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Adipocyte and Cell Biology

Contribution of lipase deficiency to mitochondrial dysfunction and insulin resistance in hMADS adipocytes

International Journal of Obesity volume 40, pages 507–513 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are key enzymes involved in intracellular lipid catabolism. We have previously shown decreased expression and activity of these lipases in adipose tissue of obese insulin resistant individuals. Here we hypothesized that lipase deficiency might impact on insulin sensitivity and metabolic homeostasis in adipocytes not just by enhancing lipid accumulation, but also by altering lipid and carbohydrate catabolism in a peroxisome proliferator-activated nuclear receptor (PPAR)-dependent manner.

Methods:

To address our hypothesis, we performed a series of in vitro experiments in a human white adipocyte model, the human multipotent adipose-derived stem (hMADS) cells, using genetic (siRNA) and pharmacological knockdown of ATGL and/or HSL.

Results:

We show that ATGL and HSL knockdown in hMADS adipocytes disrupted mitochondrial respiration, which was accompanied by a decreased oxidative phosphorylation (OxPhos) protein content. This lead to a reduced exogenous and endogenous palmitate oxidation following ATGL knockdown, but not in HSL deficient adipocytes. ATGL deficiency was followed by excessive triacylglycerol accumulation, and HSL deficiency further increased diacylglycerol accumulation. Both single and double lipase knockdown reduced insulin-stimulated glucose uptake, which was attributable to impaired insulin signaling. These effects were accompanied by impaired activation of the nuclear receptor PPARα, and restored on PPARα agonist treatment.

Conclusions:

The present study indicates that lipase deficiency in human white adipocytes contributes to mitochondrial dysfunction and insulin resistance, in a PPARα-dependent manner. Therefore, modulation of adipose tissue lipases may provide a promising strategy to reverse insulin resistance in obese and type 2 diabetic patients.

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References

  1. Fruhbeck G, Mendez-Gimenez L, Fernandez-Formoso JA, Fernandez S, Rodriguez A . Regulation of adipocyte lipolysis. Nutr Res Rev 2014; 27: 63–93.

    Article  Google Scholar 

  2. Jocken JWE, Goossens GH, Blaak EE . Targeting adipose tissue lipid metabolism to improve glucose metabolism in cardiometabolic disease. EMJ Diabet 2014; 2: 73–82.

    CAS  Google Scholar 

  3. Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de Weijer T et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 2011; 17: 1076–1085.

    Article  CAS  Google Scholar 

  4. Mottillo EP, Bloch AE, Leff T, Granneman JG . Lipolytic products activate peroxisome proliferator-activated receptor (PPAR) alpha and delta in brown adipocytes to match fatty acid oxidation with supply. J Biol Chem 2012; 287: 25038–25048.

    Article  CAS  Google Scholar 

  5. Strom K, Gundersen TE, Hansson O, Lucas S, Fernandez C, Blomhoff R et al. Hormone-sensitive lipase (HSL) is also a retinyl ester hydrolase: evidence from mice lacking HSL. FASEB J 2009; 23: 2307–2316.

    Article  Google Scholar 

  6. Zimmermann R, Haemmerle G, Wagner EM, Strauss JG, Kratky D, Zechner R . Decreased fatty acid esterification compensates for the reduced lipolytic activity in hormone-sensitive lipase-deficient white adipose tissue. J Lipid Res 2003; 44: 2089–2099.

    Article  CAS  Google Scholar 

  7. Goossens GH . The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav 2008; 94: 206–218.

    Article  CAS  Google Scholar 

  8. Karastergiou K, Fried SK . Multiple adipose depots increase cardiovascular risk via local and systemic effects. Curr Atheroscler Rep 2013; 15: 361.

    Article  Google Scholar 

  9. Karpe F, Dickmann JR, Frayn KN . Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 2011; 60: 2441–2449.

    Article  CAS  Google Scholar 

  10. Jocken JW, Goossens GH, van Hees AM, Frayn KN, van Baak M, Stegen J et al. Effect of beta-adrenergic stimulation on whole-body and abdominal subcutaneous adipose tissue lipolysis in lean and obese men. Diabetologia 2008; 51: 320–327.

