Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α (TNF-α) in circulation, we investigated whether stearic acid and TNF-α together could regulate MIP-1α/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved in MIP-1α/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-α resulted in enhanced production of MIP-1α/CCL3 compared to stearic acid or TNF-α alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-α/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-α/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-α/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-α on MIP-1α/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-α for MIP-1α/CCL3 production that was comparable to stearic acid. Individuals with obesity show high IRF3 expression in monocytes as compared to lean individuals. Furthermore, elevated levels of MIP-1α/CCL3 positively correlate with TNF-α and CD163 in fat tissues from individuals with obesity. Taken together, this study provides a novel model for the pathologic role of stearic acid to produce MIP-1α/CCL3 in the presence of TNF-α associated with obesity settings.
Background Angiopoietin-like proteins (ANGPTL), primarily 3, 4, and 8, play a major role in maintaining energy homeostasis by regulating triglyceride metabolism. This study evaluated the level of ANGPTL3, 4, and 8 in the liver, brown adipose tissue (BAT), and subcutaneous white adipose tissue (SAT) of mice maintained under acute and chronic cold conditions. Methods C57BL/6J mice were exposed to cold temperature (4 °C) for 10 days with food provided ad libitum. Animal tissues were harvested at Day 0 (Control group, n = 5) and Days 1, 3, 5, and 10 (cold treatment groups, n = 10 per group). The expression levels of various genes were measured in the liver, SAT, and BAT. ANGPTL3, 4, and 8 expressions were measured in the liver. ANGPTL4, 8, and genes involved in browning and lipid metabolism [uncoupling protein 1 (UCP1), lipoprotein lipase (LPL), and adipose triglyceride lipase (ATGL)] were measured in SAT and BAT. Western blotting (WB) analysis and immunohistochemistry (IHC) were performed to confirm ANGPTL8 expression in these tissues. Results The expressions of ANGPTL3 and 8 mRNA were significantly reduced in mouse liver tissues after cold treatment (P < 0.05); however, the expression of ANGPTL4 was not significantly altered. In BAT, ANGPTL8 expression was unchanged after cold treatment, whereas ANGPTL4 expression was significantly reduced (P < 0.05). ANGPTL4 levels were also significantly reduced in SAT, whereas ANGPTL8 gene expression exhibited over a 5-fold increase. Similarly, UCP1 gene expression was also significantly increased in SAT. The mRNA levels of LPL and ATGL showed an initial increase followed by a gradual decrease with an increase in the days of cold exposure. ANGPTL8 protein overexpression was further confirmed by WB and IHC. Conclusions This study shows that exposure to acute and chronic cold treatment results in the differential expression of ANGPTL proteins in the liver and adipose tissues (SAT and BAT). The results show a significant reduction in ANGPTL4 in BAT, which is linked to improved thermogenesis in response to acute cold exposure. ANGPTL8 was activated under acute and chronic cold conditions in SAT, suggesting that it is involved in regulating lipolysis and enhancing SAT browning.
Background It is well known that Angiopoietin like protein (ANGPTL) mainly 3, 4 and 8 play a major role in maintaining energy homeostasis by regulating lipoprotein lipase (LPL) activity, which is a key regulator of triglyceride (TG) metabolism. Our aim is to evaluate the level of ANGPTL3, 4 and 8 in mice maintained under cold conditions in the liver, brown adipose tissue (BAT), and white adipose tissue (WAT). Methods C57BL/6J mice were exposed to cold temperature at 4˚C over a period of ten days with food given ad libitum. Animal tissues were harvested at days 0, 1, 3, 5, and 10 (cold treatment groups, n = 10 in each group, control, n = 5). Liver, subcutaneous adipose tissue (SAT), and BAT were used to investigate the expression level of different genes. ANGPTL3, 4 and 8 genes expression were measured in liver. ANGPTL4, 8 and UCP1 were measured in SAT and BAT. Results ANGPTL 3 and 8 gene expression levels were significantly reduced in mice liver tissues after cold treatment (P-value < 0.05). However, the gene expression level of ANGPTL4 was not significantly changed. In BAT, ANGPTL8 expression was not changed after cold treatment while ANGPTL4 was significantly reduced (P-value < 0.05). ANGPTL4 level was also significantly reduced in SAT, whereas the gene expression level of ANGPTL8 showed over a 5-fold increase. Similarly, the UCP1 gene expression was also significantly increased in SAT. Additionally, protein overexpression of ANGPTL8 was further confirmed by immunohistochemistry after extended cold treatment. Conclusion Our data shows that ANGPTL proteins are inhibited in the liver and BAT under cold treatment. This agrees with other studies that showed that reduction in ANGPTL4 in BAT improved thermogenesis in response to acute cold exposure. However, in our study we also observed that ANGPTL8 is activated under these conditions in SAT. This suggests that it might be involved in the regulation of lipolysis as well as enhancing SAT browning.
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