Low-grade Inflammation In Adipose Tissue Research Articles

IL-6 signaling drives self-renewal and alternative activation of adipose tissue macrophages.

Obesity is associated with chronic low-grade inflammation of adipose tissue (AT) and an increase of AT macrophages (ATMs) that is linked to the onset of type 2 diabetes. We have recently shown that neutralization of interleukin (IL)-6 in obese AT organ cultures inhibits proliferation of ATMs, which occurs preferentially in alternatively activated macrophage phenotype. In this study, we investigated AT biology and the metabolic phenotype of mice with myeloid cell-specific IL-6Rα deficiency (Il6ra Δmyel) after normal chow and 20 weeks of high-fat diet focusing on AT inflammation, ATM polarization and proliferation. Using organotypical AT culture and bone marrow derived macrophages (BMDMs) of IL-4Rα knockout mice (Il4ra -/-) we studied IL-6 signaling. Obese Il6ra Δmyel mice exhibited no differences in insulin sensitivity or histological markers of AT inflammation. Notably, we found a reduction of ATMs expressing the mannose receptor 1 (CD206), as well as a decrease of the proliferation marker Ki67 in ATMs of Il6ra Δmyel mice. Importantly, organotypical AT culture and BMDM data of Il4ra -/- mice revealed that IL-6 mediates a shift towards the M2 phenotype independent from the IL-6/IL-4Rα axis. Our results demonstrate IL-4Rα-independent anti-inflammatory effects of IL-6 on macrophages and the ability of IL-6 to maintain proliferation rates in obese AT.

Macrophage-associated markers of metaflammation are linked to metabolic dysfunction in pediatric obesity

BackgpoundMetabolically driven chronic low-grade adipose tissue inflammation, so-called metaflammation, is a central feature in obesity. This inflammatory tone is largely driven by adipose tissue macrophages (ATM), which express pro- and anti-inflammatory markers and cytokines such as, e.g., IL-1 receptor antagonist (IL-1RA), CD163 and osteopontin (OPN). Metaflammation ultimately leads to the development of cardiometabolic diseases. This study aimed to evaluate the association between selected adipose tissue macrophage-associated markers and metabolic comorbidities in pediatric obesity. MethodsFrom a pediatric cohort with obesity (n = 108), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test and liver MRI, plasma IL-1RA, soluble (s)CD163 and OPN were measured by ELISA. ResultsWe observed significantly higher IL-1RA, sCD163, and OPN levels in the plasma of children with metabolic-dysfunction associated fatty liver disease (MAFLD) and metabolic syndrome. Moreover, IL-1RA and sCD163 correlated with hepatic disease and apoptosis markers alanine aminotransferase and CK-18. IL-1RA concentrations additionally correlated with insulin resistance, while children with disturbed glucose metabolism had significantly higher levels of sCD163. ConclusionMAFLD and other metabolic disorders in pediatric patients with obesity are associated with an elevation of adipose tissue macrophage-related inflammation markers.

Mechanism of TNFα-induced downregulation of salt-inducible kinase 2 in adipocytes

Salt-inducible kinase 2 (SIK2) is highly expressed in white adipocytes, but downregulated in individuals with obesity and insulin resistance. These conditions are often associated with a low-grade inflammation in adipose tissue. We and others have previously shown that SIK2 is downregulated by tumor necrosis factor α (TNFα), however, involvement of other pro-inflammatory cytokines, or the mechanisms underlying TNFα-induced SIK2 downregulation, remain to be elucidated. In this study we have shown that TNFα downregulates SIK2 protein expression not only in 3T3L1- but also in human in vitro differentiated adipocytes. Furthermore, monocyte chemoattractant protein-1 and interleukin (IL)-1β, but not IL-6, might also contribute to SIK2 downregulation during inflammation. We observed that TNFα-induced SIK2 downregulation occurred also in the presence of pharmacological inhibitors against several kinases involved in inflammation, namely c-Jun N-terminal kinase, mitogen activated protein kinase kinase 1, p38 mitogen activated protein kinase or inhibitor of nuclear factor kappa-B kinase (IKK). However, IKK may be involved in SIK2 regulation as we detected an increase of SIK2 when inhibiting IKK in the absence of TNFα. Increased knowledge about inflammation-induced downregulation of SIK2 could ultimately be used to develop strategies for the reinstalment of SIK2 expression in insulin resistance.

