A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells.

Normal repair of skeletal muscle requires local expansion of a special population of Foxp3(+)CD4(+) regulatory T (Treg) cells. Such cells failed to accumulate in acutely injured muscle of old mice, known to undergo ineffectual repair. This defect reflected reduced recruitment of Treg cells to injured muscle, as well as less proliferation and retention therein. Interleukin-33 (IL-33) regulated muscle Treg cell homeostasis in young mice, and its administration to old mice ameliorated their deficits in Treg cell accumulation and muscle regeneration. The major IL-33-expressing cells in skeletal muscle displayed a constellation of markers diagnostic of fibro/adipogenic progenitor cells and were often associated with neural structures, including nerve fibers, nerve bundles, and muscle spindles, which are stretch-sensitive mechanoreceptors important for proprioception. IL-33(+) cells were more frequent after muscle injury and were reduced in old mice. IL-33 is well situated to relay signals between the nervous and immune systems within the muscle context.

Effects of BMP7 produced by group 2 innate lymphoid cells on adipogenesis.

Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

Platelet-rich plasma promotes bone formation, restrains adipogenesis and accelerates vascularization to relieve steroids-induced osteonecrosis of the femoral head.

Steroid-associated necrosis of the femoral head (SANFH) is one of the most common and refractory chronic diseases with increasing incidence. The typical pathological changes of SANFH include decreased osteogenic differentiation, enhanced intramedullary adipocytes deposition and impaired osseous circulation. In this study, we investigated the effects and potential mechanisms of Platelet-rich plasma (PRP) on SANFH. Sixty Sprague-Dawley rats were randomly divided into the control, PRP donor, model, and PRP groups. Compared to the model group, PRP treatment significantly increased the hemorheological indexes and serum levels of bone gla-protein (BGP) and vascular endothelial growth factor (VEGF), while decreased the levels of triglyceride (TG) and total cholesterol (TC). Meanwhile, Micro-CT and histopathological stain (Hematoxylin-eosin and Alcian blue-hematoxylin/orange G staining) were performed on the femoral head for morphological and histopathological evaluation, indicating that bone trabecular microstructure and bone mineral density (BMD) were significantly improved after PRP treatment. Immunohistochemical analysis revealed that PRP remarkably up-regulated the expression of osteogenic markers including ß-catenin and alkaline phosphatase (ALP), angiogenic markers containing VEGF and platelet endothelial cell adhesion molecule-1 (CD31), while down-regulated adipogenic markers involving fatty acid-binding protein (FABP-4), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in SANFH rat models. In summary, for the first time, PRP was demonstrated to prevent the development of SANFH through stimulating bone formation and vascularization as well as retarding adipogenesis.

The Effects of Sclerostin on the Immune System.

PURPOSE OF REVIEW: We reviewed recent progress on the role of sclerostin (SOST) and its effects on the immune system in order to summarize the current state of knowledge in osteoimmunology, in regard to hematopoiesis, lymphopoiesis, and inflammation. RECENT FINDINGS: Changes in sclerostin levels affect distinct niches within the bone marrow that support hematopoietic stem cells and B cell development. Sclerostin's regulation of adipogenesis could also be important for immune cell maintenance with age. Surprisingly, B cell development in the bone marrow is influenced by Sost produced by mesenchymal stem cells and osteoblasts, but not by osteocytes. Additionally, extramedullary hematopoiesis in the spleen and increased pro-inflammatory cytokine levels in the bone marrow are observed in global Sost-/- mice. In addition to changes in bone marrow density, sclerostin depletion affects B lymphopoiesis and myelopoiesis, as well as other changes within the bone marrow cavity that could affect hematopoiesis. It is therefore important to monitor for hematopoietic changes in patients receiving sclerostin-depleting therapies.

Greater potency of adipocytes compared with preadipocytes under lipopolysaccharide exposure in grass carp Ctenopharyngodon idella.

