Mice (Fig. 3e). PPAR synthetic ligand remedy (GW501516, four days) enhanced serum Computer(18:0/18:1) levels in wt but not LPPARDKO mice (Fig. 3f). These data identified Computer(18:0/18:1) as a serum lipid regulated by hepatic PPAR diurnally in three mouse models. Intraperitoneal injection of escalating concentrations of Computer(18:0/18:1) decreased serum TG and FFA levels, (Extended Information Fig. 3h) using a trend of enhanced muscle FA uptake. TailAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNature. Author manuscript; readily available in PMC 2014 August 22.Liu et al.Pagevein injection of Pc(18:0/18:1) (five mg/kg body weight) also reduced serum TG (Fig. 3g). Notably, Computer(16:0/18:1) and Computer(18:1/18:1) had no effect. In myotubes, only Computer(18:0/18:1) improved FA uptake (Fig. 3h). Catheter-based, continuous infusion of Pc(18:0/18:1) (25 /min/kg for 200 min) through the jugular vein also lowered circulating TG and FFA levels (Fig. 3i). As such, Computer(18:0/18:1) hyperlinks hepatic PPAR-controlled lipogenic plan to serum lipid concentrations and muscle fat utilization. Mechanistically, numerous FA utilization genes inside the muscle, namely Cd36, Fabp3, Fabp4, Fatp1, Fatp4, Ppara, Cidea and Mcad (Acadm), were induced in adPPAR and/or Computer(18:0/18:1) treated mice, but repressed in LPPARDKO and LACC1KD animals (Fig. 4a). Cd36 and Fabp3 are identified mediators of muscle FA uptake17,18. Cd36 expression at mRNA and protein levels also oscillated in wt muscle peaking within the dark cycle, and shifted for the light cycle by daytime restricted feeding (Fig. 4b and Extended Information Fig. 4a). This diurnal pattern was disrupted in muscle of LPPARDKO mice. In addition, while PPAR agonist GW501516 enhanced muscle expression of Cd36 and Fabp3 (Fig. 4c), enhanced muscle FA uptake and lowered serum TG levels in wt mice (Extended Information Fig. 4b), all these ligand effects have been lost in LPPARDKO animals. These results suggest that hepatic PPAR could alter expression of muscle genes and FA utilization by way of Pc(18:0/18:1). Indeed, Pc(18:0/18:1) therapy induced Cd36/Fabp3 expression in myotubes when Cd36 knockdown abrogated the impact of Pc(18:0/18:1) on muscle cell FA uptake (Extended Data Fig. 4c,d). PPAR controls FA CYP3 Activator manufacturer metabolism in muscle19 and may be activated by specific PCs14. In reporter assays, Computer(18:0/18:1) moderately activated PPAR (Extended Data Fig. 4e). Even so, the effects of Computer(18:0/18:1) infusion on decreasing serum TG levels and escalating muscle FA uptake and Cd36/Fabp3 expression had been abolished in Ppara knockout (PPARKO) mice (Fig. 4d,e). In myotubes, elevated FA uptake by Computer(18:0/18:1) was diminished by Ppara knockdown or by a Ppar mutant lacking the c-terminus activation function domain (AF2), suggesting that Pc(18:0/18:1) or its metabolites may modulate PPAR transcriptional activity in vivo (Fig. 4f). These findings demonstrate that a hepatic PPAR-PC(18:0/18:1)-muscle PPAR signaling cascade coordinates fat synthesis and utilization. Obesity alters circadian rhythms in multiple tissues resulting in abnormal metabolism20. Diet- induced obesity altered the rhythmic pattern of serum Pc(18:0/18:) (Extended Information Fig. 4f,g). In db/db mice (a genetic model of obesity), tail vein injection of Computer(18:0/18:1) (five mg/kg/day for six days) lowered fasting TG and FFA levels (Fig. 4g). GLUT4 Inhibitor Formulation Non-fasting blood glucose levels trended reduced in Pc(18:0/18:1) treated animals (Extended Data Fig. 4h). Pc(18:0/18:1) reduced fasting glucose and improved GTT (Fig. 4h and Extended Information Table two). Glucose concen.