Chronic Inflammation In Adipose Tissue Research Articles

Suppressing adipocyte inflammation promotes insulin resistance in mice

ObjectiveObesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. MethodsRIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RIDad and RIDmac mice, respectively). ResultsRIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/β in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1β). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. ConclusionOur novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.

SUN-586 CXCR2 Repression by Glucocorticoids in Adipose Tissue

Obesity-induced type 2 diabetes (T2D) is a significant risk factor of cardiovascular disease (CVD), which affects 28.1 million adults in the United States. Adipose tissue chronic inflammation is one of the main factors that drive obesity-induced insulin resistance (IR) and T2D. Despite several studies that have shown a link between obesity, adipose tissue inflammation, and IR/T2D, the mechanisms underlying this association are not well understood. Synthetic glucocorticoids are widely used for their potent anti-inflammatory actions; however, their use is hampered due to off-target side effects. Glucocorticoids exert profound effects on adipose tissue, including the regulation of adipocyte metabolism and immune functions. However, whether their effects on adipose tissue are positive or negative it is still a controversial topic. Genome-wide microarray data obtained from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice showed that lack of GR leads to a significant increase in the expression of pro-inflammatory genes in white adipose tissue (WAT). Moreover, WAT isolated from adipoGRKO mice demonstrated significant increase in immune cell infiltration, which correlates with our gene expression data. Among the most up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (CXCR2), which is a critical mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of CXCR2 in adipocytes and suggested the contribution of CXCR2 signaling in adipocyte development, its role in obesity-driven adipose tissue inflammation is unknown. This led us to hypothesize that adipocyte specific administration of glucocorticoids can reduce obesity-induced adipocyte inflammation by inhibiting CXCR2 gene transcription and signaling. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of CXCR2 mRNA and protein levels. Correlating with these results, Dex treatment significantly inhibited macrophage migration to adipocytes in a mechanism dependent on GR activation and repression of CXCR2. Furthermore, these results were recapitulated in vivo. Together our findings suggest that local delivery of glucocorticoids to adipose tissue could ameliorate inflammation and reduce the risk of developing IR and T2D.

Macrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice.

Even after successful weight reduction, obese adults tend to quickly regain the lost weight. This raises the question of whether weight loss improves the underlying chronic adipose tissue inflammation characteristic of obesity. In order to improve our understanding of the mechanisms that reshape metabolic organs during weight loss, we investigated the macrophage and T cell function of the liver and adipose tissue on reversing high fat diet (HFD) mice to normal control diet (NCD). Obese mice that were switched to NCD showed an improvement in their metabolic profile that included enhanced glucose and insulin tolerance, decreased cholesterol, triglyceride, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT) levels that were comparable to NCD controls. However, despite weight loss, increased frequencies, but not total numbers, of IL-17+ and IL-22+ CD4+ T cells, IFN-γ+ and TNF+ CD8+ T cells and IL-17+ and IL-22+ CD8+ T cells were observed in the adipose tissue of mice switched from HFD to NCD compared to NCD and even HFD fed mice. Further, in the liver, IFN-γ+ and TNF+ CD8+ T cell, IL-17+ and IL-22+ CD8+ T cell, macrophage frequencies and their expression of antigen presenting molecules were increased. To determine if macrophages are the major determinants of the sustained inflammation observed during weight loss, we depleted macrophages, which significantly reduced IFN-γ+, TNF+, IL-17+, and IL-22+ CD8+ T cell frequencies in the liver and the adipose tissue. In conclusion, we show that although weight loss improves the metabolic profile, there is an active and ongoing CD8+ T cell inflammation in liver and adipose tissue mediated by macrophages.

