1. Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation
- Author
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Karim Nadra, Mayurranjan S. Mitra, Roman Chrast, Kari T. Chambers, Xiong Su, Hongmei Ren, Zhouji Chen, Brian N. Finck, Samuel Klein, Andrew J. Morris, Thurl E. Harris, and Angela M. Hall
- Subjects
Male ,medicine.medical_specialty ,Lipolysis ,Blotting, Western ,Phosphatidate Phosphatase ,Phosphatidic Acids ,Adipose tissue ,Biology ,Real-Time Polymerase Chain Reaction ,Gas Chromatography-Mass Spectrometry ,Glycerides ,Mice ,chemistry.chemical_compound ,3T3-L1 Cells ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,Humans ,Obesity ,Cloning, Molecular ,Protein kinase A signaling ,Protein kinase A ,Transcription factor ,Alleles ,DNA Primers ,Mice, Inbred BALB C ,Multidisciplinary ,Nuclear Proteins ,Phosphatidic acid ,Biological Sciences ,Phosphatidate phosphatase ,Cyclic AMP-Dependent Protein Kinases ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Female ,Metabolic Networks and Pathways - 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.
- Published
- 2012
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