Meteorin-Like

METRNL promotes white-to-beige adipocyte conversion by inducing PGC-1alpha, UCP1, PRDM16, and other brown fat thermogenic gene programs. The mechanism involves activation of type 2 immune signaling: METRNL stimulates eosinophil accumulation in adipose tissue, which release IL-4 and IL-13. These cytokines act on adipocyte precursors and macrophages to promote beige adipogenesis. The METRNL-eosinophil-IL-4/IL-13 axis is a distinct pathway from beta-adrenergic browning.

METRNL reduces macrophage inflammatory activation by promoting M2 (anti-inflammatory) polarization in adipose tissue macrophages. It suppresses NFkB-driven pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta) and increases anti-inflammatory markers (IL-10, Arg-1, CD206). In cardiovascular contexts, METRNL reduces endothelial inflammation, inhibits foam cell formation, and suppresses vascular smooth muscle cell inflammatory activation relevant to atherosclerosis.

METRNL improves insulin sensitivity in skeletal muscle and adipose tissue by activating AMPK and PI3K/Akt pathways. It enhances GLUT4 translocation and glucose uptake in muscle independently of insulin. METRNL also suppresses hepatic lipid accumulation by reducing SREBP-1c activity and promotes fatty acid oxidation via PGC-1alpha/PPAR-alpha activation. These combined effects improve both glucose and lipid metabolism markers in obese animal models.

METRNL knockout mice gain more weight on high-fat diet and have reduced energy expenditure. Conversely, transgenic METRNL overexpression improves metabolic parameters and increases UCP1 expression in WAT. Recombinant METRNL administration in obese mice reduces body weight, improves glucose tolerance, and increases energy expenditure primarily through adipose thermogenesis.

Human studies confirm plasma METRNL is reduced in coronary artery disease, heart failure, and after acute MI. In ApoE-knockout atherosclerosis mice, METRNL reduces atherosclerotic plaque burden through macrophage M2 polarization and endothelial protection. METRNL also reduces ischemia-reperfusion injury in rodent cardiac models via Akt/ERK activation. These findings position METRNL as a cardioprotective exercise hormone.

Plasma METRNL is reduced in rheumatoid arthritis, inflammatory bowel disease, and COPD patients, correlating inversely with disease activity markers. In mouse models of colitis and arthritis, recombinant METRNL reduces tissue inflammation and clinical scores. The IL-4/IL-13 type 2 immune axis that METRNL activates is anti-inflammatory in multiple disease contexts, suggesting broad potential in inflammatory diseases.