Mice (Fig. 3e). PPAR synthetic ligand remedy (GW501516, 4 days) improved 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 3 mouse models. Intraperitoneal injection of escalating concentrations of Pc(18:0/18:1) decreased serum TG and FFA levels, (Extended Data Fig. 3h) having a trend of increased muscle FA uptake. TailAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptNature. Author manuscript; obtainable 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 Pc(18:1/18:1) had no effect. In myotubes, only Pc(18:0/18:1) enhanced FA uptake (Fig. 3h). Catheter-based, continuous infusion of Pc(18:0/18:1) (25 /min/kg for 200 min) by way of the jugular vein also lowered Caspase 2 Activator review 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, various FA utilization genes within the muscle, namely Cd36, Fabp3, Fabp4, Fatp1, Fatp4, Ppara, Cidea and Mcad (Acadm), had been 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 towards the light cycle by daytime restricted feeding (Fig. 4b and Extended Data Fig. 4a). This diurnal pattern was disrupted in muscle of LPPARDKO mice. Moreover, when 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 Data Fig. 4b), all these ligand effects have been lost in LPPARDKO animals. These results recommend that hepatic PPAR might alter expression of muscle genes and FA utilization by means of Computer(18:0/18:1). Certainly, 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 Information Fig. 4c,d). PPAR controls FA metabolism in muscle19 and may be activated by certain PCs14. In reporter assays, Pc(18:0/18:1) moderately activated PPAR (Extended Data Fig. 4e). Even so, the effects of Computer(18:0/18:1) infusion on minimizing serum TG levels and increasing muscle FA uptake and Cd36/Fabp3 expression were abolished in Ppara knockout (PPARKO) mice (Fig. 4d,e). In myotubes, improved FA uptake by Pc(18:0/18:1) was diminished by Ppara knockdown or by a Ppar mutant H1 Receptor Modulator list lacking the c-terminus activation function domain (AF2), suggesting that Computer(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 many tissues resulting in abnormal metabolism20. Diet- induced obesity altered the rhythmic pattern of serum Computer(18:0/18:) (Extended Data Fig. 4f,g). In db/db mice (a genetic model of obesity), tail vein injection of Pc(18:0/18:1) (5 mg/kg/day for six days) lowered fasting TG and FFA levels (Fig. 4g). Non-fasting blood glucose levels trended decrease in Computer(18:0/18:1) treated animals (Extended Information Fig. 4h). Computer(18:0/18:1) decreased fasting glucose and enhanced GTT (Fig. 4h and Extended Data Table two). Glucose concen.
