Group IIA secreted phospholipase A2 (PLA2G2A) augments adipose tissue thermogenesis

Abstract

Group IIA secreted phospholipase A2 (PLA2G2A) hydrolyzes glycerophospholipids at the sn-2 position resulting in the release of fatty acids and lysophospholipids. C57BL/6 mice do not express Pla2g2a due to a frameshift mutation (wild-type [WT] mice). We previously reported that transgenic expression of human PLA2G2A in C57BL/6 mice (IIA+ mice) protects against weight gain and insulin resistance, in part by increasing total energy expenditure. Additionally, we found that brown and white adipocytes from IIA+ mice have increased expression of mitochondrial uncoupling markers, such as uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor-gamma coactivator, and PR domain containing 16, suggesting that the energy expenditure phenotype might be due to an increased thermogenic capacity in adipose tissue. Here, we further characterize the impact of PLA2G2A on thermogenic mechanisms in adipose tissue. Metabolic analysis of WT and IIA+ mice revealed that even when housed within their thermoneutral zone, IIA+ mice have elevated energy expenditure compared to WT littermates. Increased energy expenditure in IIA+ mice is associated with increased citrate synthase activity in brown adipose tissue (BAT) and increased mitochondrial respiration in both brown and white adipocytes. We also observed that direct addition of recombinant PLA2G2A enzyme to in vitro cultured adipocytes results in the marked induction of UCP1 protein expression. Finally, we report that PLA2G2A induces the expression of numerous transcripts related to energy substrate transport and metabolism in BAT, suggestive of an increase in substrate flux to fuel BAT activity. These data demonstrate that PLA2G2A enhances adipose tissue thermogenesis, in part, through elevated substrate delivery and increased mitochondrial content in BAT.

Identifying Potential Mitochondrial Proteome Signatures Associated with the Pathogenesis of Pulmonary Arterial Hypertension in the Rat Model

“…It has been found to play an essential role in inflammation and atherosclerosis. In recent years, Pla2g2a was found to affect the process of energy metabolism and insulin sensitivity in mice by activating mitochondrial uncoupling in mouse brown adipose tissue (BAT) [ 43 ]. These results suggest that mitochondrial dysfunction and metabolic abnormalities may be an important pathological process in PAH.…”

Upregulation of Metallothionein 1 G (MT1G) Negatively Regulates Ferroptosis in Clear Cell Renal Cell Carcinoma by Reducing Glutathione Consumption

“…Such defense systems are mainly comprised of enzymes (GSH-Px, superoxide dismutase, and catalase), and reducing agents (cysteine, vitamin C, and GSH) [ 34 ]. According to previous studies, phospholipase A2 (PLA2G2A) might participate in cell membrane lipid oxidation [ 35 ]. The GSEA results explained that the pathways of “glutathione metabolism,” “oxidative phosphorylation,” and “proteasome” were enriched in MT1G-upregulated samples and were involved in GSH metabolism and lipid peroxidation.…”

Modulation of immunity by the secreted phospholipase A2 family

“…Prior to studies using KO mice for various sPLA 2 s, studies using sPLA 2 -overexpressing TG mice had provided several informative hints for the potential pathophysiological functions of sPLA 2 s . 16,19,24,44,52,78,[84][85][86][90][91][92][93][95][96][97][98][100][101][102][103]105 Here, we describe general aspects in brief, rather than detailing the individual phenotypes, of sPLA 2 -TG mice. It is notable that, as opposed to the classical theory that sPLA 2 s are generally involved in inflammation by producing pro-inflammatory eicosanoids, not all sPLA 2 -TG mice display pro-inflammatory phenotypes.…”

“…Exacerbation of atherosclerosis [95,96] Global TG Protection against malaria infection [97] Global TG Uncertain Increase in adipose tissue thermogenesis [98] sPLA Reduced adiposity [16] sPLA 2 -X PLA2G10 Global TG Increase in ω3 PUFAs and their metabolites Systemic anti-inflammation [24] Global TG Increase in P-LPE (mimicking Pla2g2f-Tg)?…”