Establishment of a Nomogram Based on Inflammatory Response-Related Methylation Sites in Intraoperative Visceral Adipose Tissue to Predict EWL% at One Year After LSG.

Laparoscopic sleeve gastrectomy (LSG) is considered as an effective bariatric and metabolic surgery for patients with severe obesity. Chronic low-grade inflammation of adipose tissue is associated with obesity and obesity-related complications. This study intends to establish a nomogram based on inflammatoryresponse-related methylation sites in intraoperative visceral adipose tissue (VAT) to predict excess weight loss (EWL)% at one-year after LSG. Based on EWL% at one-year after LSG, patients were divided into two groups: the satisfied group (group-A, EWL%≥50%) and the unsatisfied group (group-B, EWL%<50%). Next, we defined genes corresponding to the methylation sites in the 850 K methylation microarray as methylation-related genes (MRGs). We then took the intersection of MRGs and inflammatoryresponse-related genes. After that, inflammatoryresponse-related methylation sites were identified based on overlapping genes. Moreover, difference analysis was carried out to obtain inflammatoryresponse-related differentially methylated sites (IRRDMSs) between group-A and group-B. LASSO analysis was used to identify the hub methylation sites. Finally, we developed a nomogram based on the hub methylation sites. There were 26 patients in the study, with 13 in group-A and 13 in group-B. After data filtering and difference analysis, 200 IRRDMSs were identified (143 hypermethylated sites and 57 hypomethylated sites). Then, we identified three hub methylation sites (cg03610073, cg03208951, and cg18746357) by LASSO analysis and built a predictive nomogram (Area under the curve=0.953). The predictive nomogram based on three inflammatory-related methylation sites (cg03610073, cg03208951, and cg18746357) in intraoperative visceral adipose tissue can predict one-year EWL% after LSG effectively.

Ablation of Siglec-E enhances adipose tissue inflammation through CXCR3 activation and induces monocytic myeloid-derived suppressor cells

Abstract Obesity is a worldwide epidemic associated with dysregulated metabolism and chronic low-grade inflammation in adipose tissue (AT). AT infiltrates with several immune cells, which secrete proinflammatory cytokines that mediate the severity of AT inflammation during obesity. During our ongoing studies, we observed the downregulation of various genes, particularly sialic acid-binding Ig-like lectin E (Siglec-E) by RNA-seq analysis in AT immune cells isolated from high-fat diet (HFD) fed mice as compared to normal diet (ND) mice. Siglec-E is mainly expressed in the cells of myeloid lineages, including macrophages, dendritic cells (DCs), and neutrophils. We confirmed the RNA-seq data of downregulation of Siglec-E in AT derived from HFD-fed mice by RT-PCR analysis. To determine the role of Siglec-E in mediating AT inflammation, we fed ND and HFD to wild-type (WT) and Siglec-E knockout mice (Siglec-E −/−), respectively. HFD consumption increased the body weight and blood glucose levels in Siglec-E −/−mice as compared to WT mice. Further, we observed increased infiltration of macrophages and decreased frequency of DCs in HFD-fed Siglec-E −/−mice AT compared to WT HFD-fed mice. We also noticed an increase in the frequency of CD8 +CXCR3 +cells and monocytic myeloid-derived suppressor cells (M-MDSCs) in AT of HFD-fed Siglec-E −/−mice as compared to WT HFD-fed mice. We also noticed the increased expression of AKT, and TNF receptor-associated factor 3 (TRAF3) in HFD-fed Siglec-E −/−mice. These results suggest that Siglec-E deletion plays a role in AT inflammation and obesity through the activation of CXCR3 and M-MDSCs. This study supports the notion that modulating Siglec-E pathways protect from AT inflammation and metabolic disorders. This research is supported by NIH grant R01 AI140405