Excessive body fat is a chronic inflammatory disorder. In this process, white adipose tissue (WAT) performs immune activities because of the dysregulated expression of adipokines. Excessive fat is accumulated in farmed fish, thereby threatening fish health. Studies have shown that adipose tissue is also an active immune organ in fish, capable of participating in and influencing immune responses. Adipocytes are the main cellular component of adipose tissue; however, little is known about the relationship between adipocyte and inflammation in fish. In this study, we analyzed transcriptome changes during adipogenesis in the primary culture of grass carp adipocytes using bioinformatics. The results showed that inflammatory signaling pathway may be activated during grass carp adipocyte differentiation, such as NFκB signaling pathway, Toll-like receptor signaling pathway and Adipocytokine signaling pathway, indicating that grass carp adipocytes have immune activities. Exposure to LPS induced expression of adipokines genes in adipocytes and preadipocytes, including NF-kB, IL-6, MCP-1 and TNFα, suggesting that preadipocytes and adipocytes both have immune response and the immune activity is conserved in vertebrates white adipocytes. Further study found that these immune marker genes were higher expressed in adipocytes compared with preadipocytes in LPS-induced inflammation. In summary, adipocyte should be considered as an active immune site in fish. Adipocytes have greater potency compared with preadipocytes in LPS-induced inflammation. This study indicated that adipocytes and preadipocytes may have different contribution in inflammation.

Adipose tissue complement factor B promotes adipocyte maturation.

OBJECTIVES: It is well-known that the complement system plays an essential role in host immunity. Observational studies have indicated that complement system-related molecules such as complement factor B (CfB) and other components are correlated with obesity and/or insulin resistance parameters. In this study, we investigated the role of adipocyte-derived CfB in adipose tissue metabolism. METHODS: We investigated the expression level of complement system-related genes in adipocytes. To understand the role of CfB in adipocyte, we performed Cfb overexpression in 3T3-L1 preadipocytes and generated adipocyte-specific Cfb transgenic mice. RESULTS: Cfb expression was markedly enhanced in 3T3-L1 adipocytes co-cultured with macrophages following endotoxin stimulation. In Cfb-overexpressing cells, the expression of adipocyte differentiation/maturation-related genes encoding peroxisome proliferator-activated receptor γ (Pparγ), adipocyte Protein 2 and perilipin was significantly enhanced. Cfb transgenic mice showed a marked increase in the expression of genes encoding Pparγ, perilipin, sterol regulatory element-binding protein 1 c, and Cd36 in the subcutaneous adipose tissue. CONCLUSIONS: CfB plays a crucial role in late-phase of adipocyte differentiation and subsequent lipid droplet formation.

Sortilin derived propeptide regulation during adipocyte differentiation and inflammation.

In this work, we aimed to correlate the expression of sortilin with the production of sortilin-derived propeptide (PE) during adipocyte differentiation, insulin resistance and inflammation. We also investigated the effect of spadin, a shorter analogue of PE that exerts a potent antidepressant in mice, on adipocyte functions. During adipogenesis, insulin resistance and inflammation, we measured the mRNA and protein expression of sortilin, by quantitative PCR and Western-blot, and quantified the expression of PE by a specific dosing method. We observed that the production of PE was correlated with the sortilin expression during adipogenesis. Immunostaining experiments allowed to visualize the co-localization of sortilin, PE and VAMP2 in 3T3-L1 adipocytes. TNFα treatment induced insulin resistance and a decrease of sortilin expression (mRNA and protein), correlated with the decrease of the PE production. By contrast, treatment with dexamethasone, which also induced insulin resistance, was without effect on sortilin expression and PE production. As a putative bioactive peptide, we have evaluated its autocrine effect by the use of spadin on 3T3-L1 adipocytes by performing glucose uptake and signalling experiments. Any effect was measured on adipocytes indicating that the use of spadin as an antidepressant would have no side effects on adipocyte physiology.

NLRP3 inflammasome activation in mesenchymal stem cells inhibits osteogenic differentiation and enhances adipogenic differentiation.

Osteoporosis is one of the most common skeletal disease featured by osteopenia and adipose accumulation in bone tissue. NLRP3 inflammasome activation is an essential player in aging-related chronic diseases like osteoporosis, particularly due to the causal caspase-1 activation and its correlation to adipose accumulation in bone tissue. Moreover, the expression of anti-aging/senescence SIRT1 was reported to decline along with aging. As the major cellular contributor of bone formation, mesenchymal stem cells (MSCs) are multipotent stem cells processing mutually exclusive differentiatability toward osteocytes or adipocytes. Therefore, we hypothesized that NLRP3 inflammasome activation promotes adipogenesis and repress osteogenesis in MSCs via inhibiting SIRT1 expression. We activated NLRP3 inflammasome in human MSCs via lipopolysaccharide and palmitic acid (LPS/PA) treatment for self-renewal maintenance, adipogenic differentiation or osteogenic differentiation. LPS/PA treatment significantly increased NLRP3 expression, decreased SIRT1 expression and promoted caspase-1 activity in MSCs. LPS/PA treatment also boosted adipogenesis of MSCs and suppressed osteogenesis. Moreover, inhibition of caspase-1 activity repressed adipogenic differentiation and partially improved osteogenic differentiation of MSCs with LPS/PA treatment. Our study demonstrated the pivotal roles of NLRP3 inflammasome and downstream mediator caspase-1 for the progress of osteo-differentiation MSCs, and offered novel therapeutic target of treatment for osteoporosis.