    Article  CAS  Google Scholar 

  11. Jocken JW, Langin D, Smit E, Saris WH, Valle C, Hul GB et al. Adipose triglyceride lipase and hormone-sensitive lipase protein expression is decreased in the obese insulin-resistant state. J Clin Endocrinol Metab 2007; 92: 2292–2299.

    Article  CAS  Google Scholar 

  12. McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM et al. Downregulation of adipose tissue fatty acid trafficking in obesity: a driver for ectopic fat deposition? Diabetes 2011; 60: 47–55.

    Article  CAS  Google Scholar 

  13. Langin D, Dicker A, Tavernier G, Hoffstedt J, Mairal A, Ryden M et al. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes 2005; 54: 3190–3197.

    Article  CAS  Google Scholar 

  14. Arner P, Langin D . Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol Metab 2014; 25: 255–262.

    Article  CAS  Google Scholar 

  15. Girousse A, Langin D . Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models. Int J Obes (Lond) 2012; 36: 581–594.

    Article  CAS  Google Scholar 

  16. Bezaire V, Mairal A, Ribet C, Lefort C, Girousse A, Jocken J et al. Contribution of adipose triglyceride lipase and hormone-sensitive lipase to lipolysis in hMADS adipocytes. J Biol Chem 2009; 284: 18282–18291.

    Article  CAS  Google Scholar 

  17. Popeijus HE, van Otterdijk SD, van der Krieken SE, Konings M, Serbonij K, Plat J et al. Fatty acid chain length and saturation influences PPARalpha transcriptional activation and repression in HepG2 cells. Mol Nutr Food Res 2014; 58: 2342–2349.

    Article  CAS  Google Scholar 

  18. Folch J, Lees M, Sloane Stanley GH . A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957; 226: 497–509.

    CAS  Google Scholar 

  19. Jocken JW, Goossens GH, Boon H, Mason RR, Essers Y, Havekes B et al. Insulin-mediated suppression of lipolysis in adipose tissue and skeletal muscle of obese type 2 diabetic men and men with normal glucose tolerance. Diabetologia 2013; 56: 2255–2265.

    Article  CAS  Google Scholar 

  20. Shepherd D, Garland PB . The kinetic properties of citrate synthase from rat liver mitochondria. Biochem J 1969; 114: 597–610.

    Article  CAS  Google Scholar 

  21. Schweiger M, Schreiber R, Haemmerle G, Lass A, Fledelius C, Jacobsen P et al. Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism. J Biol Chem 2006; 281: 40236–40241.

    Article  CAS  Google Scholar 

  22. Haemmerle G, Zimmermann R, Hayn M, Theussl C, Waeg G, Wagner E et al. Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem 2002; 277: 4806–4815.

    Article  CAS  Google Scholar 

  23. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98: 115–124.

    Article  CAS  Google Scholar 

  24. Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD . Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab 2014; 99: E209–E216.

    Article  CAS  Google Scholar 

  25. Yehuda-Shnaidman E, Buehrer B, Pi J, Kumar N, Collins S . Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 2010; 59: 2474–2483.

    Article  CAS  Google Scholar 

  26. Walker CG, Holness MJ, Gibbons GF, Sugden MC . Fasting-induced increases in aquaporin 7 and adipose triglyceride lipase mRNA expression in adipose tissue are attenuated by peroxisome proliferator-activated receptor alpha deficiency. Int J Obes (Lond) 2007; 31: 1165–1171.

    Article  CAS  Google Scholar 

  27. Maeda N, Funahashi T, Hibuse T, Nagasawa A, Kishida K, Kuriyama H et al. Adaptation to fasting by glycerol transport through aquaporin 7 in adipose tissue. Proc Natl Acad Sci USA 2004; 101: 17801–17806.

