Abstract / Summary
Abstract Metabolic syndrome is characterised by chronic low-grade inflammation and adipose tissue dysfunction. Pleiotrophin, a cytokine involved in tissue remodelling and energy metabolism, has emerged as a potential regulator of adipose tissue plasticity and systemic metabolic homeostasis. We investigated the role of pleiotrophin signalling in diet-induced obesity and adipose tissue inflammation, by genetic pleiotrophin deletion and pharmacological inhibition of RPTPβ/ζ phosphatase activity by MY10, a selective inhibitor that mimics pleiotrophin signalling. Male and female wild-type and pleiotrophin-deficient mice were fed a standard or a high-fat diet (60% kcal from fat) for three months. A parallel cohort of wild-type mice fed the standard or the high-fat diet received either vehicle or MY10. Adipose tissue morphology, fibrosis, inflammatory and thermogenic markers were analysed by histology, immunohistochemistry, qPCR and Western blotting. Pleiotrophin deletion attenuated high fat diet-induced weight gain, adipocyte hypertrophy and fibrosis, while promoting browning of white adipose tissue and enhancing thermogenic gene expression. Pleiotrophin - deficient mice showed reduced macrophage accumulation and elevated anti-inflammatory cytokine expression, particularly in subcutaneous adipose tissue. In contrast, MY10 treatment exacerbated adiposity and inflammation and suppressed browning-associated markers in a sex- and depot-dependent manner. Overall, these findings support a role for pleiotrophin in modulating adipose tissue inflammation and thermogenic programming during obesity: pleiotrophin deletion is associated with a protective phenotype, whereas pharmacological inhibition of RPTPβ/ζ phosphatase activity by MY10 aggravates obesity-associated adipose tissue dysfunction. Collectively, these observations identify the pleiotrophin–RPTPβ/ζ axis as a context-dependent regulator of adipose tissue remodelling and support its further investigation in obesity-associated metabolic dysfunction.