TY - JOUR
T1 - Genetic ablation of calcium-independent phospholipase A2γ prevents obesity and insulin resistance during high fat feeding by mitochondrial uncoupling and increased adipocyte fatty acid oxidation
AU - Mancuso, David J.
AU - Sims, Harold F.
AU - Yang, Kui
AU - Kiebish, Michael A.
AU - Su, Xiong
AU - Jenkins, Christopher M.
AU - Guan, Shaoping
AU - Moon, Sung Ho
AU - Pietka, Terri
AU - Nassir, Fatiha
AU - Schappe, Timothy
AU - Moore, Kristin
AU - Han, Xianlin
AU - Abumrad, Nada A.
AU - Gross, Richard W.
PY - 2010/11/19
Y1 - 2010/11/19
N2 - 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 A2γ (iPLA2γ-/-) are completely resistant to high fat diet-induced weight gain, adipocyte hypertrophy, hyperinsulinemia, and insulin resistance, which occur in iPLA2γ+/+ mice after high fat feeding. Notably, iPLA2γ-/- mice were lean, demonstrated 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 iPLA2γ -/- mice identified increased rates of oxidation of multiple different substrates in comparison with 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 iPLA2γ-/- mice fed either a standard diet or a high fat diet. Respirometry of skeletal muscle mitochondria from iPLA 2γ-/- 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 2γ-/- mouse. Collectively, these results identify iPLA2γ as an obligatory upstream enzyme that is necessary for efficient electron transport chain coupling and energy production through its participation in the alterations of cellular bioenergetics that promote the development of the metabolic syndrome.
AB - 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 A2γ (iPLA2γ-/-) are completely resistant to high fat diet-induced weight gain, adipocyte hypertrophy, hyperinsulinemia, and insulin resistance, which occur in iPLA2γ+/+ mice after high fat feeding. Notably, iPLA2γ-/- mice were lean, demonstrated 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 iPLA2γ -/- mice identified increased rates of oxidation of multiple different substrates in comparison with 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 iPLA2γ-/- mice fed either a standard diet or a high fat diet. Respirometry of skeletal muscle mitochondria from iPLA 2γ-/- 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 2γ-/- mouse. Collectively, these results identify iPLA2γ as an obligatory upstream enzyme that is necessary for efficient electron transport chain coupling and energy production through its participation in the alterations of cellular bioenergetics that promote the development of the metabolic syndrome.
UR - http://www.scopus.com/inward/record.url?scp=78449252456&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.115766
DO - 10.1074/jbc.M110.115766
M3 - Article
C2 - 20817734
AN - SCOPUS:78449252456
SN - 0021-9258
VL - 285
SP - 36495
EP - 36510
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -