The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

Abstract

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance. The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance. The occurrence of obesity and related metabolic disturbances, including insulin resistance and development of type 2 diabetes, has risen to epidemic proportions (1NCD Risk Factor CollaborationTrends in adult body-mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19·2 million participants.Lancet. 2016; 387 (27115820): 1377-139610.1016/S0140-6736(16)30054-XAbstract Full Text Full Text PDF PubMed Scopus (2312) Google Scholar, 2Cornier M.-A. Després J.-P. Davis N. Grossniklaus D.A. Klein S. Lamarche B. Lopez-Jimenez F. Rao G. St-Onge M.-P. Towfighi A. Poirier P. Assessing adiposity: A scientific statement from the American Heart Association.Circulation. 2011; 124 (21947291): 1996-201910.1161/CIR.0b013e318233bc6aCrossref PubMed Scopus (503) Google Scholar). The chronic inflammatory processes that closely associate with a state of obesity are now widely recognized as important drivers of insulin resistance that may eventually evolve into type 2 diabetes (3Odegaard J.I. Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance.Nat. Clin. Pract. Endocrinol. Metab. 2008; 4 (18838972): 619-62610.1038/ncpendmet0976Crossref PubMed Scopus (189) Google Scholar). In particular the activation of macrophages in expanding adipose tissue has been linked to this chronic, low-grade inflammation (3Odegaard J.I. Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance.Nat. Clin. Pract. Endocrinol. Metab. 2008; 4 (18838972): 619-62610.1038/ncpendmet0976Crossref PubMed Scopus (189) Google Scholar, 4Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; 112 (14679176): 1796-180810.1172/JCI19246Crossref PubMed Scopus (6769) Google Scholar, 5Xu X. Grijalva A. Skowronski A. van Eijk M. Serlie M.J. Ferrante A.W. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation.Cell Metab. 2013; 18 (24315368): 816-83010.1016/j.cmet.2013.11.001Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 6Cinti S. Mitchell G. Barbatelli G. Murano I. Ceresi E. Faloia E. Wang S. Fortier M. Greenberg A.S. Obin M.S. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans.J. Lipid Res. 2005; 46 (16150820): 2347-235510.1194/jlr.M500294-JLR200Abstract Full Text Full Text PDF PubMed Scopus (1571) Google Scholar, 7Kratz M. Coats B.R. Hisert K.B. Hagman D. Mutskov V. Peris E. Schoenfelt K.Q. Kuzma J.N. Larson I. Billing P.S. Landerholm R.W. Crouthamel M. Gozal D. Hwang S. Singh P.K. et al.Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.Cell Metab. 2014; 20 (25242226): 614-62510.1016/j.cmet.2014.08.010Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). Dynamic changes in tissue microenvironments can drive specific metabolic alterations in tissue-resident immune cells in an attempt to accommodate appropriate changes in immune cell functioning (8Loftus R.M. Finlay D.K. Immunometabolism: Cellular metabolism turns immune regulator.J. Biol. Chem. 2016; 291 (26534957): 1-1010.1074/jbc.R115.693903Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). It is well known that modifications in metabolic signatures are closely related to immune cell functioning, demonstrated for instance by pro-inflammatory immune cells that rely on glycolytic pathways (9Lachmandas E. Boutens L. Ratter J.M. Hijmans A. Hooiveld G.J. Joosten L.A.B. Rodenburg R.J. Fransen J.A.M. Houtkooper R.H. van Crevel R. Netea M.G. Stienstra R. Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes.Nat. Microbiol. 2016; 2 (27991883)1624610.1038/nmicrobiol.2016.246Crossref PubMed Scopus (138) Google Scholar). Activation of macrophages in the context of obese adipose tissue was found to lead to unique changes in the metabolic signature of these adipose tissue macrophages (ATMs) (5Xu X. Grijalva A. Skowronski A. van Eijk M. Serlie M.J. Ferrante A.W. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation.Cell Metab. 2013; 18 (24315368): 816-83010.1016/j.cmet.2013.11.001Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 7Kratz M. Coats B.R. Hisert K.B. Hagman D. Mutskov V. Peris E. Schoenfelt K.Q. Kuzma J.N. Larson I. Billing P.S. Landerholm R.W. Crouthamel M. Gozal D. Hwang S. Singh P.K. et al.Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.Cell Metab. 2014; 20 (25242226): 614-62510.1016/j.cmet.2014.08.010Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). This “metabolic activation” of macrophages was also linked to functional changes, such as the release of inflammatory cytokines (10Boutens L. Hooiveld G.J. Dhingra S. Cramer R.A. Netea M.G. Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.Diabetologia. 2018; 61 (29333574): 942-95310.1007/s00125-017-4526-6Crossref PubMed Scopus (70) Google Scholar). It is clear that modifications in metabolic signatures are crucial for appropriate immune cell functioning, yet might also drive immune cell dysfunction (11O'Neill L.A.J. Kishton R.J. Rathmell J. A guide to immunometabolism for immunologists.Nat. Rev. Immunol. 2016; 16 (27396447): 553-56510.1038/nri.2016.70Crossref PubMed Scopus (949) Google Scholar). Hence, specific metabolic reprogramming of adipose tissue macrophages driven by the lipid-enriched adipose tissue microenvironment during obesity might contribute to increased adipose tissue inflammation. Uncoupling protein 2 (UCP2) is a mitochondrial carrier protein belonging to the SLC25 family of transporters (12Bouillaud F. Alves-Guerra M.-C. Ricquier D. UCPs, at the interface between bioenergetics and metabolism.Biochim. Biophys. Acta. 2016; 1863 (27091404): 2443-245610.1016/j.bbamcr.2016.04.013Crossref PubMed Scopus (61) Google Scholar). Although UCP2 mRNA is widely expressed throughout different tissues in mice, UCP2 protein can only be detected in spleen, lung, stomach, adipose and isolated immune including macrophages Alves-Guerra E. S. Ricquier D. F. B. Uncoupling protein in vivo induction oxidative and for Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.-C. S. J. A. F. Ricquier D. B. the in vivo of the mitochondrial protein 2 in immune and cells during Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, G. The of UCP2 in and PubMed Scopus Google Scholar). the clear between mRNA and protein F. of UCP2 by the PubMed Scopus Google Scholar). the of UCP2 protein in immune tissues such as spleen, lung, and adipose tissue be to the of immune UCP2 a to its family protein known for although activity to UCP2 is not (12Bouillaud F. Alves-Guerra M.-C. Ricquier D. UCPs, at the interface between bioenergetics and metabolism.Biochim. Biophys. Acta. 2016; 1863 (27091404): 2443-245610.1016/j.bbamcr.2016.04.013Crossref PubMed Scopus (61) Google Scholar, F. not a a and Biophys. Acta. PubMed Scopus Google Scholar, E. M. Alves-Guerra Ricquier D. M. F. for a or activity of the protein 2 in or Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, N. M. P. of UCP2 in both oxidative and Biol. PubMed Scopus Google Scholar). in with its in immune UCP2 to an important role in immune with UCP2 knockout mice increased after by an in pro-inflammatory cytokines D. S. B. E. Alves-Guerra M.-C. M. R. F. D. S. Ricquier D. of the in mice a role in and PubMed Scopus Google Scholar, S. Ricquier D. The protein 2 the in PubMed Scopus Google Scholar). UCP2 has been to metabolic the of fatty in different cell in P. V. F. A. Ricquier D. Alves-Guerra by UCP2 cell and Res. 2014; PubMed Scopus Google Scholar, J. F. Ricquier D. B. Uncoupling by fatty acid and J. 2008; PubMed Scopus Google and in cells in vivo E. P. V. F. R. Ricquier D. S. Alves-Guerra UCP2 deficiency increases by lipid and for Full Text Full Text PDF PubMed Scopus Google Scholar). UCP2 regulates metabolism by in the of of the A. G. F. A. D. R. L. Ricquier D. E. P. F. F. G. UCP2 of and 2014; PubMed Scopus Google