Role of immunological disorders, endothelial dysfunction and hemostatic disorders in the genesis of arterial hypertension in the metabolic syndrome

Mortality from diseases of the circulatory system is a challenge for the modern health care. Arterial hypertension (AH) mostly contributes to development of cardiovascular complications. It often proceeds against the background of metabolic disorders. Pathogenesis of hypertension is currently being considered a multifactorial disease. Pathogenesis of hypertension certainly has distinct features in presence of metabolic disorders,. Therefore, it is relevant to summarize current literature on the role of immunological disorders, endothelial dysfunction and hemostatic disorders in AH genesis during metabolic syndrome (MS). Most authors agree with existence of several mechanisms that determine relationships between AH and insulin resistance. Development of hypertension in MS patients with is a consequence of immunometabolic processes. Abdominal obesity is an important component of MS. It is associated with chronic inflammation of visceral adipose tissue, its excessive infiltration by immune cells, and increased production of adipokines and cytokines (TNFα, IL-6) with hypertension. AH is associated with a significant increase in T cells, that mediate endothelial dysfunction (ED) and provide a link between hypertension and subsequent atherosclerosis. T lymphocytes trigger a cascade of reactions. IL-17 is the end product of these events It is involved not only in increasing blood pressure, but also contributes to the development of vascular wall stiffness in АН patients. Thus, the relationship between several types of immune cells leads to inflammatory reactions, including those of vascular wall, initiating endothelial dysfunction. Chronic non-specific inflammation in MS, supported by the cytokine system, is a triggering mechanism for ED progression. Excessive production of endothelin-1 and inhibition of nitric oxide production are the classic markers of ED. Immune damage leads to imbalance in the production of vasoconstrictor and vasodilating substances, proliferative and antiproliferative factors in endothelium. It was shown that ED is an integral aspect of the insulin resistance syndrome in pathogenesis of arterial hypertension associated with metabolic disorders, and contributes to its worsening, increased vascular reactivity and further AH development. According to modern studies, it has been shown that excessive synthesis of pro-inflammatory cytokines introduces disturbances in the system of vascular hemostasis. When studying the effects of metabolic disorders upon hemostatic system, we may conclude that activation of fibrinolytic and plasma chains occurs in the same way for both men and women, with small gender characteristics of individual components. The rheological properties of the blood are also changed with developing MS. Systematization of the available literature data on the issue under study can serve as a basis for determining prognostic criteria of hypertension progression and risk of thrombotic complications.

Inflammatory Signaling and Brown Fat Activity.

Obesity is characterized by a state of chronic inflammation in adipose tissue mediated by the secretion of a range of inflammatory cytokines. In comparison to WAT, relatively little is known about the inflammatory status of brown adipose tissue (BAT) in physiology and pathophysiology. Because BAT and brown/beige adipocytes are specialized in energy expenditure they have protective roles against obesity and associated metabolic diseases. BAT appears to be is less susceptible to developing inflammation than WAT. However, there is increasing evidence that inflammation directly alters the thermogenic activity of brown fat by impairing its capacity for energy expenditure and glucose uptake. The inflammatory microenvironment can be affected by cytokines secreted by immune cells as well as by the brown adipocytes themselves. Therefore, pro-inflammatory signals represent an important component of the thermogenic potential of brown and beige adipocytes and may contribute their dysfunction in obesity.

Broussonetia papyrifera Root Bark Extract Exhibits Anti-inflammatory Effects on Adipose Tissue and Improves Insulin Sensitivity Potentially Via AMPK Activation.

The chronic low-grade inflammation in adipose tissue plays a causal role in obesity-induced insulin resistance and its associated pathophysiological consequences. In this study, we investigated the effects of extracts of Broussonetia papyrifera root bark (PRE) and its bioactive components on inflammation and insulin sensitivity. PRE inhibited TNF-α-induced NF-κB transcriptional activity in the NF-κB luciferase assay and pro-inflammatory genes’ expression by blocking phosphorylation of IκB and NF-κB in 3T3-L1 adipocytes, which were mediated by activating AMPK. Ten-week-high fat diet (HFD)-fed C57BL6 male mice treated with PRE had improved glucose intolerance and decreased inflammation in adipose tissue, as indicated by reductions in NF-κB phosphorylation and pro-inflammatory genes’ expression. Furthermore, PRE activated AMP-activated protein kinase (AMPK) and reduced lipogenic genes’ expression in both adipose tissue and liver. Finally, we identified broussoflavonol B (BF) and kazinol J (KJ) as bioactive constituents to suppress pro-inflammatory responses via activating AMPK in 3T3-L1 adipocytes. Taken together, these results indicate the therapeutic potential of PRE, especially BF or KJ, in metabolic diseases such as obesity and type 2 diabetes.

