PPAR-β/δ Is Required for Metabolic and Inflammatory Adaptation to Glucose Restriction in T98G Glioblastoma Cells

Background: Glioblastoma (GBM) shows marked metabolic plasticity and resistance to conventional therapies, which has motivated the search for adjunctive metabolic strategies. Medium-chain fatty acids (MCFAs) are candidate metabolic modulators, but the mechanisms underlying their effects in GBM are poorly understood. This study investigated the role of peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ, hereafter PPAR-β) in the metabolic and inflammatory responses of GBM cells to MCFAs under different glucose conditions. Methods: T98G glioblastoma cells were cultured in normal-glucose (NG, 4.5 g/L) or low-glucose (LG, 1 g/L) medium and treated for 72 h with octanoic acid (C8:0, C8), decanoic acid (C10:0, C10) or the PPAR-β agonist GW501516. Metabolic activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT), reactive oxygen species (ROS) and superoxide production, expression of ACADM, OGDH, SLC16A1, IDH1, PTEN and BCL2 by quantitative polymerase chain reaction (qPCR), and secretion of a seven-analyte cytokine panel were evaluated. The contribution of PPAR-β was assessed by small interfering RNA (siRNA)-mediated silencing, which reduced PPARD mRNA by approximately 86%. Results: C8 and C10 increased metabolic activity under both glucose conditions, and glucose restriction reduced ROS and superoxide production in treated cells. In PPAR-β-silenced cells, glucose restriction almost abolished ACADM and SLC16A1 expression (both p < 0.0001 in untreated cells) and markedly increased OGDH expression (up to approximately 600-fold), indicating that PPAR-β is required to sustain the expression of genes involved in medium-chain fatty acid oxidation and monocarboxylate transport when glucose is limiting. Under low glucose, PPAR-β silencing reduced PTEN and BCL2 expression to approximately 1.5–1.8% of the level in non-transfected cells (both p < 0.0001), whereas under normal glucose it increased BCL2 (up to 10.8-fold, p = 0.0015) and increased PTEN in GW501516-treated cells (p = 0.0005). Interleukin (IL)-8 was the only analyte of the cytokine panel that could be quantified reliably; it was not significantly changed by glucose restriction alone but was higher in PPAR-β-silenced than in non-transfected cells under low glucose (untreated, p = 0.0099; C10, p = 0.0021). Conclusions: PPAR-β links glucose availability to metabolic reprogramming, to tumour-suppressor and survival gene expression, and to IL-8 secretion in GBM cells. These findings identify PPAR-β as a candidate therapeutic target and support the further evaluation of MCFAs as adjunctive metabolic interventions in glioblastoma.