Secretory phospholipase A2 group IIA modulates insulin sensitivity and metabolism

Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases that have been implicated in inflammation, atherogenesis, and antibacterial actions. Here, we evaluated the role of PLA2G2A in the metabolic response to a high fat diet. C57BL/6 (BL/6) mice do not express PLA2g2a due to a frameshift mutation. We fed BL/6 mice expressing the human PLA2G2A gene (IIA+ mice) a fat diet and assessed the physiologic response. After 10 weeks on the high fat diet, the BL/6 mice were obese, but the IIA+ mice did not gain weight or accumulate lipid. The lean mass in chow- and high fat-fed IIA+ mice was constant and similar to the BL/6 mice on a chow diet. Surprisingly, the IIA+ mice had an elevated metabolic rate, which was not due to differences in physical activity. The IIA+ mice were more insulin sensitive and glucose tolerant than the BL/6 mice, even when the IIA+ mice were provided the high fat diet. The IIA+ mice had increased expression of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), and PPARγ coactivator 1α (PGC-1α) in brown adipose tissue (BAT), suggesting that PLA2G2A activates mitochondrial uncoupling in BAT. Our data indicate that PLA2G2A has a previously undiscovered impact on insulin sensitivity and metabolism. Secretory phospholipase A2 group IIA (PLA2G2A) is a member of a family of secretory phospholipases that have been implicated in inflammation, atherogenesis, and antibacterial actions. Here, we evaluated the role of PLA2G2A in the metabolic response to a high fat diet. C57BL/6 (BL/6) mice do not express PLA2g2a due to a frameshift mutation. We fed BL/6 mice expressing the human PLA2G2A gene (IIA+ mice) a fat diet and assessed the physiologic response. After 10 weeks on the high fat diet, the BL/6 mice were obese, but the IIA+ mice did not gain weight or accumulate lipid. The lean mass in chow- and high fat-fed IIA+ mice was constant and similar to the BL/6 mice on a chow diet. Surprisingly, the IIA+ mice had an elevated metabolic rate, which was not due to differences in physical activity. The IIA+ mice were more insulin sensitive and glucose tolerant than the BL/6 mice, even when the IIA+ mice were provided the high fat diet. The IIA+ mice had increased expression of uncoupling protein 1 (UCP1), sirtuin 1 (SIRT1), and PPARγ coactivator 1α (PGC-1α) in brown adipose tissue (BAT), suggesting that PLA2G2A activates mitochondrial uncoupling in BAT. Our data indicate that PLA2G2A has a previously undiscovered impact on insulin sensitivity and metabolism. Phospholipases A2 (PLA2s) are a group of esterase enzymes that hydrolyze the second carbon of membrane phospholipids to release nonesterified free fatty acids and lysophospholipids (1.Lambeau G. Gelb M.H. Biochemistry and physiology of mammalian secreted phospholipases A2.Annu. Rev. 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The sPLA2s are low molecular mass phospholipases (14–18 kDa) that are secreted into the extracellular environment in response to various stimuli. Currently, eleven sPLA2s have been identified (3.Dennis E.A. Cao J. Hsu Y.H. Magrioti V. Kokotos G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.Chem. Rev. 2011; 111: 6130-6185Crossref PubMed Scopus (771) Google Scholar, 5.Murakami M. Taketomi Y. Sato H. Yamamoto K. Secreted phospholipase A2 revisited.J. Biochem. 2011; 150: 233-255Crossref PubMed Scopus (153) Google Scholar). These phospholipases mediate multiple biologic actions by targeting various noncellular phospholipids, such as microbial membranes, dietary phospholipids, and lipoproteins (5.Murakami M. Taketomi Y. Sato H. Yamamoto K. Secreted phospholipase A2 revisited.J. Biochem. 2011; 150: 233-255Crossref PubMed Scopus (153) Google Scholar). sPLA2 group IIA (PLA2G2A) was first purified from the platelets and synovial fluids of patients suffering from arthritis (6.Pruzanski W. Vadas P. Secretory synovial fluid phospholipase A2 and its role in the pathogenesis of inflammation in arthritis.J. Rheumatol. 1988; 15: 1601-1603PubMed Google Scholar). It has high affinity for anionic phospholipids such as phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol (5.Murakami M. Taketomi Y. Sato H. Yamamoto K. Secreted phospholipase A2 revisited.J. Biochem. 2011; 150: 233-255Crossref PubMed Scopus (153) Google Scholar). Many cell types, including hepatocytes, vascular smooth muscle cells, and endothelial cells, secrete PLA2G2A (7.Grass D.S. Felkner R.H. Chiang M.Y. Wallace R.E. Nevalainen T.J. Bennett C.F. Swanson M.E. Expression of human group II PLA2 in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate.J. 