Scholar). In to its metabolic in UCP2 were found to be related to obesity and type 2 diabetes S. P. Uncoupling protein 2 are associated with PubMed Scopus Google Scholar, S. G. F. S. G. J. F. of the UCP2 are associated with and of obesity in J. Clin. Invest. PubMed Scopus Google Scholar, E. M. and in the in PubMed Scopus Google Scholar, L. J. M. S. P. S. J. M. M. in the with obesity and The PubMed Scopus Google Scholar, G. J.M. S. D. J. The UCP2 insulin resistance and is associated with A of obesity and related metabolic J. 2013; Scopus Google Scholar, V. P. D. M. M. L. of type 2 2005; 2 PubMed Scopus Google Scholar, B. F. G. E. F. A in the of UCP2 is associated with decreased of obesity in PubMed Scopus Google Scholar). of its in both immune cell functioning and metabolism of fatty UCP2 an in the reprogramming and activation of macrophages in the context of obesity-induced adipose tissue inflammation and insulin resistance. To investigate UCP2 a role in activation of adipose tissue macrophages, we to the role of UCP2 in macrophages during inflammatory we the of the of UCP2 in macrophages on the development of obesity and its including adipose tissue and insulin resistance. results that UCP2 deficiency drives a distinct in glycolytic and oxidative metabolism in Furthermore, specific Ucp2 deletion pro-inflammatory activation in macrophages not the development of obesity-induced adipose tissue inflammation and insulin resistance. compared the of UCP2 in adipose tissue macrophage isolated from mice a high-fat a (10Boutens L. Hooiveld G.J. Dhingra S. Cramer R.A. Netea M.G. Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.Diabetologia. 2018; 61 (29333574): 942-95310.1007/s00125-017-4526-6Crossref PubMed Scopus (70) Google macrophages with obese adipose and human adipose tissue macrophages isolated from obese obese E. N. I. J. S. J. S. M. inflammation in human adipose to obesity and type 2 2014; PubMed Scopus Google and In Ucp2 mRNA was Furthermore, after to 16 of in mice, Ucp2 was increased in the adipose tissue with the of immune cells into the adipose increased Ucp2 in the adipose tissue of mice is to the including and not to To be to the role of UCP2 in macrophage metabolism and activation in we mice with a myeloid-specific deletion of the to the in Ucp2ΔLysM mice and their floxed The myeloid-specific deletion of UCP2 significantly protein of UCP2 in from Ucp2ΔLysM mice compared with Ucp2fl/fl mice and in a toward decreased Ucp2 mRNA in tissues such as adipose spleen, and To the of UCP2 on we glycolysis and glycolytic were significantly increased in Ucp2ΔLysM Ucp2fl/fl macrophages, both during and during inflammation. Furthermore, mRNA of the glycolytic was increased in Ucp2ΔLysM macrophages after as was the of A and and were significantly increased in Ucp2ΔLysM macrophages compared with Ucp2fl/fl cells during and only this after inflammation. Strikingly, fatty acid loading abolished differences in and glycolysis and and and between Ucp2ΔLysM and Ucp2fl/fl macrophages, in to differences in Hence, UCP2 deficiency increases in glycolysis and low-grade adipose tissue inflammation is linked to inflammatory activation of macrophages in adipose tissue with an important of and receptor activation in metabolic inflammation Toll-like inflammation to Endocrinol. Metab. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). To the role of UCP2 in macrophage we the inflammatory response of Ucp2ΔLysM and Ucp2fl/fl macrophages toward receptor and receptor lipopolysaccharide on both a and a functional and for or with or significantly increased the mRNA and protein secretion of Although differences were the pro-inflammatory response was attenuated in Ucp2ΔLysM Ucp2fl/fl macrophages with by after and for both was not different the was in for both was up-regulated in Ucp2ΔLysM compared with Ucp2fl/fl macrophages, was up-regulated after stimulation protein macrophage-specific