Adipokines, have regulatory roles on expression and secretion of various cytokines, by this fact they have significant effects on the immune system. Therefore, they can play a crucial role in inflammatory diseases like IBD, which also have a metabolic background . Several studies have shown that, adipokines such as leptin, resistin, visfatin, retinol-binding protein-4, adiponectin, glucose, and insulin are deregulated in the IBD patients . Metrnl is a novel adipokine, which has a major role in improvement of inflammation and insulin resistance improvement . Accordingly, this adipokine has been investigated in several metabolic and inflammatory diseases. Lee et al. showed that, patients with diabetes mellitus type 2 (T2DM) had lower level of Metrnl in their serum . Similarly, Dadmanesh et al. found that Metrnl concentration in the serum of patients with coronary artery disease and T2DM were lower . While, Chung et al. reported that levels of METRNL were significantly higher in T2D patients . Most of the previous studies have focused on the tissues level of Metrnl in inflammatory disorders, thus there is no data on the serum levels of Metrnl in these complications. Bridgewood et al. investigated the level of Metrnl in synovial tissue in the patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Osteoarthritis. As a result, they found the elevated level of Metrnl in Psoriatic Arthritis . To the authors knowledge, so far, current study is the novel one that reporting the serum levels of Metrnl in the IBD patients. In addition, the results show the lower serum levels of Metrnl in the IBD patients compared to the controls. However, Metrnl was not different between patients groups. Li et al. demonstrated that, Metrnl is highly expressed in the gastrointestinal tract of normal donors as well as mice. On the other hand, they produced intestinal epithelial cell-specific knockout mice, in spite of reduction in Metrnl expression in the gastrointestinal tract, it’s level is not decreased in serum . A recent study performed by Zuo et al. reported that Metrnl expression is higher in mesenteric adipose tissue (MAT) of the CD patients compared to the controls. They also showed that, systemic treatment of Metrnl can improve the adipocyte function, and reduce the macrophage infiltration and inflammation by acting on the peroxisome proliferator-activated receptors (PPARγ) pathway in mice. Therefore, they suggested that, upregulation of Metrnl in the MAT of the patients may be a compensatory response . Regarding the inconsistent results, it seems likely that, Metrnl expression can have an organ dependent pattern; however, further longitudinal research is needed to support this hypothesis.
Furthermore, present study indicated an inverse relationship of Metrnl with the inflammatory cytokines in the IBD patients. It was also observed that, Metrnl may have regulatory action in inﬂammation pathways. Zuo et al. administered the Metrnl in IL-10-/- mice and then observed a significant decrease in the score of inflammation and pro-inflammatory factors such as TNF-α, interferon (IFN)-γ, and IL-6 . Additionally, Zhi-yong LI et al. reported that, Metrnl plays a regulatory role in the expression of antimicrobial peptides such as islet-derived 3 gamma (Reg3g), lactotransferrin, and amyloid A-3 (SAA3) . Since TNF-α and IL-6 are considered as the markers of inflammation, the results suggest a relationship between Metrnl and IBD pathogenesis. In addition, adiponectin decreased in the patient’s groups, however, there were no relation between Metrnl and adiponectin that suggested a different regulation of these two adipokines.
When the population were stratified based on obesity, the serum level of Metrnl was significantly lower in obese subjects than in non-obese ones. Consistently, AlKhairi et al. reported that, Metrnl is significantly higher in the T2DM obese patients, in a way that this elevation can be explained as a compensatory response . However, Zhi-Yong Li et al. showed no correlation between serum Metrnl levels and BMI . As the adipose tissue is the main source of Metrnl secretion, it is expected that, BMI can affect the levels of this adipokine, and adipose tissue inflammation and dysfunction may be considered as the causes for the decrease in Metrnl levels.
Study strength and limitations
The present study for the first time measured Metrnl serum levels in patients UC and CD disease and its relation with inflammatory cytokines. The studied population were matched in terms of age, sex and BMI with control group that eliminated the impact of these confounding factor on the results. On the other hand, the present study has no data on body fat distribution that could be more clinically significant than BMI. Furthermore, the cross-sectional design of the study limited us in concluding a cause and effect relationship, so further studies are waranted to dissect the possible mechanism for the reported relationship.