Metabolic markers and oxidative stress in children’s obesity pathogenesis

The article presents a modern view of obesity as a chronic inflammation of adipose tissue. Obesity is accompanied by metabolic changes in lipid, protein, carbohydrate, mineral metabolism and disorders in the hormonal function of adipose tissue as an endo- and paracrine organ. At the moment, there are searched the biochemical markers of metabolic disorders of obesity. The obesity-related factors (hyperglycemia, increased lipid levels, insulin resistance, chronic inflammation, hyperleptinemia, endothelial dysfunction, impaired respiratory function of mitochondria, minerals and microelements deficiency) form and increase oxidative stress making it an integral component of the pathogenesis of obesity and possible complications. Given the important role of Q10 coenzyme in antioxidant tissue protection, the authors discuss the relationship of obesity and metabolic disorders to the endogenous levels of Q10 coenzyme and its possible use for pharmacological correction.

Проблема остеоартроза (ОА) коленного сустава у пациентов с избыточной массой тела и ожирением: вопросы этиологии и патогенеза (обзор литературы)

Introduction Based on WHO report, in 2008, the global prevalence of overweight reached over 1.4 billion people aged 20 years and over including more than 200 million men and 300 million women who suffered from obesity in 2012. More than 34 % of U.S. adults are overweight, and more than 27 % are obese. In European countries, the prevalence of obesity is 35–40 % among adult population. More than 30 percent of the Russia’s working population is overweight, 25 percent of whom are obese. Material and methods Search engines used included MEDLINE, the primary component of Pubmed; the Electronic Library System, products from Elsevier and Springer publishing companies; open access articles of PubMed Central; BioMed Central; Free Medical Journals and open access publications using the keywords 'knee osteoarthritis', 'etiology and pathogenesis', 'knee osteoarthritis in obesity'. Results and discussion Osteoarthritis (OA) is multifactorial in origin and closely associated with genetic predisposition, sex and age, greater body mass index (BMI) and obesity. Family history, age, gender, previous injury or abnormal mechanical loading are common risk factors of knee OA. While the above risk factors can increase the chances of developing knee OA, they are not absolute. In clinical practice, in patients with new onset of knee pain 5.1 % of cases are due to previous knee injury and 24.6 % related to being overweight or obese. Such metabolic factors as obesity and dyslipidemia might be involved in the pathophysiology of knee OA. Increased free radical production associated with obesity results in degradation of articular cartilage and synovial involvement. The pathogenesis of knee OA attributable to obesity is predominantly related to unfavorable mechanical environment at the joint; chronic inflammation in adipose tissue and dyslipidemia; pro-inflammatory cytokines and adipokines secreted by the adipose tissue; cytokines secreted by infrapatellar fat pad. Conclusion Inflammatory mediators of adipose origin play a major role in the initiation and perpetuation of the obesity-induced OA. There is a significant multifactorial association between OA and obesity with central roles for LDL oxyforms, HDL synthesis and excessive activation of matrix metalloproteinases, adiponectin synthesis, the release of adipokines and excessive mechanical stress.

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes.

Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.

Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation

ObjectiveChronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity-associated systemic inflammation and metabolic disorder remain complicated. Here, we report that inactive rhomboid-like protein 2 (iRhom2) was increased in overweight mice with adipose inflammation. MethodsMice with deletion of iRhom2 on a C57BL/6J background, mice without deletion of this gene (controls), and mice with deficiency of iRhom2 only in myeloid cells were fed a standard chow diet (SCD) or a high-fat diet (HFD; 60% fat calories). Then the adipose tissues or bone marrow cells were isolated for the further detection. ResultsAfter 16 weeks on a high-fat diet (HFD), obesity, chronic inflammation in adipose tissues, and insulin resistance were markedly mitigated in iRhom2 knockout (iRhom2 KO) mice, whereas these parameters were exaggerated in iRhom2 overactivated mice. The adverse influences of iRhom2 on adipose inflammation and associated pathologies were determined in db/db mice. We further demonstrated that, in response to an HFD, iRhom2 KO mice and mice with deletion only in the myeloid cells showed less severe adipose inflammation and insulin resistance than control groups. Conversely, transplantation of bone marrow cells from normal mice to iRhom2 KO mice unleashed severe systemic inflammation and metabolic dysfunction after HFD ingestion. ConclusionWe identified iRhom2 as a key regulator that promotes obesity-associated metabolic disorders. Loss of iRhom2 from macrophages in adipose tissues may indirectly restrain inflammation and insulin resistance via blocking crosslinks between macrophages and adipocytes. Hence, iRhom2 may be a therapeutic target for obesity-induced metabolic dysfunction.

