title: Palmitate induces endoplasmic reticulum stress and autophagy in mature adipocytes: implications for apoptosis and inflammation.
abstract: Endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to adipocyte dysfunction, with the impairment of the insulin pathway. Recent studies have indicated that understanding the physiological role of autophagy is of great significance. In the present study, an in vitro model was used in which 3T3-L1 adipocytes were pre-loaded with palmitate (PA) to generate artificially hypertrophied mature adipocytes. PA induced an autophagic flux, determined by an increased microtubule-associated protein 1 light chain 3 (LC3)-II formation, as shown by western blot analysis and fluorescence microscopy, and was confirmed using transmission electron microscopy (TEM). Using TEM and western blot analysis, we observed increased ER stress in response to PA, as indicated by the increased levels of the ER stress markers, BiP, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and the phosphoralytion of eukaryotic translation initiation factor 2α and c-Jun N-terminal kinase (JNK). Of note, we observed that the PA-induced ER stress occurred prior to the activation of autophagy. We confirmed that autophagy was induced in response to JNK-dependent ER stress, as autophagy was suppressed by treatment with the ER stress inhibitor, 4-phenyl butyrate (4-PBA), and the JNK inhibitor, SP600125. Upon the inhibition of autophagy using chloroquine (CQ), we observed exacerbated ER stress and an increased level of cell death. Importantly, to determine whether autophagy is linked to inflammation, the autophagy inhibitor, 3-methyladenine (3-MA) was used. The inhibition of autophagy led to a further increase in the PA-induced expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). Consistently, such an increase was also observed following treatment with SP600125. In conclusion, our data indicate that PA elicits a ER stress-JNK-autophagy axis, and that this confers a pro-survival effect against PA-induced cell death and stress in hypertrophied adipocytes. The JNK-dependent activation of autophagy diminishes PA-induced inflammation. Therefore, the stimulation of autophagy may become a method with which to attenuate adipocyte dysfunction and inflammation.
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Jiajing
authors: J
authors: Yin
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Yufan
authors: Y
authors: Wang
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Liping
authors: L
authors: Gu
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Nengguang
authors: N
authors: Fan
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Yuhang
authors: Y
authors: Ma
authors: Department of Endocrinology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China.
authors: Yongde
authors: Y
authors: Peng
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D010168:Palmitates / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D010168:Palmitates; D048031:JNK Mitogen-Activated Protein Kinases
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