Figure 8. Canonical and proposed non-canonical pathways of triglyceride accumulation.

(A) Upon agonist binding, PPARγ, in cooperation with its co-activators (i.e. PGC1α, CREB, Cebpα, RXR), binds to the promoter region of target genes and induces transcriptional changes that facilitate adipocyte differentiation and maturation, TG accumulation, and mitochondrial biogenesis. Mitochondrial retrograde signaling is also depicted, as recent evidence suggests mitochondrial signaling may play a role in adipocyte differentiation (Tormos et al., 2011). (B) Exposure to the electron transport chain inhibitor, antimycin A (AA), causes mitochondrial dysfunction that triggers CREB activation, while inhibiting adipocyte differentiation, PPARγ activation, FAO, and lipogenesis through traditional mechanisms (i.e. through the fatty acid synthase complex). CREB, a transcriptional regulator of lipid and glucose metabolism, promotes increased glucose uptake (via GLUT4) and glycolysis. The glycolytic intermediate, DHAP, can then be converted to G3P and used to fuel the re-esterification of free fatty acids (FFAs) resulting in TG formation and accumulation. Please note, pyruvate and Krebs cycle intermediates can also be used to generate G3P through a process known as glyceroneogenesis; however, radiolabeled glucose experiments suggest a direct glucose-to-TG conversion (Vankoningsloo et al., 2005). Given that pyraclostrobin and AA are both complex III inhibitors that induce similar phenotypes in 3T3-L1 cells, it is plausible that pyraclostrobin is inducing TG accumulation through a similar mechanism. Abbreviations: Cebpα, CCAAT/enhancer binding protein alpha; CREB, cAMP responsive element binding protein; DHAP, dihydroxyacetone phosphate; FAO, fatty acid β-oxidation; G3P, glycerol 3-phosphate; GLUT4, glucose transporter 4; MMP, mitochondrial membrane potential; OXPHOS, oxidative phosphorylation; PPARg, peroxisome proliferator activated nuclear receptor gamma; PCG1α, PPARg coactivator 1-alpha; RXR, retinoid X receptor.