The relationship between insulin resistance, obesity, and endotrophin

Endotrophin is the cleavage product COL6. Recent findings indicate that endotrophin is actively involved in inflammation, angiogenesis, and fibrosis. It also seems to play a critical role in obesity-induced systemic insulin resistance by increasing chronic inflammation and fibrosis in adipose tissues. In this study, we aimed to reveal the relationship between human adipose tissue, inflammation, and insulin resistance (IR). The study included 51 IR patients and 37 healthy controls. The presence of IR was based on Homeostatic model of assessment-insulin resistance (HOMA-IR) level of 2, 7, or higher. Fasting plasma samples were obtained from the patients and the control group. The IR patients had a higher HOMA-IR, waist circumference, fasting plasma glucose (FPG), fasting insulin (FI), and triglyceride levels than the control subjects (p < 0.05). Endotrophin and CRP levels were significantly higher in patients with IR than controls (23.12 ± 18.32 ng/mL; 11.20 ± 6.60 ng/mL p < 0,001; 5.5 ± 3.37 ng/L; 1.97 ± 0.89 ng/L p < 0.001). The serum endotrophin level showed a positive correlation with HOMA-IR (r = 0.359; p < 0.001), waist circumference (r = 0.214; p < 0.05), FI (r = 0.386; p < 0.001), and CRP level (r = 0.251; p < 0.05) The serum endotrophin level was higher in patients with IR, independently of BMI, fasting glucose, and all other factors. Therefore, we foresee that high levels of endotrophin may be a new biomarker for early diagnosis of metabolic worsening in overweight and obesity. We also found a positive correlation between endotrophin and CRP. This indicates that endotrophin is closely related to inflammatory processes.

Viscoelastic characterization of diabetic and non-diabetic human adipose tissue.

Obesity-induced chronic inflammation and fibrosis in adipose tissue contributes to the progression of type 2 diabetes mellitus (DM). While fibrosis is known to induce mechanical stiffening of numerous tissue types, it is unknown whether DM is associated with alterations in adipose tissue mechanical properties. The purpose of this study was to investigate whether DM is associated with differences in bulk viscoelastic properties of adipose tissue from diabetic (DM) and non-diabetic (NDM) obese subjects. Bulk shear rheology was performed on visceral (VAT) and subcutaneous (SAT) adipose tissue, collected from obese subjects undergoing elective bariatric surgery. Rheology was also performed on the remaining extracellular matrix (ECM) from decellularized VAT (VAT ECM). Linear mixed models were used to assess whether correlations existed between adipose tissue mechanical properties and DM status, sex, age, and body mass index (BMI). DM was not associated with significant differences in adipose tissue viscoelastic properties for any of the tissue types investigated. Tissue type dependent differences were however detected, with VAT having significantly lower shear storage and loss moduli than SAT and VAT ECM independent of DM status. Although DM is typically associated with adipose tissue fibrosis, it is not associated with differences in macroscopic adipose tissue mechanical properties.

Fat and Iron Don't Mix.

Low-grade chronic adipose tissue (AT) inflammation is now recognized as a pivotal driver of the multi-organ dysfunction associated with obesity-related complications; and adipose tissue macrophages (ATMs) are key to the development of this inflammatory milieu. Along with their role in immunosurveillance, ATMs are central regulators of AT iron homeostasis. Under optimal conditions, ATMs maintain a proper homeostatic balance of iron in adipocytes; however, during obesity, this relationship is altered, and iron is repartitioned into adipocytes as opposed to ATMs. This adipocyte iron overload leads to systemic IR and the mechanism for these effects is still under investigation. Here, we comment on the most recent findings addressing the interplay between adipocyte and ATM iron handling, and metabolic dysfunction.