deficiency of UCP2 decreased the secretion of inflammatory cytokines and TNFα secretion of UCP2 secretion toward a pro-inflammatory phenotype in of TNFα and in Ucp2fl/fl and Ucp2ΔLysM with or for or are as was to test UCP2 in macrophages adipose tissue inflammation and insulin resistance in an in vivo of high-fat Ucp2ΔLysM and their Ucp2fl/fl were rendered obese and insulin resistant by a high-fat for 16 a as differences between the two were found in or adipose tissue and and of fatty and not show differences between Ucp2ΔLysM and Ucp2fl/fl mice and we isolated adipose tissue macrophages from the Ucp2ΔLysM and Ucp2fl/fl mice a high-fat To these to macrophages that not in a we isolated macrophages from the of these mice and the release of inflammatory cytokines of both of macrophages or an inflammatory In the Ucp2ΔLysM adipose tissue macrophages, no was found in a was found in the of TNFα and and a for after stimulation. In both and TNFα in macrophages isolated from Ucp2ΔLysM Ucp2fl/fl mice after ex vivo stimulation and we inflammation of adipose of the from adipose tissue of obese Ucp2ΔLysM and Ucp2fl/fl mice that was no in or pro-inflammatory macrophage between the two mRNA of macrophage and not significantly mRNA of cytokines in the inflammatory response of adipose tissue and was not found to be significantly between the as was the release of and The of for macrophage not between obese adipose tissue from Ucp2ΔLysM their Ucp2fl/fl and no differences were found in the mRNA of inflammatory in the differences in a we found no differences in insulin A and or and in Ucp2ΔLysM and Ucp2fl/fl Furthermore, of both insulin and not significantly between the two after or high-fat and deletion in macrophages not insulin or insulin test and and test and of Ucp2fl/fl and Ucp2ΔLysM mice an for 16 and insulin and in of Ucp2fl/fl and Ucp2ΔLysM mice or for 16 as the This is the the function of UCP2 in macrophages during low-grade adipose tissue inflammation in the context of obesity and type 2 diabetes. Here, we demonstrate that of UCP2 to an of both glycolytic and oxidative metabolism in macrophages, is after an of Furthermore, the macrophage response to adipose tissue inflammation or The of UCP2 protein is not linked to mRNA of of UCP2 F. of UCP2 by the PubMed Scopus Google Scholar). In this we a macrophage-specific deletion of UCP2 that was by a UCP2 Alves-Guerra E. S. Ricquier D. F. B. Uncoupling protein in vivo induction oxidative and for Biol. Chem. Full Text Full Text PDF PubMed Scopus Google to UCP2 the induction of The results of the role that was to were to show that of UCP2 to of the pro-inflammatory response of macrophages toward and in Ucp2ΔLysM adipose tissue macrophages isolated from obese adipose tissue an response to ex vivo, with decreased TNFα and in of Ucp2 was to into of mice in D. S. B. E. Alves-Guerra M.-C. M. R. F. D. S. Ricquier D. of the in mice a role in and PubMed Scopus Google Scholar, S. Ricquier D. The protein 2 the in PubMed Scopus Google Scholar). these mice, macrophage-specific Furthermore, the of inflammation by Ucp2 knockout is to increased although the induction of in cells is not or J. F. Ricquier D. B. Uncoupling by fatty acid and J. 2008; PubMed Scopus Google Scholar). macrophage-specific to results related to induction Wang J. D.A. Uncoupling lipid metabolism from inflammation through fatty acid of Biol. PubMed Scopus Google Scholar, Uncoupling protein mitochondrial activity PubMed Scopus Google leading to results related to the of UCP2 in inflammatory responses in A showed that of mice in a of was to a decreased inflammatory phenotype S. M.-A. M. M. J. fatty acid promotes activation during Clin. Invest. PubMed Scopus Google Scholar). In their and S. M.