The role of innate immunity in the regulation of brown and beige adipogenesis.

The adipose tissue (AT) is multifunctional, acting as an endocrine tissue and participating in the regulation of the organism's homeostasis. Metabolic, endocrine and inflammatory mechanisms are tightly intertwined within the AT, regulating its function. Disruption of the equilibrium among these mechanisms leads to pathologies, the most common being obesity-related insulin resistance. Two types of AT exist, the white and the brown AT. Traditionally the white AT (WAT) was thought to store energy in the form of lipids, while the brown AT (BAT) was known to mediate heat generation. Recently, the 'brite' or 'beige' AT was identified, which is localized predominantly in subcutaneous WAT, but shares functional features with the BAT and is capable of heat production. The major stimulus triggering beige and brown adipogenesis is cold exposure and catecholamine signalling. However, several further signals and mechanisms exist, which can orchestrate and fine-tune beige and brown AT function. Immune cells and inflammation have emerged as regulators of beige and brown AT function. The present review will focus on the recently identified crosstalk between innate immunity and the regulation of beige and brown adipogenesis.

CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein.

Obesity-induced adipose tissue (AT) dysfunction results in a chronic low-grade inflammation that predisposes to the development of insulin resistance and type 2 diabetes. During the development of obesity, the AT-resident immune cell profile alters to create a pro-inflammatory state. Very recently, CD1d-restricted invariant (i) natural killer T (NKT) cells, a unique subset of lymphocytes that are reactive to so called lipid antigens, were implicated in AT homeostasis. Interestingly, recent data also suggest that human and mouse adipocytes can present such lipid antigens to iNKT cells in a CD1d-dependent fashion, but little is known about the lipid antigen presentation machinery in adipocytes. Here we show that CD1d, as well as the lipid antigen loading machinery genes pro-saposin (Psap), Niemann Pick type C2 (Npc2), α-galactosidase (Gla), are up-regulated in early adipogenesis, and are transcriptionally controlled by CCAAT/enhancer-binding protein (C/EBP)-ß and -δ. Moreover, adipocyte-induced Th1 and Th2 cytokine release by iNKT cells also occurred in the absence of exogenous ligands, suggesting the display of endogenous lipid antigen-D1d complexes by 3T3-L1 adipocytes. Furthermore, we identified microsomal triglyceride transfer protein, which we show is also under the transcriptional regulation of C/EBPß and -δ, as a novel player in the presentation of endogenous lipid antigens by adipocytes. Overall, our findings indicate that adipocytes can function as non-professional lipid antigen presenting cells, which may present an important aspect of adipocyte-immune cell communication in the regulation of whole body energy metabolism and immune homeostasis.

Adipose tissue macrophages as potential targets for obesity and metabolic diseases.

Macrophage infiltration into adipose tissue is a key pathological factor inducing adipose tissue dysfunction and contributing to obesity-induced inflammation and metabolic disorders. In this review, we aim to present the most recent research on macrophage heterogeneity in adipose tissue, with a focus on the molecular targets applied to macrophages as potential therapeutics for metabolic diseases. We begin by discussing the recruitment of macrophages and their roles in adipose tissue. While resident adipose tissue macrophages display an anti-inflammatory phenotype and promote the development of metabolically favorable beige adipose tissue, an increase in pro-inflammatory macrophages in adipose tissue has negative effects on adipose tissue function, including inhibition of adipogenesis, promotion of inflammation, insulin resistance, and fibrosis. Then, we presented the identities of the newly discovered adipose tissue macrophage subtypes (e.g. metabolically activated macrophages, CD9+ macrophages, lipid-associated macrophages, DARC+ macrophages, and MFehi macrophages), the majority of which are located in crown-like structures within adipose tissue during obesity. Finally, we discussed macrophage-targeting strategies to ameliorate obesity-related inflammation and metabolic abnormalities, with a focus on transcriptional factors such as PPARγ, KLF4, NFATc3, and HoxA5, which promote macrophage anti-inflammatory M2 polarization, as well as TLR4/NF-κB-mediated inflammatory pathways that activate pro-inflammatory M1 macrophages. In addition, a number of intracellular metabolic pathways closely associated with glucose metabolism, oxidative stress, nutrient sensing, and circadian clock regulation were examined. Understanding the complexities of macrophage plasticity and functionality may open up new avenues for the development of macrophage-based treatments for obesity and other metabolic diseases.

