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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., (© 2021. The Author(s).)

Background: The hepatokine fetuin-A is linked to obesity and type 2 diabetes, but its presence and expression in adipose tissue remain unclear. In this study, we aimed to assess the circulating levels of fetuin-A and its expression in subcutaneous adipose tissue (SAT) from diabetic and non-diabetic obese subjects and their modulation by exercise., Methods: SAT and blood were obtained from adults obese (diabetic, n=118 and non-diabetic, n=166) before and after a 3-month exercise program (diabetic, n=40 and non-diabetic, n=36, respectively). Plasma fetuin-A was assayed using ELISA. The presence and expression of fetuin-A in SAT, peripheral blood mononuclear cells (PBMCs) and cell lines (3T3-L1, THP-1, HepG2, RAW 264.7) were analysed using confocal microscopy, immunoblotting and qRT-PCR., Results: Plasma fetuin-A level did not significantly differ between diabetic and non-diabetic obese subjects. However, when the non-diabetic group was divided into metabolically healthy and unhealthy phenotypes, significantly higher fetuin-A level was observed in the unhealthy sub-group. Circulating fetuin-A was mainly associated with glycaemic markers. In SAT, fetuin-A protein level was significantly higher in the diabetic obese subjects but its mRNA was not detected. Similarly, fetuin-A protein was detected in PBMCs, but its mRNA was not. In line with this, the use of various cell lines and culture media indicated that the presence of fetuin-A in SAT and PBMCs was due to its uptake from circulation rather than its endogenous expression. Finally, physical exercise decreased fetuin-A levels in both plasma and SAT in both groups., Conclusions: Fetuin-A levels increased in association with diabetes in SAT but not in circulation in the obese subjects. Moreover, physical exercise decreased fetuin-A level. Fetuin-A potentially acts as a hepatokine taken up by other tissues, such as adipose tissue.

Background: ANGPTL8 also called betatrophin is a regulator of lipid metabolism through its interaction with ANGPTL3. It has also been suggested to play a role in insulin resistance and beta-cell proliferation. Based on its function, we hypothesized that ANGPTL8 will play a role in Metabolic Syndrome (MetS). To test this hypothesis we designed this study to measure ANGPTL8 level in subjects with MetS as well as its association with high sensitivity C-reactive protein (HsCRP) level in humans., Methods: ANGPTL8 level was measured using ELISA in subjects with MetS as well as their controls, a total of 1735 subjects were enrolled. HsCRP was also measured and its association with ANGPTL8 was examined., Results: ANGPTL8 level was higher in subjects with MetS 1140.6 (171.9-11736.1) pg/mL compared to 710.5 (59.5-11597.2) pg/mL in the controls. Higher levels of ANGPTL8 were also observed with the sequential increase in the number of MetS components (p value = <0.0001). ANGPTL8 showed strong positive correlation with HsCRP (r = 0.15, p value = <0.0001). Stratifying the population into tertiles according to the level of HsCRP showed increased ANGPTL8 level at higher tertiles of HsCRP in the overall population (p value = <0.0001).A similar trend was also observed in MetS and non-MetS subjects as well as in non-obese and obese subjects. Finally, multiple logistic regression models adjusted for age, gender, ethnicity and HsCRP level showed that subjects in the highest tertiles of ANGPTL8 had higher odds of having MetS (odd ratio [OR] = 2.3, 95 % confidence interval [CI] = (1.6-3.1), p value <0.0001., Conclusion: In this study we showed that ANGPTL8 is increased in subjects with MetS and it was significantly associated with HsCRP levels in different subgroups highlighting its potential role in metabolic and inflammatory pathways.

Background: Obesity is characterized by a chronic low-grade inflammation and altered stress responses in key metabolic tissues. Impairment of heat shock response (HSR) has been already linked to diabetes and insulin resistance as reflected by decrease in heat shock proteins (HSPs) expression. However, the status of HSR in non-diabetic human obese has not yet been elucidated. The aim of the current study was to investigate whether obesity triggers a change in the HSR pattern and the impact of physical exercise on this pattern at protein and mRNA levels., Methods: Two groups of adult non-diabetic human subjects consisting of lean and obese (n = 47 for each group) were enrolled in this study. The expression pattern of HSP-27, DNAJB3/HSP-40, HSP-60, HSC-70, HSP72, HSP-90 and GRP-94 in the adipose tissue was primarily investigated by immunohistochemistry and then complemented by western blot and qRT-PCR in Peripheral blood mononuclear cells (PBMCs). HSPs expression levels were correlated with various physical, clinical and biochemical parameters. We have also explored the effect of a 3-month moderate physical exercise on the HSPs expression pattern in obese subjects., Results: Obese subjects displayed increased expression of HSP-60, HSC-70, HSP-72, HSP-90 and GRP-94 and lower expression of DNAJB3/HSP-40 (P < 0.05). No differential expression was observed for HSP-27 between the two groups. Higher levels of HSP-72 and GRP-94 proteins correlated positively with the indices of obesity (body mass index and percent body fat) and circulating levels of IFN-gamma-inducible protein 10 (IP-10) and RANTES chemokines. This expression pattern was concomitant with increased inflammatory response in the adipose tissue as monitored by increased levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), and RANTES (P < 0.05). Physical exercise reduced the expression of various HSPs in obese to normal levels observed in lean subjects with a parallel decrease in the endogenous levels of IL-6, TNF-α, and RANTES., Conclusion: Taken together, these data indicate that obesity triggers differential regulation of various components of the HSR in non-diabetic subjects and a 3-month physical moderate exercise was sufficient to restore the normal expression of HSPs in the adipose tissue with concomitant attenuation in the inflammatory response.