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

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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 PPARalpha, and restored on PPARalpha agonist treatment. CONCLUSIONS: The present study indicates that lipase deficiency in human white adipocytes contributes to mitochondrial dysfunction and insulin resistance, in a PPARalpha-dependent manner. Therefore, modulation of adipose tissue lipases may provide a promising strategy to reverse insulin resistance in obese and type 2 diabetic patients.International Journal of Obesity advance online publication, 3 November 2015; doi:10.1038/ijo.2015.211.
Original languageEnglish
Pages (from-to)507-513
Number of pages7
JournalInternational Journal of Obesity
Volume40
Issue number3
DOIs
Publication statusPublished - Mar 2016

Keywords

  • HORMONE-SENSITIVE LIPASE
  • ADIPOSE TRIGLYCERIDE LIPASE
  • PROLIFERATOR-ACTIVATED RECEPTOR
  • PPAR-ALPHA
  • 3T3-L1 ADIPOCYTES
  • SKELETAL-MUSCLE
  • HUMAN OBESITY
  • WHOLE-BODY
  • TNF-ALPHA
  • TISSUE

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