Deletion of Pleiotrophin protects against high-fat diet-induced liver metabolic disease, independently of the sexual dimorphism in dietary response.

Obesity is a global health problem linked to the development of metabolic syndrome and comorbidities such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Pleiotrophin (PTN) is a cytokine known for its role in tissue regeneration and energy metabolism. However, its function in hepatic metabolism and its role in MASLD progression remain to be elucidated. Here, we investigated the contribution of PTN to hepatic metabolism using male and female wild-type (Ptn+/+) and PTN-deficient (Ptn-/-) mice fed a standard or high-fat diet (HFD) for 6 months, as well as primary hepatocytes and Huh7 cells. Ptn-deletion protected both sexes against HFD-induced body weight gain, fasting hyperglycemia, hyperinsulinemia, insulin resistance and metainflammation. Furthermore, PTN deficiency prevented hepatic steatosis, reduced triacylglyceride accumulation and protected against liver fibrosis. Mechanistically, PTN deficiency was associated with increased AMPK activation, reduced ACC abundance and phosphorylation, constitutively low DGAT2 expression and altered AKT signalling. In vitro, PTN directly promoted lipid accumulation and triacylglyceride synthesis in primary hepatocytes and Huh7 cells, supporting a direct role for PTN in regulating hepatocyte lipid metabolism. Our results highlight PTN as a key modulator of hepatic lipid metabolism, systemic inflammation and extracellular matrix remodelling during obesity. These findings identify PTN as a promising therapeutic target for 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.