title: Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation.
abstract: Lipin 1 is a coregulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that catalyzes a critical step in the synthesis of glycerophospholipids. Lipin 1 is highly expressed in adipocytes, and constitutive loss of lipin 1 blocks adipocyte differentiation; however, the effects of Lpin1 deficiency in differentiated adipocytes are unknown. Here we report that adipocyte-specific Lpin1 gene recombination unexpectedly resulted in expression of a truncated lipin 1 protein lacking PAP activity but retaining transcriptional regulatory function. Loss of lipin 1-mediated PAP activity in adipocytes led to reduced glyceride synthesis and increased PA content. Characterization of the deficient mice also revealed that lipin 1 normally modulates cAMP-dependent signaling through protein kinase A to control lipolysis by metabolizing PA, which is an allosteric activator of phosphodiesterase 4 and the molecular target of rapamycin. Consistent with these findings, lipin 1 expression was significantly related to adipose tissue lipolytic rates and protein kinase A signaling in adipose tissue of obese human subjects. Taken together, our findings identify lipin 1 as a reciprocal regulator of triglyceride synthesis and hydrolysis in adipocytes, and suggest that regulation of lipolysis by lipin 1 is mediated by PA-dependent modulation of phosphodiesterase 4.
authors.affiliation: Department of Medicine, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Mayurranjan S
authors.initials: MS
authors.lastname: Mitra
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ren
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.forename: Kari T
authors.initials: KT
authors.lastname: Chambers
authors.forename: Angela M
authors.initials: AM
authors.lastname: Hall
authors.forename: Karim
authors.initials: K
authors.lastname: Nadra
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology*; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D003001:Cloning, Molecular; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005989:Glycerides / Q000096:biosynthesis; D006801:Humans; D008066:Lipolysis / Q000235:genetics / Q000502:physiology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D010711:Phosphatidate Phosphatase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D005989:Glycerides; D009687:Nuclear Proteins; D010712:Phosphatidic Acids; D017868:Cyclic AMP-Dependent Protein Kinases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4