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The finding that PLA2G2A is highly abundant in biological fluids of patients suffering from inflammatory diseases, like arthritis, sepsis, and myocardial infarctions, suggested that PLA2G2A promotes inflammation (5.Murakami M. Taketomi Y. Sato H. Yamamoto K. Secreted phospholipase A2 revisited.J. Biochem. 2011; 150: 233-255Crossref PubMed Scopus (153) Google Scholar, 13.Mallat Z. Benessiano J. Simon T. Ederhy S. Sebella-Arguelles C. Cohen A. Huart V. Wareham N.J. Luben R. Khaw K.T. et al.Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1177-1183Crossref PubMed Scopus (95) Google Scholar, 14.Rosenson R.S. Phospholipase A2 inhibition and atherosclerotic vascular disease: prospects for targeting secretory and lipoprotein-associated phospholipase A2 enzymes.Curr. Opin. Lipidol. 2010; 21: 473-480Crossref PubMed Scopus (28) Google Scholar). In support of this concept, under inflammatory conditions PLA2g2a knockout BALB/c mice have attenuated joint inflammation compared BALB/c mice Y. K. B. F. R. M.E. et role for secretory phospholipase A2 in 2010; PubMed Scopus Google Scholar). In to its inflammatory PLA2G2A is elevated of PLA2G2A a for disease K. Y. K. Y. H. Y. T. H. H. H. et al.Circulating of secretory type II phospholipase A(2) coronary events in patients coronary PubMed Scopus Google Scholar). of a role for PLA2G2A in from PLA2G2A transgenic C57BL/6 (BL/6) mice do not express PLA2g2a due to frameshift in The human PLA2G2A gene was into BL/6 mice to mice B. M. M. D.S. Swanson M.E. et of group II secretory phospholipase A2 in and lipoproteins in transgenic mice expressing group phospholipase Thromb. Vasc. Biol. PubMed Scopus Google Scholar, P. J. Vadas P. W. M. C. A of the secretory group II phospholipase A2 gene in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). fed a high diet, the IIA+ mice had increased atherosclerotic and increased B. M. M. D.S. Swanson M.E. et of group II secretory phospholipase A2 in and lipoproteins in transgenic mice expressing group phospholipase Thromb. Vasc. Biol. PubMed Scopus Google Scholar). had elevated suggesting that PLA2G2A R. M. P. W. in transgenic mice human secretory phospholipase A2 group PubMed Scopus Google Scholar). from IIA+ mice into mice increased atherosclerotic and expression of PLA2G2A in the of and the of from to cells M. I. B. M.H. of group sPLA2 and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, A. group IIA secretory phospholipase A2 atherosclerotic in Thromb. Vasc. Biol. PubMed Scopus Google Scholar). of an of for weeks in mice H. C. R.M. J. a secretory phospholipase A2 and in PubMed Scopus Google Scholar). the of to myocardial and in has into the that PLA2 is the role of sPLA2s and in coronary Thromb. Vasc. Biol. 2015; PubMed Scopus Google Scholar, R.S. W. V. et and events in patients an acute coronary the PubMed Scopus Google Scholar). is a inflammatory and the of PLA2G2A to metabolic regulation have not been In this we the metabolic of PLA2G2A in to high fat Our that IIA+ mice are to weight and fat mass in response to a high fat diet. IIA+ mice have glucose and insulin and are in has identified a role of PLA2G2A in the regulation of metabolism. The IIA+ mice, which express the human PLA2G2A gene under the regulation of the human were provided by the P. T. E.A. the expression of secretory Res. PubMed Scopus Google Scholar). mice for the PLA2G2A gene were BL/6 BL/6 and IIA+ mice were were on weeks In dietary we had BL/6 mice, 10 IIA+ mice, BL/6 high fat mice, and IIA+ high fat were a constant and phase of were by the of and The chow diet was the diet and the high fat diet was from The high fat diet provided of the from the chow diet of the as The mice were free to the The was and the was based on of the of the and the weight of the were and fat and mass were by glucose were in from a a in glucose or insulin insulin was and glucose and B. Y. K. A. M. et molecular and in PubMed Scopus Google Scholar). The data are as glucose and the under the glucose After weeks of diet, mice were in the were on chow or high fat diet. was A. S. J. J. to free and muscle mitochondrial in J. PubMed Scopus Google Scholar). and are to The was to activity was by the of were to to tissue for and The mice were by and by brown adipose tissue (BAT), and adipose tissue were and in was from by was transcription The for were as for of for for and for 10 was as a The of the was the P. S. E.A. mediate the of phospholipase A2 group gene transcription by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The and for are in The PLA2G2A were from and in the are in a new protein from and was in 1 and R.R. P. E.A. of kinase by protein Biol. Chem. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). Protein were in and were on were and to were in to were the in in and in in were P. S. E.A. mediate the of phospholipase A2 group gene transcription by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The were from from from from from uncoupling protein 1 (UCP1), from from from from from from sirtuin 1 (SIRT1), from from and lipoproteins in were the of was by from mice and the was from the were first in and were a the J. M. A for the and of from Biol. Chem. Full Text PDF PubMed Google Scholar). the phase was were the as by the was the are the results of the were by or was to we evaluated the of PLA2G2A on weight gain and by the in response to 10 weeks of high fat diet in BL/6 and the IIA+ mice Y. K. B. F. R. M.E. et role for secretory phospholipase A2 in 2010; PubMed Scopus Google Scholar). In response to the high fat diet, BL/6 mice more weight than the BL/6 mice or the IIA+ mice on the chow or high fat diet. The IIA+ mice were to high fat weight gain The mass of BL/6 and IIA+ mice was similar on the chow and high fat BL/6 mice the high fat diet had elevated fat compared their chow fat mass was in the IIA+ groups of the diet We the of the mice and that the 10 the BL/6 and IIA+ mice similar of of weight the BL/6 mice on the high fat diet more than the IIA+ mice, but weeks was similar groups not The was that the IIA+ mice on the high fat diet were from the BL/6 mice on the high fat diet. we assessed and physical activity The BL/6 mice on the high fat diet had than the BL/6 mice Surprisingly, the IIA+ mice on chow and high fat had than the BL/6 suggesting increased of diet. In to the elevated the IIA+ mice had increased The BL/6 and IIA+ mice on the high fat diet had compared their chow The activity of the IIA+ mice were similar to the BL/6 mice on the the increased was not due to in activity the mice on the high fat diet were than on the chow diet. the data in that the lean of the IIA+ mice was due to elevated metabolism. We the glucose and insulin of mice 10 weeks on the from the that the IIA+ mice were to glucose even 10 weeks on a high fat diet the BL/6 mice on the high fat diet had glucose and of glucose glucose compared the BL/6 was of the high fat diet on glucose in the IIA+ In the glucose the is insulin we an The BL/6 mice on the high fat diet had insulin sensitivity and in glucose in response to insulin In the IIA+ mice insulin sensitive of the diet and glucose low insulin The in glucose the is in These data that PLA2G2A insulin have that the IIA+ mice have a to we evaluated the of the mice B. M. M. D.S. 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The BL/6 mice on the high fat diet had elevated compared The IIA+ mice on the high fat diet had elevated to the IIA+ but the was in the IIA+ mice when compared the BL/6 mice were in the IIA+ chow were in the IIA+ mice on the high fat diet, but this was when to their chow diet was elevated in the BL/6 mice on high fat diet, and were in the IIA+ groups to their dietary BL/6 was in the IIA+ mice on a high fat diet, was the The increased the in the high fat-fed IIA+ was in the IIA+ mice, we the in the was in the BL/6 and IIA+ mice, the was in BL/6 and IIA+ on the high fat diet we the in the The were elevated in the BL/6 mice on the high fat diet, but the in the IIA+ mice were increased PLA2G2A was we various for the expression of We PLA2G2A in and The of PLA2G2A in the was In the and PLA2G2A and protein were increased by the high fat diet, that the gene is by high fat the molecular the metabolic of we the impact of PLA2G2A on the of various metabolic in the we the of in fatty and including and in the IIA+ mice compared the IIA+ mice on high fat diet but the were not Surprisingly, the was in the IIA+ mice was elevated in response to the high fat diet in BL/6 mice, but not in the IIA+ mice we the of for mitochondrial and The of and were in the IIA+ mice on the chow diet, but not the high fat diet in protein we the of in metabolic regulation by The of was elevated in the BL/6 and IIA+ mice on high fat diet The protein was elevated in the BL/6 mice in response to the high fat diet, nuclear was elevated in the IIA+ mice on the high fat diet the IIA+ mice had elevated we of mitochondrial including PPARγ coactivator 1α (PGC-1α) and We did not in or protein in the suggesting that in the do not mitochondrial in metabolic in of IIA+ were from the the of the and the of various was by are and the data was nuclear are The data are as protein is the of data from four The data were by the IIA+ mice are more insulin we to in the insulin were in the IIA+ was increased in the IIA+ mice and was elevated of based on the to in the IIA+ mice on the chow and on the high fat diet In we which is of Our data that was increased of kinase and in the IIA+ mice These data that is insulin in the IIA+ were in that for the increased and in the IIA+ mice, we and protein of and in and We did not differences in and in muscle not In was gene or protein expression of metabolic not in the and were increased We the of as and that were elevated These data that of the of the metabolic from increased mitochondrial uncoupling increased as from BAT. of the PLA2G2A are inflammation and disease M. Taketomi Y. Girard C. Yamamoto K. Lambeau G. Emerging roles of secreted phospholipase A2 enzymes: lessons from transgenic and knockout mice.Biochimie. 2010; 92: 561-582Crossref PubMed Scopus (116) Google Scholar, M. Taketomi Y. Miki Y. Sato H. Yamamoto K. Lambeau G. Emerging roles of secreted phospholipase A2 enzymes: the PubMed Scopus Google Scholar). Here, we the metabolic response of IIA+ mice to a high fat diet. Our data indicate that PLA2G2A provided from the of high fat the IIA+ mice did not gain weight or accumulate fat mass in response to the high fat diet insulin sensitive and glucose the IIA+ mice had elevated and due to the of mitochondrial uncoupling in BAT. Our results that PLA2G2A insulin and The of on PLA2G2A has been on the regulation of and the impact of PLA2G2A on M. I. B. M.H. of group sPLA2 and Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, A. group IIA secretory phospholipase A2 atherosclerotic in Thromb. Vasc. Biol. PubMed Scopus Google Scholar, W. M. Z. C. H. II secretory phospholipase A2 and in patients coronary disease: 2011; PubMed Scopus Google Scholar). sPLA2 including and are due to their to the of and and to the of cells from (5.Murakami M. Taketomi Y. Sato H. Yamamoto K. Secreted phospholipase A2 revisited.J. Biochem. 2011; 150: 233-255Crossref PubMed Scopus (153) Google Scholar). of cells into mice increased the of atherosclerotic A. group IIA secretory phospholipase A2 atherosclerotic in Thromb. Vasc. Biol. PubMed Scopus Google Scholar). has been to the of and H. R. Y. G. M. Taketomi Y. Yamamoto K. K. J. S. et of group secreted phospholipase A2 transgenic mice of this in cell and Biol. Chem. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). PLA2G2A promotes in IIA+ mice fed a high diet B. M. M. D.S. Swanson M.E. et of group II secretory phospholipase A2 in and lipoproteins in transgenic mice expressing group phospholipase Thromb. Vasc. Biol. PubMed Scopus Google and IIA+ mice had on an diet R. M. P. W. in transgenic mice human secretory phospholipase A2 group PubMed Scopus Google Scholar). Our from in that of but the mice on we that was in IIA+ mice Our IIA+ mice had and The the that the mice have The elevated in the IIA+ mice on the high fat diet are increased The and elevated to the in the IIA+ mice B. M. M. D.S. Swanson M.E. et of group II secretory phospholipase A2 in and lipoproteins in transgenic mice expressing group phospholipase Thromb. Vasc. Biol. PubMed Scopus Google Scholar). A elevated was previously in IIA+ mice on an diet B. M. M. D.S. Swanson M.E. et of group II secretory phospholipase A2 in and lipoproteins in transgenic mice expressing group phospholipase Thromb. Vasc. Biol. PubMed Scopus Google Scholar). The IIA+ mice had suggesting fatty In the IIA+ mice had of and nuclear which to the data are of in in the IIA+ finding of was that the IIA+ mice did not gain weight or accumulate fat mass on the high fat diet. the BL/6 mice on the high fat diet The IIA+ mice were than the BL/6 mice and similar of weight the 10 The increased was the of the weight gain by the IIA+ was not due to increased activity in the IIA+ mice, as were not more than the BL/6 mice were not In the of in fatty such as and were not The events that a brown have been and the transcription and adipose tissue as P. Z. R. M. A coactivator of nuclear to 92: Full Text Full Text PDF PubMed Scopus Google Scholar, S. P. K. of to brown fat by a PubMed Scopus Google Scholar, P. S. Transcriptional of brown and mice and PubMed Scopus Google Scholar). We increased expression of and in the of the IIA+ mice, suggesting that