Mice deficient in Group VIB phospholipase A₂ (iPLA ₂γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

Phospholipases A₂ (PLA₂) play important roles in metabolic processes, and the Group VI PLA₂ family is comprised of intracellular enzymes that do not require Ca²⁺ for catalysis. Mice deficient in Group VIA PLA₂ (iPLA₂β) develop more severe glucose intolerance than wild-type (WT) mice in response to dietary stress. Group VIB PLA₂ (iPLA₂γ) is a related enzyme distributed in membranous organelles, including mitochondria, and iPLA ₂γ knockout (KO) mice exhibit altered mitochondrial morphology and function. We have compared metabolic responses of iPLA₂γ-KO and WT mice fed a Western diet (WD) with a high fat content. We find that KO mice are resistant to WD-induced increases in body weight and adiposity and in blood levels of cholesterol, glucose, and insulin, even though WT and KO mice exhibit similar food consumption and dietary fat digestion and absorption. KO mice are also relatively resistant to WD-induced insulin resistance, glucose intolerance, and altered patterns of fat vs. carbohydrate fuel utilization. KO skeletal muscle exhibits impaired mitochondrial β-oxidation of fatty acids, as reflected by accumulation of larger amounts of long-chain acylcarnitine (LCAC) species in KO muscle and liver compared with WT in response to WD feeding. This is associated with increased urinary excretion of LCAC and much reduced deposition of triacylglycerols in liver by WD-fed KO compared with WT mice. The iPLA₂γ-deficient genotype thus results in a phenotype characterized by impaired mitochondrial oxidation of fatty acids and relative resistance to the metabolic abnormalities induced by WD.