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Mancuso 2010 J Biol Chem

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Mancuso DJ, Sims HF, Yang K, Kiebish MA, Su X, Jenkins CM, Guan S, Moon SH, Pietka T, Nassir F, Schappe T, Moore K, Han X, Abumrad NA, Gross RW (2010) Genetic ablation of calcium-independent phospholipase A2{gamma} prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation. J Biol Chem 285:36495-510.

» PMID: 20817734 Open Access

Mancuso DJ, Sims HF, Yang K, Kiebish MA, Su X, Jenkins CM, Guan S, Moon SH, Pietka T, Nassir F, Schappe T, Moore K, Han X, Abumrad NA, Gross RW (2010) J Biol Chem

Abstract: Phospholipases are critical enzyme mediators participating in many aspects of cellular function through modulating the generation of lipid 2nd messengers, membrane physical properties and cellular bioenergetics. Here we demonstrate that mice null for calcium independent phospholipase A(2)γ (iPLA(2)γ-/-) are completely resistant to high fat diet-induced weight gain, adipocyte hypertrophy, hyperinsulinemia, and insulin resistance which occur in iPLA(2)γ+/+ mice after high fat feeding. Notably, iPLA(2)γ-/- mice were lean, demonstrate abdominal lipodystrophy, and remained insulin sensitive despite having a marked impairment in glucose-stimulated insulin secretion after high fat feeding. Respirometry of adipocyte explants from iPLA(2)γ-/- mice identified increased rates of oxidation of multiple different substrates in comparison to adipocyte explants from wild-type littermates. Shotgun lipidomics of adipose tissue from wild-type mice demonstrated the anticipated 2-fold increase in triglyceride content after high fat feeding. In sharp contrast, the adipocyte triglyceride content was identical in iPLA(2)γ-/- mice fed either a standard diet or a high fat diet. Respirometry of skeletal muscle mitochondria from iPLA(2)γ-/- mice demonstrated marked decreases in State 3 respiration using multiple substrates whose metabolism was uncoupled from ATP production. Shotgun lipidomics of skeletal muscle revealed a decreased content of cardiolipin with an altered molecular species composition thereby identifying the mechanism underlying mitochondrial uncoupling in the iPLA(2)γ-/- mouse. Collectively, these results identify iPLA(2)γ as an obligatory upstream enzyme that is necessary for efficient electron transport chain coupling and energy production that participates in the alterations of cellular bioenergetics that promote the development of the metabolic syndrome.

O2k-Network Lab: US MO St Louis Gross RW, US MO St Louis Abumrad NA

Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Diabetes, Obesity 

Organism: Mouse  Tissue;cell: Skeletal muscle, Fat  Preparation: Homogenate, Isolated mitochondria 

Coupling state: OXPHOS 

HRR: Oxygraph-2k