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

Mayurranjan S. Mitra, Zhouji Chen, Hongmei Ren, Thurl E. Harris, Kari T. Chambers, Angela M. Hall, Karim Nadra, Samuel Klein, Roman Chrast, Xiong Su, Andrew J. Morris, Brian N. Finck

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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 retainingtranscriptional 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.

Original languageEnglish
Pages (from-to)642-647
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number2
DOIs
StatePublished - Jan 8 2013

ASJC Scopus subject areas

  • General

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