Abstract
Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor alpha and interleukin-6 (IL-6). Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages toward a more classical and pro-inflammatory phenotype. Here, we explore the effect of peroxisome proliferator-activated receptor gamma activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass, and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides, and changed adipose tissue morphology toward smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down-regulated, whereas markers characteristic for alternatively activated macrophages (arginase 1, IL-10) were up-regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in peroxisome proliferator-activated receptor gamma-dependent expansion and remodeling of adipose tissue.
Highlights
Increase morbidity risk, which are collected in the metabolic syndrome and include hypertension, dyslipidemia, and insulin resistance [2]
Obesity is associated with the infiltration of macrophages into adipose tissue, which may contribute to an elevated inflammatory status by secreting a variety of pro-inflammatory mediators, including tumor necrosis factor ␣ and IL-6
Previous studies suggest that PPAR␥ may counteract obesityinduced inflammation in adipose tissue via several mechanisms [26] including down-regulation of chemo-attractant and proinflammatory genes [5], apoptosis of adipose-resident macrophages [19], and changing the morphology of adipose tissue toward smaller adipocytes [27]
Summary
Increase morbidity risk, which are collected in the metabolic syndrome and include hypertension, dyslipidemia, and insulin resistance [2]. The secretion of pro-inflammatory mediators such as tumor necrosis factor ␣ and IL-63 from adipose tissue is increased, leading to disruption of normal homeostatic control of metabolism either locally or systemically (4 – 6). Activated macrophages express high levels of pro-inflammatory mediators including tumor necrosis factor ␣, which may contribute to insulin resistance. Alternatively activated macrophages are considered anti-inflammatory by expressing genes such as IL-10, IL-1 receptor antagonist, and arginase I [9]. Target genes of PPAR␥ identified so far include fatty acid-binding protein 4, GLUT4, glycogen synthase 2, glycerol-3-phosphate dehydrogenase, lipoprotein lipase, glycerol kinase, and aquaporin 7 [12, 13]
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