-A. M. M. J. fatty acid promotes activation during Clin. Invest. PubMed Scopus Google that macrophage-specific of UCP2 to activation through of fatty acid in inflammatory with these results the of UCP2 in metabolic signatures and inflammatory in macrophages are to to inflammatory and demonstrate an attenuated inflammatory UCP2 was as a protein that can metabolism by oxidative P. V. F. A. Ricquier D. Alves-Guerra by UCP2 cell and Res. 2014; PubMed Scopus Google Scholar, J. F. Ricquier D. B. Uncoupling by fatty acid and J. 2008; PubMed Scopus Google Scholar, A. G. F. A. D. R. L. Ricquier D. E. P. F. F. G. UCP2 of and 2014; PubMed Scopus Google Scholar, Wang J. D.A. Uncoupling lipid metabolism from inflammation through fatty acid of Biol. PubMed Scopus Google Scholar). of UCP2 been found to lead to metabolic in E. P. V. F. R. Ricquier D. S. Alves-Guerra UCP2 deficiency increases by lipid and for Full Text Full Text PDF PubMed Scopus Google and to metabolic in macrophages of D. B. Ricquier D. F. in macrophages of Ucp2 Biophys. Acta. 2008; PubMed Scopus Google Scholar). in macrophages we an increased glycolytic both in cells as well as after Although increased glycolytic is as a for inflammatory macrophages L.A.J. cell and macrophage 2016; PubMed Scopus Google Ucp2ΔLysM macrophages an attenuated pro-inflammatory response after In these macrophages, metabolic metabolic from inflammatory by the to inflammatory after to fatty for macrophages in adipose differences in glycolytic and oxidative metabolism between Ucp2ΔLysM and Ucp2fl/fl macrophages This is in with from et Wang J. D.A. Uncoupling lipid metabolism from inflammation through fatty acid of Biol. PubMed Scopus Google found no in fatty between and macrophages after lipid The of metabolic differences after fatty acid loading that changes in immune cell metabolism are from the or activation of UCP2 during the of although UCP2 an important in metabolic during or inflammatory is not a crucial in macrophage metabolism in the of of after of the cell is to the and on to with the increased of fatty these the receptor the of in macrophages M. J.M. N. M. R.M. and The the and the 2013; PubMed Scopus Google to Ucp2 S. Ricquier D. S. of the is for Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). on in we that UCP2 deficiency in adipose tissue macrophages might inflammatory leading to a in adipose tissue inflammation in obese Ucp2ΔLysM The inflammatory response of Ucp2ΔLysM Ucp2fl/fl adipose tissue macrophages after ex vivo stimulation with is in with no of decreased adipose tissue inflammation was found in may as to of UCP2 in macrophages not on inflammation of the adipose tissue or Although the response of adipose tissue macrophages toward a in inflammatory phenotype between Ucp2ΔLysM and Ucp2fl/fl macrophages, this phenotype only after ex vivo stimulation with UCP2 to be a of metabolism E. P. V. F. R. Ricquier D. S. Alves-Guerra UCP2 deficiency increases by lipid and for Full Text Full Text PDF PubMed Scopus Google is for metabolic processes in the of (12Bouillaud F. Alves-Guerra M.-C. Ricquier D. UCPs, at the interface between bioenergetics and metabolism.Biochim. Biophys. Acta. 2016; 1863 (27091404): 2443-245610.1016/j.bbamcr.2016.04.013Crossref PubMed Scopus (61) Google are to the of UCP2 Hence, the inflammatory in obese adipose tissue that lead to metabolic activation of adipose tissue macrophages and PubMed Scopus Google might not be to lead to a phenotype to activation by to as in the of of to an metabolic in both Ucp2ΔLysM and Ucp2fl/fl macrophages, to the in vivo in the adipose to the of differences in adipose tissue inflammation between Ucp2ΔLysM and Ucp2fl/fl in this functional UCP2 is and UCP2 protein is not linked to mRNA studies are Furthermore, the Ucp2ΔLysM is myeloid-specific in the differences in the in vivo phenotype been to deletion of UCP2 in cells in including the S. S. UCP2 inflammation and obesity by high-fat Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). only mice were for the in vivo leading to In UCP2 has a role in both metabolism and inflammatory