PMID- 26471343
OWN - NLM
STAT- MEDLINE
DCOM- 20170102
LR  - 20220311
IS  - 1476-5497 (Electronic)
IS  - 0307-0565 (Linking)
VI  - 40
IP  - 3
DP  - 2016 Mar
TI  - Contribution of lipase deficiency to mitochondrial dysfunction and insulin 
      resistance in hMADS adipocytes.
PG  - 507-13
LID - 10.1038/ijo.2015.211 [doi]
AB  - 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.
FAU - Jocken, J W E
AU  - Jocken JW
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Goossens, G H
AU  - Goossens GH
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Popeijus, H
AU  - Popeijus H
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Essers, Y
AU  - Essers Y
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Hoebers, N
AU  - Hoebers N
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
FAU - Blaak, E E
AU  - Blaak EE
AD  - Department of Human Biology, NUTRIM School for Nutrition and Translational 
      Research in Metabolism, Maastricht University Medical Center, Maastricht, The 
      Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151016
PL  - England
TA  - Int J Obes (Lond)
JT  - International journal of obesity (2005)
JID - 101256108
RN  - 0 (PPAR alpha)
RN  - EC 3.1.1.13 (Sterol Esterase)
RN  - EC 3.1.1.3 (Lipase)
SB  - IM
MH  - Adipocytes, White/*metabolism
MH  - Adiposity/*physiology
MH  - Cells, Cultured
MH  - Energy Metabolism
MH  - Humans
MH  - Insulin Resistance/*physiology
MH  - Lipase/*deficiency/physiology
MH  - Lipolysis/physiology
MH  - Mitochondria/*metabolism
MH  - Obesity/complications/*metabolism
MH  - PPAR alpha/*agonists
MH  - Sterol Esterase/metabolism
EDAT- 2015/10/17 06:00
MHDA- 2017/01/04 06:00
CRDT- 2015/10/17 06:00
PHST- 2015/06/18 00:00 [received]
PHST- 2015/09/02 00:00 [revised]
PHST- 2015/09/21 00:00 [accepted]
PHST- 2015/10/17 06:00 [entrez]
PHST- 2015/10/17 06:00 [pubmed]
PHST- 2017/01/04 06:00 [medline]
AID - ijo2015211 [pii]
AID - 10.1038/ijo.2015.211 [doi]
PST - ppublish
SO  - Int J Obes (Lond). 2016 Mar;40(3):507-13. doi: 10.1038/ijo.2015.211. Epub 2015 
      Oct 16.