Commentary on Camell et al., Aging Induces Nlrp3 Inflammasome Dependent Adipose B Cell Expansion to Impair Metabolic Homeostasis

The burden of aging and obesity is urging extended investigation into the molecular mechanisms that underlie chronic adipose tissue inflammation. B cell-targeted therapies are emerging as novel tools to modulate the immune system and thereby mitigate aging and obesity-related metabolic complications.

IRhom2 Ablation Mitigates Obesity by Suppressing Pro-Inflammatory Macrophage Activation-Triggered Adipose Inflammation

Chronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity-associated systemic inflammation and metabolic disorder remain complicated. Here, we report that inactive rhomboid-like protein 2 (iRhom2) was increased in overweight mice with adipose inflammation. Mice with deletion of iRhom2 on a C57BL/6J background, mice without deletion of this gene (controls), and mice with deficiency of iRhom2 only in myeloid cells were fed a standard chow diet or a high-fat diet (HFD; 60% fat calories). Then the adipose tissues or bone-marrow cells were isolated for the further detection. After 16 weeks on a high-fat diet (HFD), obesity, chronic inflammation in adipose tissues, and insulin resistance were markedly mitigated in iRhom2-knockout (iRhom2 KO) mice, whereas these parameters were exaggerated in iRhom2-overactivated mice. The adverse influences of iRhom2 on adipose inflammation and associated pathologies were determined in db/db mice. Also, we further demonstrated that, in response to an HFD, iRhom2 KO mice and mice with deletion only in myeloid cells showed less severe adipose inflammation and insulin resistance than that of control groups. Conversely, transplantation of bone-marrow cells from normal mice to iRhom2 KO mice unleashed a severity of systemic inflammation and metabolic dysfunction after HFD ingestion. We identify iRhom2 as a key regulator that promotes obesity-associated metabolic disorders. Loss of iRhom2 from macrophages in adipose tissues inhibited inflammation and insulin resistance. Hence, iRhom2 may be a therapeutic target for obesity-induced metabolic dysfunction. Funding Statement: This work was jointly supported by (1) National Natural Science Foundation of China (NSFC Grant No.: 81703527); (2) Chongqing Research Program of Basic Research and Frontier Technology (Grant No.: cstc2017jcyjAX0356, cstc2018jcyjA3686, cstc2018jcyjAX0784, cstc2018jcyjA1472, cstc2018jcyjAX0811, cstc2018jcyjA3533 and KJZD-M201801601); (3) School-level Research Program of Chongqing University of Education (Grant No.: KY201710B and 17GZKP01); (4) Advanced Programs of Post-doctor of Chongqing (Grant No.: 2017LY39); (5) Science and Technology Research Program of Chongqing Education Commission of China (Grant No.: KJQN201901608, KJQN201901615, KJ1601402) and (6) Children's Research Institute of National Center for Schooling Development Programme and Chongqing University of Education (Grant No.: CSDP19FSO1108). Declaration of Interests: Minxuan Xu, Chenxu Ge, Yuting Qin, Deshuai Lou, Qiang Li, Jing Feng, Yekuan Wu , Linfeng Hu, Bochu Wang & Jun Tan declare that they have no conflict of interest. Ethics Approval Statement: All research procedures associating with mice were approved by the Institutional Animal Care and Use Committee in Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, and were performed in accordance with the Guide for the Care and Use of Laboratory Animals, issued by the National Institutes of Health in 1996. The protocols used in this study were in accordance with the Regulations of Experimental Animal Administration issued by the Ministry of Science and Technology of the People's Republic of China.

α-Mangostin remodels visceral adipose tissue inflammation to ameliorate age-related metabolic disorders in mice.

Low-grade chronic adipose tissue inflammation contributes to the onset and development of aging-related insulin resistance and type 2 diabetes. In the current study, α-mangostin, a xanthone isolated from mangosteen (Garcinia mangostana), was identified to ameliorate lipopolysaccharides-induced acute adipose tissue inflammation in mice, by reducing the expression of pro-inflammatory cytokines and chemokines. In a cohort of young (3 months) and old (18–20 months) mice, α-mangostin mitigated aging-associated adiposity, hyperlipidemia, and insulin resistance. Further study showed that α-mangostin alleviated aging-related adipose tissue inflammation by reducing macrophage content and shifting pro-inflammatory macrophage polarization. Moreover, α-mangostin protected the old mice against liver injury through suppressing the secretion of microRNA-155-5p from macrophages. The above results demonstrated that α-mangostin represents a new scaffold to alleviate adipose tissue inflammation, which might be a novel candidate to treat aging-related metabolic disorders.

