title: A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use.
abstract: Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/β and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.
authors.affiliation: 1] Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA [2].
authors.forename: Sihao
authors.initials: S
authors.lastname: Liu
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Brown
authors.forename: Kristopher J
authors.initials: KJ
authors.lastname: Stanya
authors.forename: Edwin
authors.initials: E
authors.lastname: Homan
authors.forename: Mathias
authors.initials: M
authors.lastname: Leidl
authors.forename: Karen
authors.initials: K
authors.lastname: Inouye
authors.forename: Prerna
authors.initials: P
authors.lastname: Bhargava
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gangl
authors.forename: Lingling
authors.initials: L
authors.lastname: Dai
authors.forename: Ben
authors.initials: B
authors.lastname: Hatano
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D002940:Circadian Rhythm; D003920:Diabetes Mellitus / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D008055:Lipids / Q000097:blood*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009132:Muscles / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D010713:Phosphatidylcholines / Q000097:blood; D025341:Principal Component Analysis
chemical_list: D005227:Fatty Acids; D008055:Lipids; D047494:PPAR delta; D010713:Phosphatidylcholines; D000103:Acetyl-CoA Carboxylase