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AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency

Abstract

A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A2, AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E2 that binds the Gαi-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.

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Figure 1: AdPLA tissue distribution, regulation of expression and body weights of AdPLA-null mice.
Figure 2: AdPLA ablation causes a reduction in fat pad weight, triacylglycerol (TAG) content and adipocyte size but does not affect adipocyte differentiation.
Figure 3: AdPLA ablation increases lipolysis in vivo, ex vivo and in vitro.
Figure 4: AdPLA deficiency increases lipolysis by decreasing PGE2 abundance and increasing cAMP levels.
Figure 5: AdPLA deficiency prevents obesity in ob/ob leptin-deficient mice.
Figure 6: AdPLA deficiency impairs glycemic control, increases energy expenditure and promotes fatty acid oxidation in WAT.

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References

  1. Duncan, R.E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H.S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gregoire, F.M., Smas, C.M. & Sul, H.S. Understanding adipocyte differentiation. Physiol. Rev. 78, 783–809 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Jaworski, K., Sarkadi-Nagy, E., Duncan, R.E., Ahmadian, M. & Sul, H.S. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G1–G4 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Dircks, L. S.H. Acyltransferases of de novo glycerophospholipid biosynthesis. Prog. Lipid Res. 38, 461–479 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Yet, S.F., Lee, S., Hahm, Y.T. & Sul, H.S. Expression and identification of p90 as the murine mitochondrial glycerol-3-phosphate acyltransferase. J. Biochem. 32, 9486–9491 (1993).

    Article  CAS  Google Scholar 

  6. Vance, D.E. & Vance, J.E. Biochemistry of lipids, lipoproteins and membranes. 277–303 (Elsevier, Oxford, 2008).

  7. Duncan, R.E., Sarkadi-Nagy, E., Jaworski, K., Ahmadian, M. & Sul, H.S. Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). J. Biol. Chem. 283, 25428–25436 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schaloske, R.H. & Dennis, E.A. The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta (2006).

  9. Yuan, C., Rieke, C.J., Rimon, G., Wingerd, B.A. & Smith, W.L. Partnering between monomers of cyclooxygenase-2 homodimers. Proc. Natl. Acad. Sci. USA 103, 6142–6147 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Richelsen, B. Release and effects of prostaglandins in adipose tissue. Prostaglandins Leukot. Essent. Fatty Acids 47, 171–182 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Aubert, J. et al. Prostacyclin IP receptor up-regulates the early expression of C/EBPβ and C/EBPδ in preadipose cells. Mol. Cell. Endocrinol. 160, 149–156 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Fajas, L., Miard, S., Briggs, M.R. & Auwerx, J. Selective cyclo-oxygenase-2 inhibitors impair adipocyte differentiation through inhibition of the clonal expansion phase. J. Lipid Res. 44, 1652–1659 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Forman, B.M. et al. 15-Deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR γ. Cell 83, 803–812 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Yan, H., Kermouni, A., Abdel-Hafez, M. & Lau, D.C. Role of cyclooxygenases COX-1 and COX-2 in modulating adipogenesis in 3T3–L1 cells. J. Lipid Res. 44, 424–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Cohen-Luria, R. & Rimon, G. Prostaglandin E2 can bimodally inhibit and stimulate the epididymal adipocyte adenylyl cyclase activity. Cell. Signal. 4, 331–335 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Kather, H. & Simon, B. Biphasic effects of prostaglandin E2 on the human fat cell adenylate cyclase. J. Clin. Invest. 64, 609–612 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Smas, C.M. S.H. Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell 73, 725–734 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Latasa, M.J. G.M., Moon YS, Kang C, Sul HS. Occupancy and funtion of the −150 SRE and −65 E-box in nutritional regulation of the fatty acid synthase gene in living animals. Mol. Cell. Biol. 23, 5896–5907 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Turner, S.M. et al. Measurement of TG synthesis and turnover in vivo by 2H2O incorporation into the glycerol moiety and application of MIDA. Am. J. Physiol. Endocrinol. Metab. 285, E790–E803 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Bell-Parikh, L.C. et al. Biosynthesis of 15-deoxy-(12,14–PGJ2 and the ligation of PPARγ. J. Clin. Invest. 112, 945–955 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Reginato, M.J., Krakow, S.L., Bailey, S.T. & Lazar, M.A. Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator-activated receptor γ. J. Biol. Chem. 273, 1855–1858 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Vassaux, G., Gaillard, D., Ailhaud, G. & Negrel, R. Prostacyclin is a specific effector of adipose cell differentiation. Its dual role as a cAMP- and Ca2+-elevating agent. J. Biol. Chem. 267, 11092–11097 (1992).