Adipose-Derived Stromal Cells Attenuate Adipose Inflammation in Obesity through Adipocyte Browning and Polarization of M2 Macrophages.

Obesity is a metabolic condition associated with multiple health problems such as endocrine and metabolic dysfunction and chronic inflammation in adipose tissues. In this study, the ADSCs could be stimulated to differentiate into brown adipocyte with rosiglitazone treatment based on the Oil-Red-O staining trial. Furthermore, the multilocular lipid droplets located in the center was increased in differentiated brown adipocytes, and brown fat-associated proteins, UCP1, PPAR-γ, and LPL were highly expressed in brown adipocytes differentiated from ADSCs. Additionally, the results of animal experiments showed that both weight and amount of VLDL and LDL were decreased in the serum of obese mice after transplantation of rosiglitazone-induced brown adipocytes, while the level of HDL increased. Moreover, the proteins associated with lipid metabolism, LPA and UCP1, were downregulated, and the inflammatory response was suppressed through inhibition of the ITGAM/NF-κB-mediated proinflammatory responses and polarization of M2 macrophages. Similarly, the amounts of proinflammatory cytokines, TNF-α, IL-6, and IL-1β were decreased after rosiglitazone-induced brown adipocyte transplantation. On the contrary, anti-inflammatory cytokine IL-10 was significantly increased in both groups of obese mice, with or without brown adipocyte transplantation. Therefore, the adipose-derived stromal cells with induced browning could promote lipid consumption and alternative polarization of M2 macrophages to attenuate adipose inflammation in obesity mouse models, which thus provides a potential therapy for obesity.

Gallic acid regulates adipocyte hypertrophy and suppresses inflammatory gene expression induced by the paracrine interaction between adipocytes and macrophages in vitro and in vivo

Obesity-induced chronic inflammation in adipose tissue plays a critical role in the development of insulin resistance and various lifestyle-related diseases. Although gallic acid (GA) is known to exert protective effects on obesity-related complications, its function in adipose tissue inflammation has not been elucidated. Recently, we reported that GA exerts protective effects against inflammation. To test our hypothesis that the anti-inflammatory effect of GA partially contributes to the improvement of metabolic diseases, we examined the effect of GA on inflammation caused by adipocyte-macrophage crosstalk in obesity. We showed that GA enhanced adipocyte differentiation in 3 T3-L1 adipocytes. Consistent with the enhancement of adipogenesis, GA decreased the gene expression of monocyte chemoattractant protein-1 and increased that of adiponectin and the upstream mediator peroxisome proliferator-activated receptor gamma. GA also reduced inflammatory mediator expression induced by the co-culture of 3 T3-L1 adipocytes with RAW 264 macrophages. Diet-induced obese mice treated with GA showed decreased serum cholesterol levels and adipocyte size, and improved insulin sensitivity without changes in body weight. Moreover, GA-treated mice had decreased expression of interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2, F4/80, and sterol regulatory element binding transcription factor-1 in their adipose tissue. These results indicate that GA suppresses adipocyte hypertrophy and inflammation caused by the interaction between adipocytes and macrophages, thereby improving metabolic disorders such as insulin resistance and dyslipidemia.

Subcutaneous administration of α-GalCer activates iNKT10 cells to promote M2 macrophage polarization and ameliorates chronic inflammation of obese adipose tissue

