Supplementary key words cardiolipin • mitochondria • muscle • phospholipidsPhospholipase A 2 (PLA 2 ) enzymes catalyze the cleavage of the sn -2 ester bond of glycerophospholipids to yield free fatty acids and lysophospholipids, thereby playing critical roles in cellular lipid metabolisms linked to energy storage, membrane remodeling, and lipid mediator signaling. In the membrane remodeling reaction, fatty acyl groups are fi rst removed (deacylated) by PLA 2 and then replaced (reacylated) with different fatty acyl groups by acyltransferases, which allow membrane phospholipids to acquire a variation of molecular species. In the signaling reaction, polyunsaturated fatty acids [typically arachidonic acid (AA)] and lysophospholipids released by the action of PLA 2 s are metabolized to various lipid mediators, such as prostaglandins (PG), leukotrienes, and platelet-activating factor, which exert a variety of biological actions through their cognate receptors. Abstract Group VIB Ca2+ -independent phospholipase A 2 ␥ (iPLA 2 ␥ ) is a membrane-bound iPLA 2 enzyme with unique features, such as the utilization of distinct translation initiation sites and the presence of mitochondrial and peroxisomal localization signals. Here we investigated the physiological functions of iPLA 2 ␥ by disrupting its gene in mice. iPLA 2 ␥ -knockout (KO) mice were born with an expected Mendelian ratio and appeared normal and healthy at the age of one month but began to show growth retardation from the age of two months as well as kyphosis and significant muscle weakness at the age of four months. Electron microscopy revealed swelling and reduced numbers of mitochondria and atrophy of myofi laments in iPLA 2 ␥ -KO skeletal muscles. Increased lipid peroxidation and the induction of several oxidative stress-related genes were also found in the iPLA 2 ␥ -KO muscles. These results provide evidence that impairment of iPLA 2 ␥ causes mitochondrial dysfunction and increased oxidative stress, leading to the loss of skeletal muscle structure and function. We further found that the compositions of cardiolipin and other phospholipid subclasses were altered and that the levels of myoprotective prostanoids were reduced in iPLA 2 ␥ -KO skeletal muscle. Thus, in addition to maintenance of homeostasis of the mitochondrial membrane, iPLA 2 ␥ may contribute to modulation of lipid mediator production in vivo. -Yoda, E., K. Hachisu, Y. Taketomi, K. Yoshida, M. Nakamura, K. Ikeda, R. Taguchi, Y. Nakatani, H. Kuwata, M. Murakami, I. Kudo, and S. Hara. Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of Group VIB Ca 2+ -independent phospholipase A2 ␥ -defi cient mice. J. Lipid Res.

Adipogenic differentiation is a complex process by which fibroblast-like undifferentiated cells are converted into cells that accumulate lipid droplets. We here investigated the effect of gene deletion of calciumindependent phospholipase A 2 γ (iPLA 2 γ), a membrane-bound PLA 2 enzyme, on adipogenic differentiation in mice. Since iPLA 2 γ knockout (KO) mice showed reduced fat volume and weight, we prepared mouse embryonic fibroblasts (MEF) from wild-type (WT) and iPLA 2 γ KO mice and examined the effect of iPLA 2 γ deletion on in vitro adipogenic differentiation. iPLA 2 γ increased during adipogenic differentiation in WT mousederived MEFs, and the differentiation was partially abolished in iPLA 2 γ KO-derived MEFs. In KO-derived MEFs, the inductions of peroxisome proliferator activator receptor γ (PPARγ) and CAAT/enhancer-binding protein α (C/EBPα) were also reduced during adipogenic differentiation, and the reductions in PPARγ and C/EBPα expressions and the defect in adipogenesis were restored by treatment with troglitazone, a PPARγ ligand. These results indicate that iPLA 2 γ might play a critical role in adipogenic differentiation by regulating PPARγ expression.