Ndidate molecules, we performed untargeted liquid chromatography-mass spectrometry (LC-MS) primarily based metabolite profiling of hepatic lipids10,11. Metabolite set enrichment analyses ranked acetyl-CoA carboxylase (Acaca/Acc1, a rate limiting enzyme in de novo lipogenesis) as a major altered pathway in the adPPAR/adGFP comparison (Extended Information Fig. 1a and Extended Data Table 1), constant with a positive correlation of ACC1 and PPARD expression in human livers (Extended Data Fig. 1b). Transient liver-specific Acc1 knockdown (LACC1KD) lowered hepatic TG content and elevated serum TG and FFA levels (Fig. 1c). FA uptake was decreased in isolated soleus muscle from LACC1KD mice (Fig. 1d). In vivo FA uptake assays revealed that muscle FA uptake was decreased in LACC1KD mice inside the dark/ feeding cycle, when the lipogenic system is active (ZT18 or 12 am. Zeitgeber time ZT0: lights on at 6 am; ZT12: lights off at 6 pm) (Fig.161827-02-7 Formula 1e). This defect was accompanied by slower clearance of circulating 3H-oleic acid (Fig. 1f). These benefits demonstrate that hepatic de novo lipogenesis is linked to muscle FA utilization. Ppard expression oscillated diurnally, peaking at night, coincident with mRNA levels of your molecular clock Bmal1 (Arntl) within the liver and in dexamethasone-synchronized principal hepatocytes (Extended Data Fig. 2a,b). In liver-conditional Ppard knockout (LPPARDKO) mice, induction of hepatic Acc1 through the dark cycle was abolished; diurnal expression of Acc2, fatty acid synthase (Fasn) and stearoyl-CoA desaturase 1 (Scd1) was also altered (Fig. 2a), indicating PPAR regulates rhythmic lipogenic gene expression in the liver. Daytime restricted feeding reversed expression patterns of all significant molecular clocks (Extended Information Fig.(S)-4-Oxopyrrolidine-2-carboxylic acid web 2c)12.PMID:24078122 Peak mRNA levels of Ppard and lipogenic genes also shifted for the light cycle in manage but not LPPARDKO mice (Fig. 2b). The expression of diglycerol acyltransferase (Dgat1, triglyceride synthesis), choline kinase (Chka, phosphocholine synthesis) and core circadian clock genes have been unchanged in LPPARDKO mice (Extended Data Fig. 2a,c). Body weight, feeding activity and insulin sensitivity had been related involving genotypes (Extended Data Fig. 2d,e and Extended Information Table two). LPPARDKO reduced muscle FA uptake within the dark cycle in vivo (Fig. 2c), mirroring benefits from LACC1KD mice and demonstrating a functional consequence of this hepatic transcriptional circuitry in muscle physiology.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptNature. Author manuscript; available in PMC 2014 August 22.Liu et al.PageProducts of de novo lipogenesis can exert signaling effects, e.g., palmitoleate as a lipokine and 1- palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine as an endogenous ligand of your nuclear receptor PPAR in hepatocytes13,14. In humans and mice, serum lipid composition closely resembles that with the liver15 (Extended Information Fig. 2f), suggesting that modifications in hepatic de novo lipogenesis could have systemic metabolic effects. Certainly, serum or serumderived lipid extracts – but not delipidated serum -collected inside the dark cycle from wt mice enhanced FA uptake in C2C12 myotubes (vs. LPPARDKO, Fig. 2d,e). Strong phase extraction of plasma lipids (Extended Data Fig. 2g) identified that the phospholipid (PL) fraction stimulated FA uptake in myotubes (Fig. 2f). To determine PLs mediating functional interactions between PPAR, hepatic lipid synthesis and muscle FA utilization, we profiled serum lipid metabolites of sam.