Pleiotrophin deficiency protects against high-fat diet-induced neuroinflammation: Implications for brain mitochondrial dysfunction and aberrant protein aggregation

Metabolic Syndrome (MetS) is a risk factor for the development of neurodegenerative diseases. Neuro-inflammation associated with MetS may contribute significantly to neurodegeneration. Pleiotrophin (PTN) is a neurotrophic factor that modulates neuroinflammation and is a key player in regulating energy metabolism and thermogenesis, suggesting that PTN could be important in the connection between MetS and neuroinflammation. We have now used a high-fat diet (HFD)-induced obesity model in Ptn- /- mice.HFD and Ptn deletion caused alterations in circulating hormones including GIP, leptin and resistin. HFD produced in Ptn+/+ mice a neuro-inflammatory state as observed in cerebral quantifications of proinflammatory markers, including Il1 beta, Tnf alpha and Ccl2. The upregulation of neuroinflammatory markers was prevented in Ptn-/-mice. Changes induced by HFD in genes related to mitochondrial biogenesis and dynamics were less pronounced in the brain of Ptn-/-mice and were accompanied by significant increases in the protein expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I and IV. HFD-induced changes in genes related to the elimination of protein aggregates were also less pronounced in the brain of Ptn- /- mice.This study provides substantial evidence that Ptn deletion protects against HFD-induced neuroinflammation, mitochondrial dysfunction, and aberrant protein aggregation, prominent features in neurodegenerative diseases.