Targeting Pleiotrophin to mitigate high fat diet-induced liver metabolic disease: Insights into sex-specific metabolic protection

ABSTRACT Obesity is a global health problem linked to the development of metabolic syndrome (MetS) and comorbidities such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). These diseases are characterised by systemic inflammation, lipid accumulation and tissue damage, which contribute to liver fibrosis and dysfunction. Pleiotrophin (PTN), a cytokine known for its role in tissue regeneration and energy metabolism, has emerged as a potential regulator of liver homeostasis. Herein, we demonstrate that Ptn deletion protects against body weight gain, metainflammation and high-fat diet (HFD)-induced MASLD and MASH development. Furthermore, our work uncovers the molecular mechanisms by which PTN may promote lipid synthesis and hepatic extracellular matrix remodelling. Results highlight PTN as a critical modulator of liver metabolism and systemic inflammation in the context of obesity, identifying it as a promising therapeutic target for the treatment of MASLD, MASH and related metabolic disorders, and point to a sexual dimorphism in adaptive metabolic strategies, with females demonstrating a greater degree of protection against the liver-damaging effects of diet-induced obesity. HIGHLIGHTS Females are more protected against the liver-damaging effects of the high-fat diet (HFD), suggesting a sexual dimorphism in adaptive metabolic strategies. PTN regulates lipid metabolism by promoting lipogenesis and lipid accumulation in liver cells through the activation of AKT and the inhibition of AMPKα; the absence of PTN reverses this process. Deletion of Ptn protects against high-fat diet (HFD)-induced weight gain, systemic inflammation, hepatic lipid accumulation, and the development of steatosis and liver fibrosis. PTN is a key modulator of metabolic, inflammatory and remodelling processes in the liver, and it is proposed as a promising therapeutic target for MASLD, MASH and other metabolic comorbidities. Graphical abstract. PTN liver signalling pathway. acetyl-CoA carboxylase (ACC); 5’ adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (AKT); aquaporin 9 (AQP9); diacylglycerides (DAG); diacylglycerol O-acyltransferase 2 (DGAT2); free fatty acids (FFA); hepatic stellate cell (HSC); insulin receptor (IR); pleiotrophin (PTN); triacylglycerides (TAG).