Obesity is characterized by chronic,low-grade inflammation,which is driven by macrophage infiltration of adipose tissue.PPARγ is well established to have an anti-inflammatory function in macrophages,but the mechanism...Obesity is characterized by chronic,low-grade inflammation,which is driven by macrophage infiltration of adipose tissue.PPARγ is well established to have an anti-inflammatory function in macrophages,but the mechanism that regulates its function in these cells remains to be fully elucidated.PPARγundergoes post-translational modifications(PTMs),including acetylation,to mediate ligand responses,including on metabolic functions.Here,we report that PPARγacetylation in macrophages promotes their infiltration into adipose tissue,exacerbating metabolic dysregulation.We generated a mouse line that expresses a macrophage-specific,constitutive acetylation-mimetic form of PPARγ(K293Q^(flox/flox):LysM-cre,mK293Q)to dissect the role of PPARγacetylation in macrophages.Upon highfat diet feeding to stimulate macrophage infiltration into adipose tissue,we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice,including responses to the PPARγagonist Rosiglitazone.Macrophage-specific PPARγK293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue,but not in subcutaneous or brown adipose tissue,leading to decreased energy expenditure,insulin sensitivity,glucose tolerance,and adipose tissue function.Furthermore,mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling.Our study reveals that acetylation is a new layer of PPARγregulation in macrophage activation,and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.展开更多
基金This work was supported by the National Institutes of Health F31DK124926(N.A.),T32DK007328(N.A.),R01DK112943(L.Q.),R01DK128848(L.Q.),R01DK131169(U.B.P.and L.Q.),and P01 HL087123(L.Q.).
文摘Obesity is characterized by chronic,low-grade inflammation,which is driven by macrophage infiltration of adipose tissue.PPARγ is well established to have an anti-inflammatory function in macrophages,but the mechanism that regulates its function in these cells remains to be fully elucidated.PPARγundergoes post-translational modifications(PTMs),including acetylation,to mediate ligand responses,including on metabolic functions.Here,we report that PPARγacetylation in macrophages promotes their infiltration into adipose tissue,exacerbating metabolic dysregulation.We generated a mouse line that expresses a macrophage-specific,constitutive acetylation-mimetic form of PPARγ(K293Q^(flox/flox):LysM-cre,mK293Q)to dissect the role of PPARγacetylation in macrophages.Upon highfat diet feeding to stimulate macrophage infiltration into adipose tissue,we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice,including responses to the PPARγagonist Rosiglitazone.Macrophage-specific PPARγK293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue,but not in subcutaneous or brown adipose tissue,leading to decreased energy expenditure,insulin sensitivity,glucose tolerance,and adipose tissue function.Furthermore,mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling.Our study reveals that acetylation is a new layer of PPARγregulation in macrophage activation,and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.
