Dephosphorylation of phosphatidic acid (PA) is the penultimate step in triglyceride synthesis. Adipocytes express soluble intracellular PA-specific phosphatases (Lipins) and broader specificity membrane-associated lipid phosphate phosphatases (LPPs) that can also dephosphorylate PA. Inactivation of lipin1 causes lipodystrophy in mice due to defective developmental adipogenesis. Triglyceride synthesis is diminished but not ablated by inactivation of lipin1 in differentiated adipocytes implicating other PA phosphatases in this process. To investigate the possible role of LPPs in adipocyte lipid metabolism and signaling we made mice with adipocyte-targeted inactivation of LPP3 encoded by the Plpp3(Ppap2b) gene. Adipocyte LPP3 deficiency resulted in blunted ceramide and sphingomyelin accumulation during diet-induced adipose tissue expansion, accumulation of the LPP3 substrate sphingosine 1- phosphate, and reduced expression of serine palmitoyl transferase. However, adiposity was unaffected by LPP3 deficiency on standard, high fat diet or Western diets, although Western diet-fed mice with adipocyte LPP3 deficiency exhibited improved glucose tolerance. Our results demonstrate functional compartmentalization of lipid phosphatase activity in adipocytes and identify an unexpected role for LPP3 in the regulation of diet-dependent sphingolipid synthesis that may impact on insulin signaling.
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This work was supported by NIH R01HL120507 to SSS and AJM by the National Institutes of Heart Lung and Blood and the U.S. Department of Veterans Affairs Award 210CX001550 to AJM.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Frederico, Lorenzo; Yang, Liping; Brandon, Jason; Panchatcharam, Manikandan; Ren, Hongmei; Mueller, Paul; Sunkara, Manjula; Escalante-Alcalde, Diana; Morris, Andrew J.; and Smyth, Susan S., "Lipid Phosphate Phosphatase 3 Regulates Adipocyte Sphingolipid Synthesis, but Not Developmental Adipogenesis or Diet-Induced Obesity in Mice" (2018). Gill Heart & Vascular Institute Faculty Publications. 13.
S1 Fig. Glucose tolerance in mice fed normal chow diet.
journal.pone.0198063.s002.pptx (77 kB)
S2 Fig. Insulin levels after glucose or insulin administration in male mice.
journal.pone.0198063.s003.pptx (69 kB)
S3 Fig. Effect of diet and LPP3 expression on adipose tissue lipid composition.
journal.pone.0198063.s004.pptx (68 kB)
S4 Fig. No effect of adipose LPP3 expression on liver lipid composition.