response in UCP2 is in macrophages, both glycolytic and oxidative metabolism are although metabolic differences after fatty acid Furthermore, UCP2 deficiency in macrophages the pro-inflammatory response toward also in adipose tissue macrophages, not adipose tissue inflammation after high-fat feeding. although UCP2 macrophage metabolism and inflammatory its is not to activation during lipid or the Ucp2ΔLysM mice and their floxed were mice were from The and at with mice were with mice to mice with a specific deletion of UCP2 in the cell were in and specific conditions. to and were in with the for To induce obesity and insulin resistance, Ucp2ΔLysM mice and their floxed were on a high-fat for 16 To the on were of mice a high-fat may on compared with mice a in responses might lead to an 2 or To the we a analysis of with a of and a of leading to an of mice To for the of or of mice during the mice were mice were to a high-fat or a for 16 and with and were the of the mice were with and was in mice were by after tissues were and in or for from were at were by the of The was to during and insulin were after or by of or of insulin were for to the and was at and after of or insulin by was and a the in was for at and at was and at of insulin and fatty and the of adipose tissue of the was and on in with and an of was in for in with and after was for or as of was isolated by for in with and was pooled for mice of the after were and were with the cells were for cells were for were isolated by the with and were in in with and for in the or of to cells were with and were on a and results were analysis and were in and in were with and to were with were or to was for controls. macrophages were from the mice by the with and was to macrophages were in for in with and with or the of to to Ucp2ΔLysM and their Ucp2fl/fl were by were was and in with and of were and as and were and and to in at for was at a of 200 or a of and was in a of and in a of was as for fatty acid was in a of was in a of both were in cells were with tissue were in and after an was with of adipose tissue isolated from mice a or for were with adipose tissue for To in the was were in in a of and with or fatty cells were and for an in at in a the The was to a of and was with 2 for glycolytic or 2 and for mitochondrial the of after glycolysis was after glycolytic was and the of after was and A was were at with and were at and the were cells and was isolated was isolated with the the The was to to The was to a and were to for human and The for were (10Boutens L. Hooiveld G.J. Dhingra S. Cramer R.A. Netea M.G. Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.Diabetologia. 2018; 61 (29333574): 942-95310.1007/s00125-017-4526-6Crossref PubMed Scopus (70) Google Scholar, E. N. I. J. S. J. S. M. inflammation in human adipose to obesity and type 2 2014; PubMed Scopus Google Scholar). protein were by on a and a cell from in and at with and for with appropriate at were with the and were with the The for UCP2 were Alves-Guerra E. S. Ricquier D. F. B. Uncoupling protein in vivo induction oxidative and for Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Full are in and were in cell or with for to To the the of well was for adipose tissue macrophages and macrophages the was for were from cell acid to with were of by and of into by was as a are as as in the were the test or analysis of by and or and were both found A of was are the that were were (10Boutens L. Hooiveld G.J. Dhingra S. Cramer R.A. Netea M.G. Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.Diabetologia. 2018; 61 (29333574): 942-95310.1007/s00125-017-4526-6Crossref PubMed Scopus (70) Google Scholar, E. N. I. J. S. J. S. M. inflammation in human adipose to obesity and type 2 2014; PubMed Scopus Google Scholar). van and Hijmans for with adipose tissue macrophage adipose tissue high-fat macrophages lipopolysaccharide of acid and acid

Topics & Concepts