    Article  CAS  Google Scholar 

  28. Girousse A, Tavernier G, Valle C, Moro C, Mejhert N, Dinel AL et al. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 2013; 11: e1001485.

    Article  CAS  Google Scholar 

  29. Bakke SS, Moro C, Nikolic N, Hessvik NP, Badin PM, Lauvhaug L et al. Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase. Biochim Biophys Acta 2012; 1821: 1323–1333.

    Article  CAS  Google Scholar 

  30. van de Weijer T, Havekes B, Bilet L, Hoeks J, Sparks L, Bosma M et al. Effects of bezafibrate treatment in a patient and a carrier with mutations in the PNPLA2 gene, causing neutral lipid storage disease with myopathy. Circ Res 2013; 112: e51–e54.

    Article  CAS  Google Scholar 

  31. Smih F, Rouet P, Lucas S, Mairal A, Sengenes C, Lafontan M et al. Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose. Diabetes 2002; 51: 293–300.

    Article  CAS  Google Scholar 

  32. Kim JY, Tillison K, Lee JH, Rearick DA, Smas CM . The adipose tissue triglyceride lipase ATGL/PNPLA2 is downregulated by insulin and TNF-alpha in 3T3-L1 adipocytes and is a target for transactivation by PPARgamma. Am J Physiol Endocrinol Metab 2006; 291: E115–E127.

    Article  CAS  Google Scholar 

  33. Kershaw EE, Hamm JK, Verhagen LA, Peroni O, Katic M, Flier JS . Adipose triglyceride lipase: function, regulation by insulin, and comparison with adiponutrin. Diabetes 2006; 55: 148–157.

    Article  CAS  Google Scholar 

  34. Kralisch S, Klein J, Lossner U, Bluher M, Paschke R, Stumvoll M et al. Isoproterenol, TNFalpha, and insulin downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. Mol Cell Endocrinol 2005; 240: 43–49.

    Article  CAS  Google Scholar 

  35. Coppack SW, Fisher RM, Humphreys SM, Clark ML, Pointon JJ, Frayn KN . Carbohydrate metabolism in insulin resistance: glucose uptake and lactate production by adipose and forearm tissues in vivo before and after a mixed meal. Clin Sci (Lond) 1996; 90: 409–415.

    Article  CAS  Google Scholar 

  36. Horowitz JF, Coppack SW, Klein S . Whole-body and adipose tissue glucose metabolism in response to short-term fasting in lean and obese women. Am J Clin Nutr 2001; 73: 517–522.

    Article  CAS  Google Scholar 

  37. Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S et al. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med 2014; 370: 2307–2315.

    Article  Google Scholar 

Download references

Acknowledgements

The authors gratefully thank all volunteers for their time and motivation, and Jos Stegen and Wendy Sluijsmans for their excellent technical support. This work was supported by a VENI grant (016.116.074) from the Netherlands Organization for Scientific Research (NWO) to JWEJ and a clinical research grant from the European Foundation for the Study of Diabetes (EFSD) to EEB and JWEJ.

Author contributions

All clinical studies were performed and samples were obtained in the laboratory of EEB (Maastricht, the Netherlands) and analytical experiments were conducted at the laboratories of EEB. (Maastricht, the Netherlands). Substantial contribution to concept and design, acquisition of data, or analysis and interpretation of data: JWEJ, GHG, HP, YE, NH and EEB. Drafting the article and revising it critically for intellectual content: JWEJ, GHG and EEB. Final approval of the version to be published: JWEJ, GHG, HP, YE, NH and EEB.

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Authors and Affiliations

  1. Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands,

    J W E Jocken, G H Goossens, H Popeijus, Y Essers, N Hoebers & E E Blaak

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  1. J W E Jocken
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  2. G H Goossens
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  3. H Popeijus
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Correspondence to J W E Jocken.

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Jocken, J., Goossens, G., Popeijus, H. et al. Contribution of lipase deficiency to mitochondrial dysfunction and insulin resistance in hMADS adipocytes. Int J Obes 40, 507–513 (2016). https://doi.org/10.1038/ijo.2015.211

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