ObjectiveThe role of iNKT cells was investigated in chronic adipose tissue inflammation in obese mice after administration of α-GalCer in different pathways. MethodsC57BL/6J mice were fed high-fat diet (HFD) for 12 weeks to establish the obese mouse model. The pathology of adipose tissue was observed by H&E staining. The rates of iNKT cells, macrophages and cell subsets in adipose tissue were detected by FCM. Cytokine levels in serum and adipose tissue lymphocyte-stimulated supernatants were assessed with the CBA kit. The expression levels of related transcription factor in adipose tissue were detected by Western blot. ResultsThe proportions of iNKT cells, iNKT10 cells and M2 macrophages were decreased, while those of iNKT1 and M1 macrophages were increased in adipose tissue of HFD-fed mice. The expression levels of the related transcriptional proteins E4BP4 and Arg-1 were decreased while iNOS expression was increased in adipose tissue. Administration of α-GalCer by subcutaneous injection resulted in increased rates of iNKT10 cells and M2 macrophages, and decreased amounts of M1 macrophages in adipose tissue of HFD-fed mice. The expression of E4BP4 and Arg-1 were up-regulated, but iNOS was down-regulated. Meanwhile, infiltration of inflammatory cells into adipose tissue was further reduced. ConclusionThe imbalance between the proportions of iNKT1 and iNKT10 cells may be involved in the development of chronic inflammation in obese adipose tissue. Administration of α-GalCer by subcutaneous injection in HFD-fed mice activates adipose tissue iNKT10 cells, which promote M2 macrophage polarization and improve chronic inflammation in obese adipose tissue.

P1939Tumor necrosis factor receptor-associated factor 5 (TRAF-5) deficiency exacerbates diet-induced adipose tissue inflammation and aggravates metabolic syndrome in mice

Abstract Introduction Many clinical and experimental observations have established an association between visceral obesity and chronic adipose tissue inflammation. Potent pro-inflammatory mediators such as TNFα, CD40 and IL-1β are regulated by Tumor necrosis factor (TNF) receptor-associated factors (TRAFs). TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory leukocyte recruitment. Since inflammatory cell invasion is also a prerequisite of adipose tissue inflammation, we tested the hypothesis that deficient TRAF5 signaling aggravates adipose tissue inflammation and its metabolic complications in a murine diet-induced obesity (DIO) model. Purpose We aimed to clarify the role of TRAF5 in adipose tissue inflammation and metabolic syndrome. Methods TRAF5−/− mice and gender- and age-matched wild-type (WT) mice consumed a high fat diet (HFD, 45%kcal from fat) or a matched low-fat diet (LFD, 10%kcal from fat) for 18 weeks to induce DIO and adipose tissue inflammation. All mice were then subjected to subsequent analysis, including glucose and insulin tolerance testing, body composition assessment by MRI imaging, flow cytometry, gene expression of different tissues, plasma analysis and histology. Finally, we studied if TRAF5 expression was associated with metabolic syndrome in humans by analyzing plasma and adipocytes samples from 62 patients of the Tumor-Necrosis-Factor Receptor Associated in Cardiovascular Risk Study (TRAFICS). Results TRAF5 expression was significantly attenuated in isolated WT-adipocytes and WT-macrophages after 18 weeks of HFD compared to LFD-fed controls. TRAF5−/− mice on HFD gained significantly more weight compared to TRAF5-competent mice and showed an aggravated metabolic phenotype, including impaired insulin tolerance, hyperinsulinemia and increased fasting glucose plasma levels. The weight gain in TRAF5−/− mice was attributable to a significant increase in adipose tissue and liver weight. Further analysis of the visceral adipose tissue revealed enhanced macrophage accumulation and increased pro-inflammatory CD11c+ subset polarization in HFD-fed TRAF5−/− mice. In line with an increased migratory capacity of inflammatory cells, we observed enhanced peritoneal invasion of leukocytes and subsets in TRAF5−/− mice. Accordingly, TRAF5 deficiency increased inflammatory cytokine expression and ameliorated parameters of insulin sensitivity in adipose tissue. Finally, patients with metabolic syndrome displayed decreased TRAF5 expression in blood and adipocytes compared to humans without metabolic syndrome. Conclusion We show that genetic deficiency of TRAF5 aggravates metabolic syndrome in murine diet-induced obesity. Enhanced accumulation of leukocytes subsets in adipose tissue serves as the likely mechanism. We conclude that TRAF5 signaling properties may favorably affect metabolic disease. Acknowledgement/Funding Forschungskommission Medizinische Fakultät Universität Freiburg, MOTI-VATE Promotionskolleg der Medizinischen Fakultät Freiburg (EKFS)