ATF3 inhibits adipocyte differentiation of 3T3-L1 cells.

ATF3 is a stress-adaptive gene that regulates proliferation or apoptosis under stress conditions. However, the role of ATF3 is unknown in adipocyte cells. Therefore, in this study, we investigated the functional role of ATF3 in adipocytes. Both lentivirus-mediated overexpression of ATF3 and stably-overexpressed ATF3 inhibited adipocyte differentiation in 3T3-L1 cells, as revealed by decreased lipid staining with oil red staining and reduction in adipogenic genes. Thapsigargin treatment and overexpression of ATF3 decreased C/EBPα transcript and repressed the activity of the 3.6-kb mouse C/EBPα promoter, demonstrating that ATF3 downregulates C/EBPα expression. Transfection studies using mutant constructs containing 5'-deletions in the C/EBPα promoter revealed that a putative ATF/CRE element, GGATGTCA, is located between -1921 and -1914. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 directly binds to mouse C/EBPα promoter spanning from -1928 to -1907. Both chemical hypoxia-mimetics or physical hypoxia led to reduce the C/EBPα mRNA and repress the promoter activity of the C/EBPα gene, whereas increase ATF3 mRNA, suggesting that ATF3 may contribute to the inhibition of adipocyte differentiation in hypoxia through downregulation of C/EBPα expression. Collectively, these results demonstrate that ATF3 represses the C/EBPα gene, resulting in inhibition of adipocyte differentiation, and thus plays a role in hypoxia-mediated inhibition of adipocyte differentiation.

IL-17 regulates adipogenesis, glucose homeostasis, and obesity.

Inflammatory mediators have the potential to impact a surprising range of diseases, including obesity and its associated metabolic syndrome. In this paper, we show that the proinflammatory cytokine IL-17 inhibits adipogenesis, moderates adipose tissue (AT) accumulation, and regulates glucose metabolism in mice. IL-17 deficiency enhances diet-induced obesity in mice and accelerates AT accumulation even in mice fed a low-fat diet. In addition to potential systemic effects, IL-17 is expressed locally in AT by leukocytes, predominantly by γδ T cells. IL-17 suppresses adipocyte differentiation from mouse-derived 3T3-L1 preadipocytes in vitro, and inhibits expression of genes encoding proadipogenic transcription factors, adipokines, and molecules involved in lipid and glucose metabolism. IL-17 also acts on differentiated adipocytes, impairing glucose uptake, and young IL-17-deficient mice show enhanced glucose tolerance and insulin sensitivity. Our findings implicate IL-17 as a negative regulator of adipogenesis and glucose metabolism in mice, and show that it delays the development of obesity.

Crosstalk between EET and HO-1 downregulates Bach1 and adipogenic marker expression in mesenchymal stem cell derived adipocytes.

Epoxygenase activity and synthesis of epoxyeicosatrienoic acids (EETs) have emerged as important modulators of obesity and diabetes. We examined the effect of the EET-agonist 12-(3-hexylureido)dodec-8(2) enoic acid on mesenchymal stem cell (MSC) derived adipocytes proliferation and differentiation. MSCs expressed substantial levels of EETs and inhibition of soluble epoxide hydrolase (sEH) increased the level of EETs and decreased adipogenesis. EET agonist treatment increased HO-1 expression by inhibiting a negative regulator of HO-1 expression, Bach-1. EET treatment also increased ßcatenin and pACC levels while decreasing PPARγ C/EBPα and fatty acid synthase levels. These changes were manifested by a decrease in the number of large inflammatory adipocytes, TNFα, IFNγ and IL-1α, but an increase in small adipocytes and in adiponectin levels. In summary, EET agonist treatment inhibits adipogenesis and decreases the levels of inflammatory cytokines suggesting the potential action of EETs as intracellular lipid signaling modulators of adipogenesis and adiponectin.

Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution.

Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor gamma (PPARgamma), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARgamma in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARgamma-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging.

The Alterations in and the Role of the Th17/Treg Balance in Metabolic Diseases.

