the ET-1 stimulation of preadipocyte proliferation.

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