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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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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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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DOI: https://doi.org/10.1038/ijo.2015.211
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