Abstract
Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. An in vitro model was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2α phosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction.
Highlights
Over recent decades, it is clear that obesity is associated with the activation of endoplasmic reticulum (ER) stress signalling and inflammatory pathways, which contributes to obesity-related metabolic syndrome and type 2 diabetes [1]
ER Stress Is Induced by Palmitate and Contributes to the Increase of monocyte chemoattractant protein-1 (MCP-1) and IL-6 Expression in Mature Adipocytes
A corresponding increase in ER stress proteins markers was shown by an induction of activating transcription factor 4 (ATF4), C/ebp homologous protein (CHOP), and eIF2α as well as jun N-terminal kinase (JNK) phosphorylation with indicated PA dose (Figure 1(b))
Summary
It is clear that obesity is associated with the activation of endoplasmic reticulum (ER) stress signalling and inflammatory pathways, which contributes to obesity-related metabolic syndrome and type 2 diabetes [1]. Individuals with larger adipocytes typically have elevated proinflammatory factors including leptin, IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and reduced levels of the insulin-sensitivity-related adiponectin and IL-10 [4]. Saturated fatty acids (SFA) are systemically elevated in dietinduced obesity and trigger ER stress, which has been proposed as the immediate cause of chronic inflammation and reduction of insulin action [5]. ER stress signalling referred to as the unfolded protein response (UPR) is triggered by three downstream proteins: PKR-like eukaryotic initiation factor 2 kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring 1α (IRE1α). The PERK-elongation initiation factor 2α-activating transcription factor 4 (ATF4) signaling pathway connects ER stress to C/ebp homologous protein (CHOP) and contributes to ER stress-induced apoptosis [6]. ER stress intersects with many different inflammatory signalling pathways, such as NFκB signalling and contributes to the increase of inflammatory cytokines [7]
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