PLA2G2A promotes mitochondrial uncoupling in It was previously that lipoproteins by sPLA2 were more to in the of lipoproteins and the The mitochondrial uncoupling of and an J.L. M. R. S. et role for in regulation of mitochondrial J. PubMed Scopus Google Scholar). the we have in brown of and as as of in the IIA+ mice, a is that of PLA2G2A The mitochondrial uncoupling its actions on of the fatty acids by sPLA2 activity is a for of a group of and in the inflammatory response and of cellular and PubMed Google Scholar). was that the mitochondrial by in and brown mitochondrial I. A. S. Y. of and cells Full Text Full Text PDF PubMed Scopus Google Scholar). a similar that by fatty from by cytosolic PLA2 A. Y. of uncoupling in brown fat Full Text Full Text PDF PubMed Scopus Google Scholar). The IIA+ mice on chow and high fat had elevated and due to release of or fatty by to and mitochondrial uncoupling activity. PLA2G2A is inflammation and we that the IIA+ mice insulin as inflammation has been insulin A. C. R. C. G. et insulin is to and to 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, for insulin and Full Text Full Text PDF PubMed Scopus Google Scholar). was that the IIA+ mice were more sensitive to as by the and the the insulin were as by the increased and of is that as the IIA+ mice were to high fat the insulin sensitivity was to the that in the of IIA+ mice on an diet R. M. P. W. in transgenic mice human secretory phospholipase A2 group PubMed Scopus Google Scholar). The of the BL/6 mice on high fat diet more than of groups We a in in the IIA+ mice on high fat diet compared the chow The attenuated of in the IIA+ mice an as to the IIA+ mice on high fat diet are not insulin have that sPLA2 and roles in and metabolic and that the knockout of provided and insulin and insulin in group J. 2002; PubMed Scopus Google Scholar). is secreted into the from the and the from The knockout mice had elevated fatty that the more on fatty acids for M.H. fatty the molecular group phospholipase A2 and J. 2010; PubMed Scopus Google Scholar, C. phospholipase A(2) and metabolic in Full Text Full Text PDF PubMed Scopus Google Scholar). of to mitochondrial of fatty acids M. W. in on mitochondrial but in PubMed Scopus Google Scholar). from Murakami and the interplay of and in the adipose tissue to metabolic actions H. Taketomi Y. A. Y. T. T. Miki Y. Yamamoto K. Y. T. et secreted phospholipases and roles in 20: Full Text Full Text PDF PubMed Scopus Google Scholar). that knockout mice insulin and and were to suggesting that from In the was that in mice and and that H. Taketomi Y. A. Y. T. T. Miki Y. Yamamoto K. Y. T. et secreted phospholipases and roles in 20: Full Text Full Text PDF PubMed Scopus Google Scholar). A metabolic role for PLA2g2a was in A. J. H. J. of phospholipase A2 group IIA and metabolic in PubMed Scopus Google Scholar). a high fat diet, the of PLA2g2a were elevated in rat adipose tissue A. J. H. J. of phospholipase A2 group IIA and metabolic in PubMed Scopus Google Scholar). In we previously that BALB/c mice on a high fat diet had increased PLA2g2a in the and that the of to rat increased PLA2g2a P. T. E.A. the expression of secretory Res. PubMed Scopus Google Scholar). In by of the PLA2g2a diet induced weight gain and glucose A. J. H. J. of phospholipase A2 group IIA and metabolic in PubMed Scopus Google Scholar). The that PLA2g2a inhibition fat in A. J. H. J. of phospholipase A2 group IIA and metabolic in PubMed Scopus Google Scholar). These results from that elevated PLA2G2A activity in and insulin It that the results in the rat from an of the impact of the high fat diet, as et A. J. H. J. of phospholipase A2 group IIA and metabolic in PubMed Scopus Google increased fat in the of the It is from multiple that the various secretory phospholipases have and et Y. K. B. F. R. M.E. et role for secretory phospholipase A2 in 2010; PubMed Scopus Google that has an role that the inflammation by PLA2g2a in the role of PLA2G2A and sPLA2 in In we have that PLA2G2A insulin sensitivity and to high fat weight gain in PLA2G2A the of the mice of activity and diet, and of BAT. We have identified a previously role of this secretory phospholipase in the of and metabolism. the this brown adipose tissue C57BL/6 adipose tissue glucose C57BL/6 mice expressing the human PLA2G2A gene interleukin insulin fatty PPARγ coactivator 1α PLA2, phospholipase A2 secretory phospholipase A2 group IIA sirtuin 1 secretory phospholipase A2 uncoupling protein 1 adipose tissue

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