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Abstract
Through analysis of mice with spatially and temporally restricted inactivation of Lpin1, we characterized its cell autonomous function in both white (WAT) and brown (BAT) adipocyte development and maintenance. We observed that the lipin 1 inactivation in adipocytes of aP2Cre/+/LpfEx2-3/fEx2-3 mice resulted in lipodystrophy and the presence of adipocytes with multilocular lipid droplets. We further showed that time-specific loss of lipin 1 in mature adipocytes in aP2Cre-ERT2/+/LpfEx2-3/fEx2-3 mice led to their replacement by newly formed Lpin1-positive adipocytes, thus establishing a role for lipin 1 in mature adipocyte maintenance. Importantly, we observed that the presence of newly formed Lpin1-positive adipocytes in aP2Cre-ERT2/+/LpfEx2-3/fEx2-3 mice protected these animals against WAT inflammation and hepatic steatosis induced by a high-fat diet. Loss of lipin 1 also affected BAT development and function, as revealed by histological changes, defects in the expression of peroxisome proliferator-activated receptor alpha (PPARα), PGC-1α, and UCP1, and functionally by altered cold sensitivity. Finally, our data indicate that phosphatidic acid, which accumulates in WAT of animals lacking lipin 1 function, specifically inhibits differentiation of preadipocytes. Together, these observations firmly demonstrate a cell autonomous role of lipin 1 in WAT and BAT biology and indicate its potential as a therapeutical target for the treatment of obesity.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00512-12.
ACKNOWLEDGMENTS
We thank Jean-Christophe Stehle, Janine Horlbeck, and the Mouse Metabolic Evaluation Facility platform (University of Lausanne, Lausanne, Switzerland) for technical assistance.
This work was supported by grants from the Swiss National Science Foundation to R.C. (grants PP00P3_124833/1 and 31003A_135735) and to B.D. (grant 31003A_135583/1), from the Association Française contre les Myopathies (to K.N.), and from the National Institutes of Health (grant GM-28140; to G.M.C.).