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1 Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
2 Genetics, Boston University School of Medicine, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: wguo{at}bu.edu.
Although fatty acids enhance preadipocyte differentiation in the presence of adequate hormone cocktails, little is known regarding their effects in the absence of these hormones. We now show that palmitate, a common long chain saturated fatty acid, induced apoptosis in both mouse 3T3-L1 and rat primary preadipocytes grown in a normal serum-containing medium. Treatment of preadipocytes with palmitate induced multiple ER stress responses, evidenced by increased protein content of CHOP and GRP78, XBP-1 mRNA splicing, as well as altered phosphorylation of eIF2
and increased phosphorylation of JNK and Erk1/2. Intriguingly, palmitate induced an early activation of Akt but diminished both Akt activation and its protein mass after prolonged incubation (> 6 h). In association with these changes, palmitate reduced expression of 
-catenin and its downstream target c-myc and cyclin D1, two key pro-survival proteins. Over-expression of constitutively active Akt did not block the apoptotic effect of palmitate. Co-treatment with unsaturated fatty acids (oleate, linoleate) or with LiCl (a GSK3 inhibitor) attenuated the palmitate-induced apoptosis. Subsequent analysis suggests that the unsaturated fatty acids probably counteracted palmitate by reducing, not eliminating, ER stress whereas LiCl probably improved viability by activating the Wnt signaling pathway. Co-treatment of palmitate with a standard adipogenic hormone cocktail also abolished the apoptotic effect and promoted adipocyte differentiation. Collectively, our results suggest that palmitate causes multiple cellular stresses which may lead to apoptosis in preadipocytes in the absence of adipogenic stimuli; highlighting the importance of exogenous hormones in directing cell fate in response to increased fatty acid influx.
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