(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown and white adipose tissue (AT) in a high-fat diet-induced (HFD) obesity mice model. (2) Methods: We analyzed circulating variables, lipid metabolism (hepatic lipid content and mRNA expression), brown AT thermogenesis (UCP-1 expression) and periovarian AT browning (brown adipocyte markers mRNA and immunodetection) in Ptn^−/− mice either fed with standard-chow diet or with HFD and in their corresponding Ptn^+/+ counterparts. (3) Results: HFD-Ptn^−/− mice are protected against the development of HFD-induced insulin resistance, had lower liver lipid content and lower expression of the key enzymes involved in triacylglycerides and fatty acid synthesis in liver. HFD-Ptn^−/− mice showed higher UCP-1 expression in brown AT. Moreover, Ptn deletion increased the expression of specific markers of brown/beige adipocytes and was associated with the immunodetection of UCP-1 enriched multilocular adipocytes in periovarian AT. (4) Conclusions: Ptn deletion protects against the development of HFD-induced insulin resistance and liver steatosis, by increasing UCP-1 expression in brown AT and promoting periovarian AT browning.

Although recent studies have investigated the effect of maternal nutrition on metabolic programming of the offspring, the question whether a nutritional insult during early gestation favours an altered metabolic state of the mother that persists during the remainder period of pregnancy, when foetal growth is maximal, remains to be answered.

Pleiotrophin (PTN) is crucial for embryonic development and pancreas organogenesis as it regulates metainflammation, metabolic homeostasis, thermogenesis, and glucose tolerance. Pleiotrophin deletion is associated with a lipodystrophic phenotype in which adipose tissue plasticity is altered in late life. This study explored the impact of pleiotrophin deletion on pancreatic morphology and function in later life. We analyzed glucose tolerance and circulating parameters on female wild-type (Ptn^+/+) and knock-out (Ptn^−/−) mice. At 9 and 15 months, we conducted morphometric analyses of pancreatic islets and evaluated the levels of insulin, glucagon, somatostatin, glucose transporter 2 (GLUT2), vesicle-associated membrane protein 2 (VAMP2), and synaptosome-associated protein 25 (SNAP25) via immunofluorescence. The effect of PTN on glucose-stimulated insulin secretion (GSIS) was evaluated in INS1E cells and isolated islets. Ptn^−/− mice showed hyperinsulinemia, impaired glucose tolerance, and increased homeostatic model assessment for insulin resistance (HOMA-IR) with age. While Ptn^+/+ islets enlarge with age, in Ptn^−/− mice, the median size decreased, and insulin content increased. Vesicle transport and exocytosis proteins were significantly increased in 9-month-old Ptn^−/− islets. Islets from Ptn^−/− mice showed impaired GSIS and decreased cell membrane localization of GLUT2 whereas, PTN increased GSIS in INS1E cells. Ptn deletion accelerated age-related changes in the endocrine pancreas, affecting islet number and size, and altering VAMP2 and SNAP25 levels and GLUT2 localization leading to impaired GSIS and insulin accumulation in islets.

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 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).