Chronic inflammation plays an important role in the development of metabolic diseases. These include obesity, type 2 diabetes mellitus, and metabolic dysfunction-associated fatty liver disease. The proinflammatory environment maintained by the innate immunity, including macrophages and related cytokines, can be influenced by adaptive immunity. The function of T helper 17 (Th17) and regulatory T (Treg) cells in this process has attracted attention. The Th17/Treg balance is regulated by inflammatory cytokines and various metabolic factors, including those associated with cellular energy metabolism. The possible underlying mechanisms include metabolism-related signaling pathways and epigenetic regulation. Several studies conducted on human and animal models have shown marked differences in and the important roles of Th17/Treg in chronic inflammation associated with obesity and metabolic diseases. Moreover, Th17/Treg seems to be a bridge linking the gut microbiota to host metabolic disorders. In this review, we have provided an overview of the alterations in and the functions of the Th17/Treg balance in metabolic diseases and its role in regulating immune response-related glucose and lipid metabolism.

Prolonged Nrf1 overexpression triggers adipocyte inflammation and insulin resistance.

Adipose tissue is currently being recognized as an important endocrine organ, carrying defects in a number of metabolic diseases. Mitochondria play a key role in normal adipose tissue function and mitochondrial alterations can result in pathology, like lipodystrophy or type 2 diabetes. Although Pgc1α is regarded as the main regulator of mitochondrial function, downstream Nrf1 is the key regulator of mitochondrial biogenesis. Nrf1 is also involved in a wide range of other processes, including proliferation, innate immune response, and apoptosis. To determine transcriptional targets of Nrf1, 3T3-L1 preadipocytes were transfected with either pNrf1 or a control vector. Two days post-confluence, 3T3-L1 preadipocytes were allowed to differentiate. At day 8 of differentiation, Nrf1 overexpressing cells had an increased mtDNA copy number and reduced lipid content. This was not associated with an increased ATP production rate per cell. Using global gene expression analysis, we observed that Nrf1 overexpression stimulated cell proliferation, apoptosis, and cytokine expression. In addition, prolonged Nrf1 induced an adipokine expression profile of insulin resistant adipocytes. Nrf1 has a wide range of transcriptional targets, stimulators as well as inhibitors of adipose tissue functioning. Therefore, post-transcriptional regulation of Nrf1, or stimulating specific Nrf1 targets may be a more suitable approach for stimulating mitochondrial biogenesis and treating adipose tissue defects, instead of directly stimulating Nrf1 expression. In addition, our results show that short-term effects can drastically differ from long-term effects.

Adipose tissue inflammation: novel insight into the role of macrophages and lymphocytes.

PURPOSE OF REVIEW: Obesity is associated with low-grade chronic inflammation in adipose tissue. This review presents an update on human and rodent studies analyzing the nature of fat-infiltrating immune cells, the time course of adipose tissue infiltration and underlying mechanisms. RECENT FINDINGS: Intensive studies in rodents have shown that not only cells of the innate immune system traffic into adipose tissue but also various lymphocytes of the adaptive immunity are involved in inflammatory processes in fat. Several studies also provide insight in the order of appearance of macrophages and lymphocytes during the onset of obesity. Adipocytes and preadipocytes are also active players by their secretion of chemotactic adipokines. SUMMARY: This review summarizes strong evidence for a link between the action of innate and adaptive immune systems in adipose tissue in the context of obesity and metabolism in rodents, but more studies in humans are necessary to relate this topic to human physiology. Targeting different immune cells at different stages of obesity may eventually lead to novel therapeutic approaches for the metabolic syndrome.

Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature.

Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear receptor and transcription factor in the steroid superfamily. PPAR-gamma agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-gamma also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-gamma activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-gamma activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-gamma activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor kappaB. This system is likely to be even more prominent in modulating disease in vascular cells. The effects of PPAR-gamma in the vascular cells translate into the beneficial function of this transcription factor in vascular disorders, including hypertension and atherosclerosis. Both human genetic studies and animal studies using transgenic mice have demonstrated the importance of PPAR-gamma in these disorders. However, recent clinical studies have raised significant concerns about the cardiovascular side effects of thiazolidinediones, particularly rosiglitazone. Weighing the potential benefit and harm of PPAR-gamma activation and exploring the functional mechanisms may provide a balanced view on the clinical use of these compounds and new approaches to the future therapeutics of vascular disorders associated with diabetes.