    CAS  PubMed  Google Scholar 

  23. Savage, D.B., Petersen, K.F. & Shulman, G.I. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Yoon, M.-J. et al. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase and peroxisome proliferator-activated receptor. Diabetes 55, 2562–2570 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Johansson, S.M., Yang, J.N., Lindgren, E. & Fredholm, B.B. Eliminating the antilipolytic adenosine A1 receptor does not lead to compensatory changes in the antilipolytic actions of PGE2 and nicotinic acid. Acta. Physiol. Scand. 190, 87–96 (2007).

    Article  CAS  Google Scholar 

  26. Fain, J.N., Leffler, C.W. & Bahouth, S.W. Eicosanoids as endogenous regulators of leptin release and lipolysis by mouse adipose tissue in primary culture. J. Lipid Res. 41, 1689–1694 (2000).

    CAS  PubMed  Google Scholar 

  27. Girouard, H. & Savard, R. The lack of bimodality in the effects of endogenous and exogenous prostaglandins on fat cell lipolysis in rats. Prostaglandins Other Lipid Mediat. 56, 43–52 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Fain, J.N., Madan, A.K., Hiler, M.L., Cheema, P. & Bahouth, S.W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 145, 2273–2282 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Gaillard, D., Negrel, R., Lagarde, M. & Ailhaud, G. Requirement and role of arachidonic acid in the differentiation of pre-adipose cells. Biochem. J. 257, 389–397 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Massiera, F. et al. Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? J. Lipid Res. 44, 271–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Petersen, R.K. et al. Arachidonic acid–dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases. J. Lipid Res. 44, 2320–2330 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Kopecky, J., Hodny, Z., Rossmeisl, M., Syrovy, I. & Kozak, L.P. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution. Am. J. Physiol. 270, E768–E775 (1996).

    CAS  PubMed  Google Scholar 

  33. Hertzel, A.V. et al. Lipid metabolism and adipokine levels in fatty acid–binding protein null and transgenic mice. Am. J. Physiol. Endocrinol. Metab. 290, E814–E823 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Lucas, S., Tavernier, G., Tiraby, C., Mairal, A. & Langin, D. Expression of human hormone-sensitive lipase in white adipose tissue of transgenic mice increases lipase activity but does not enhance in vitro lipolysis. J. Lipid Res. 44, 154–163 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Martinez-Botas, J. et al. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat. Genet. 26, 474–479 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Tansey, J.T. et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl. Acad. Sci. USA 98, 6494–6499 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim, K.H., Lee, K., Moon, Y.S. & Sul, H.S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J. Biol. Chem. 276, 11252–11256 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Viswanadha, S. & Londos, C. Optimized conditions for measuring lipolysis in murine primary adipocytes. J. Lipid Res. 47, 1859–1864 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Bligh, E.G. & Dyer, W.J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959).

    Article  CAS  PubMed  Google Scholar 

  40. Folch, J., Lees, M. & Sloane Stanley, G.H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226, 497–509 (1957).

    CAS  PubMed  Google Scholar 

  41. Youn, J.H. & Buchanan, T.A. Fasting does not impair insulin-stimulated glucose uptake but alters intracellular glucose metabolism in conscious rats. Diabetes 42, 757–763 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Samuel, V.T. et al. Targeting foxo1 in mice using antisense oligonucleotides improves hepatic and peripheral insulin action. Diabetes 55, 2042–2050 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Lucas, K.K. & Dennis, E.A. Distinguishing phospholipase A2 types in biological samples by employing group-specific assays in the presence of inhibitors. Prostaglandins Other Lipid Mediat. 77, 235–248 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, J.L. et al. Physiologic and pharmacologic factors influencing glyceroneogenic contribution to triacylglyceride glycerol measured by mass isotopomer distribution analysis. J. Biol. Chem. 280, 25396–25402 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Bansode, R.R., Huang, W., Roy, S.K., Mehta, M. & Mehta, K.D. Protein kinase Cβ deficiency increases fatty acid oxidation and reduces fat storage. J. Biol. Chem. 283, 231–236 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by DK75682 from the US National Institutes of Health to H.S.S. and DK59635 to G.I.S. R.E.D. and K.A.V. are recipients of postdoctoral fellowships from the Natural Sciences and Engineering Research Council of Canada. R.E.D. is a recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research. The authors would like to thank O. Barauskas for technical help; D. Frasson for fatty acid oxidation measurement; Y. Wang for performing WR1339 injections; J. Lu, J. Chen, R. Mantara and N. Nag for assistance with animal maintenance; A. Birkenfled and D. Frederick for assistance with clamping studies; C. Lange and J. Chithalen for assistance with graphics; and Merck Frosst Canada for the kind gift of L826266.

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Correspondence to Hei Sook Sul.

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Jaworski, K., Ahmadian, M., Duncan, R. et al. AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15, 159–168 (2009). https://doi.org/10.1038/nm.1904

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