The Adipokine Metrnl Ameliorates Chronic Colitis in Il-10–/– Mice by Attenuating Mesenteric Adipose Tissue Lesions During Spontaneous Colitis

Abstract

Background Crosstalk between mesenteric adipose tissue [MAT] and the intestines affects the progression of Crohn’s disease [CD]. The adipokine metrnl regulates adipocyte function and has anti-inflammatory activity. We aimed to explore metrnl expression in CD MAT, investigate the influence of metrnl on the experimental colitis disease course and determine the mechanism underlying this effect. Methods Metrnl expression in MAT specimens obtained from patients with and without CD was tested by immunohistochemistry. Male Il-10–/– mice with spontaneous enteritis were divided into positive control and metrnl-treated [Metrnl-Fc, 10 mg/kg/d, intraperitoneally, 8 weeks] groups. Age-matched male wild-type [WT] mice were used as negative controls. The effects of metrnl on enteritis and mesenteric lesions and the potential controlling mechanisms were evaluated. Results Metrnl expression was higher in human CD MAT than in control MAT. Systemic delivery of metrnl significantly ameliorated chronic colitis in Il-10–/– mice, as demonstrated by decreases in the disease activity index, inflammatory score and proinflammatory mediators. The protective effects of metrnl on MAT included reduced mesenteric hypertrophy, increased adipocyte size, improved adipocyte intrinsic function and ameliorated inflammation. Metrnl treatment activated STAT5/PPAR-γ signaling and promoted adipocyte differentiation in the MAT. Conclusions Metrnl expression was increased in the MAT of CD patients. Metrnl administration attenuated mesenteric lesions by promoting adipocyte function and differentiation partly through STAT5/PPAR-γ signaling pathway activation, thereby ameliorating CD-like colitis in mice.

Role of Obesity, Mesenteric Adipose Tissue, and Adipokines in Inflammatory Bowel Diseases

“…This adipo-myokine is induced in skeletal muscle upon cold exposure, and this peptide has been shown to exert an anti-inflammatory activity due to an increase in beige fat thermogenesis [161,162]. Metrnl expression is higher in mWAT of CD patients in comparison to the controls [163].…”

“…Zuo et al [163] 2019 Spontaneously developing chronic colitis in IL-10 −/− mice In IL-10 −/− mice with spontaneous colitis, administration of metrnl decreases pathological alterations in mWAT, increases adipocyte size, and ameliorates inflammation.…”

Characterization of the Serum Levels of Meteorin-like in Patients with Inflammatory Bowel Disease and its Association with Inflammatory Cytokines

“…Therefore, they suggested that, upregulation of Metrnl in the MAT of the patients may be a compensatory response [14]. Regarding the inconvenient results, it seems likely that, Metrnl expression can have an organ dependent pattern; however, further longitudinal research is needed to support this hypothesis.…”

“…Meteorin-like (Metrnl, known as Subfatin) is a novel adipo-myokine that is mainly expressed in WAT, however, it was also reported that Metrnl is expressed colon epithelium. The anti-in ammatory function of Metrnl has been revealed recently [14]. Moreover, it can enhance lipid metabolism, decrease adipose in ammation, and ameliorate obesity-mediated insulin resistance (IR).…”

Characterization of the Serum Levels of Meteorin-like in Patients with Inflammatory Bowel Disease and its Association with Inflammatory Cytokines

“…Meteorin-like (Metrnl, known as Subfatin) is a novel adipo-myokine that is mainly expressed in WAT, however, it was reported that Metrnl is also expressed in colon epithelium. The anti-in ammatory function of Metrnl has been revealed recently and also has other roles including enhancing lipid metabolism, decreasing adipose in ammation, and ameliorating obesity-mediated insulin resistance (IR) [14]. Notably, Metrnl expression was higher in mesenteric WAT of the CD patients in comparison to the controls [15] .…”