Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-01, Vol.110 (2), p.642-647
• Main Authors: Mitra, Mayurranjan S., Chen, Zhouji, Ren, Hongmei, Harris, Thurl E., Chambers, Kari T., Hall, Angela M., Nadra, Karim, Klein, Samuel, Chrast, Roman, Su, Xiong, Morris, Andrew J., Finck, Brian N.
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes; Adipocytes - enzymology; Adipose tissues; Alleles; Allosteric regulation; Animals; Biological Sciences; Blotting, Western; Cloning, Molecular; Cyclic AMP-Dependent Protein Kinases - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; DNA Primers - genetics; Female; Gas Chromatography-Mass Spectrometry; Gene expression; Glycerides - biosynthesis; Humans; Kinases; Lipid metabolism; Lipolysis; Lipolysis - genetics; Lipolysis - physiology; Male; Metabolic Networks and Pathways - physiology; Metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Obesity; Obesity - enzymology; Obesity - physiopathology; Phosphatidate Phosphatase - deficiency; Phosphatidate Phosphatase - genetics; Phosphatidate Phosphatase - metabolism; Phosphatidic acids; Phosphatidic Acids - metabolism; Phosphorylation; Proteins; Real-Time Polymerase Chain Reaction; Rodents; Signal transduction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1213493110

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.