Obesity and metabolic disorders are linked with neurodegenerative diseases through persistent peripheral inflammation caused by metabolic alterations, which underlies chronic neuroinflammation. Pleiotrophin (PTN) is a cytokine that regulates neuroinflammation and metabolism in different contexts. Thus, our study aimed to determine the role of PTN in the brain-periphery crosstalk in a high-fat diet (HFD)-induced obesity model. Three-month-old C57BL/6J wild-type (Ptn+/+) and Ptn genetically deficient (Ptn−/−) mice were fed with standard chow diet or HFD (60% kcal fat) for 6 months. HFD-Ptn−/− mice exhibited lower increment of body weight than HFD-Ptn+/+ mice. In the novel object recognition test, HFD-Ptn+/+ mice showed long-term memory loss after three months and both short- and long-term memory loss after six months on diet, which correlated with astrocyte depletion and microgliosis. In contrast, HFD-Ptn−/− mice did not show memory loss or glial alterations. Moreover, PTN signalling pathway regulates perineuronal nets (PNNs), critical for hippocampal function. We observed that HFD decreased the number of PNNs in the Cornus Amonis (CA) and increased them in the dentate gyrus (DG) in Ptn+/+ mice. Surprisingly, Ptn−/− mice showed an increased number of PNNs in the CA and a decrease in the DG independently of the diet. Additionally, PNNs intensity was significantly increased in Ptn−/− mice. In conclusion, the data demonstrate that Ptn deletion protects against HFD-induced obesity and that endogenous PTN is involved in HFD-induced memory loss and glial alterations. Also, PTN is key in the formation and maintenance of PNNs and their HFD-induced alterations.