Increased expression level of ANGPTL8 in white adipose tissue under acute and chronic cold treatment

Abstract

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.

Effects of ambient temperatures between 5 and 35 °C on energy balance, body mass and body composition in mice

“…The increase in metabolism as ambient temperature fell below the LCT was correlated with increased levels of T3, expansion of the BAT mass, increases in BAT mitochondrial protein, BAT COX activity and direct measures of non-shivering thermogenesis. These observations all support extensive previous work showing thermogenesis after about 10 days of cold exposure is provided predominantly by elevated heat production in BAT [ 26 , [76] , [77] , [78] ]. Our work shows that these responses are closely calibrated to the exact levels of cold, and the thermoregulatory requirements to sustain body temperature.…”

Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes

“…angptl8 is regulated by nutritional and hormonal factors, and feeding induces an increase in its levels (192). It has been reported that ANGPTL8 not only induces the expression of brown adipocyte markers (193) but also promotes subcutaneous white adipose tissue (SAT) browning under acute and chronic hypothermic conditions (194). Fibroblast growth factor 21 (FGF21) is known to be a hepatokine induced by fasting and is being pursued as a therapeutic target for diabetes and obesity due to its rapid and effective action in improving insulin sensitivity (195).…”