Аномальные маточные кровотечения и ожирение: современная парадигма

Abnormal uterine bleeding (AUB) remains one of the most common gynecological disorders that reduce the quality of life and reproductive potential in women. Obesity is recognized as an independent risk factor for the development of AUB associated with irregular endometrial proliferation (endometrial hyperplasia and endometrial cancer), ovulatory dysfunction and disease recurrence. The role of obesity in the pathogenesis of AUB due to endometrial dysfunction is an interesting and understudied aspect. Chronic adipose tissue inflammation is mechanistically linked to metabolic disease and organ tissue complications in overweight and obese women. Despite its minor nature, low-grade adipose tissue inflammation negatively impacts remote organ functions, thus being a cause of obesity complications. The results of recent studies suggest that obesity creates conditions for a proinflammatory environment in the endometrium during menstrual bleeding, which may inhibit endometrial regeneration and increase the volume of menstrual blood loss. Key words: abnormal uterine bleeding, obesity, chronic latent inflammation, endometrial dysfunction, endothelial dysfunction

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation.

Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines — proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation.

Targeting Adiposity and Inflammation With Movement to Improve Prognosis in Breast Cancer Survivors (The AIM Trial): Rationale, Design, and Methods.

BackgroundObesity is a significant contributor to breast cancer recurrence and mortality. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise interventions to target chronic inflammation has a potential to improve obesity- and breast cancer-related outcomes; however, no studies have investigated the roles of exercise in modulating adipose tissue inflammation in breast cancer survivors. Also, it is unclear which exercise prescription would be optimal to maximize the outcomes. Therefore, we designed a randomized controlled trial (Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors [AIM] Trial) to examine the mechanisms by which different modalities of exercise impact chronic inflammation as a biomarker of breast cancer prognosis.MethodsThe AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program versus a traditional aerobic and resistance exercise (TARE) program and attention control (AC) on adipose tissue inflammation in breast cancer survivors. 276 patients who are diagnosed with stage 0-III breast cancer, post-treatment, sedentary, and centrally obese are randomized to one of the three groups. The CARE and TARE groups participate in thrice-weekly supervised exercise sessions for 16 weeks. The AC group are offered the CARE program after the intervention period. The primary endpoint is adipose tissue inflammation assessed by core biopsy and blood draw. The secondary and tertiary endpoints are sarcopenic obesity, physical fitness and function, and patient reported outcomes. The exploratory outcomes are long-term breast cancer outcomes.DiscussionThis is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Our findings are anticipated to contribute to a better understanding of exercise modalities and mechanisms on adipose tissue inflammation that can potentially improve breast cancer prognosis.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT03091842 identifier [NCT#03091842].

Targeting adiposity and inflammation with movement to improve prognosis in breast cancer survivors (the AIM trial): Rationale, design, and methods.

TPS12140 Background: Obesity is considered a leading modifiable contributor to breast cancer mortality worldwide due to its association with increased recurrence and decreased overall survival rate. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise has shown potential in improving inflammation but has not been implemented with breast cancer survivors. Our hypothesis is that exercise designed to target chronic inflammation and associated sarcopenic obesity will improve prognosis in obese breast cancer survivors. Methods: The AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program compared to a traditional aerobic and resistance exercise (TARE) program, and attention control (AC) group, on adipose tissue inflammation in 300 breast cancer survivors. Main inclusion criteria are histologically confirmed breast cancer stage 0-III, completion of chemotherapy and/or radiation, sedentary, centrally obese, and free from musculoskeletal disorders. The primary endpoint is adipose tissue inflammation as assessed by core biopsy and blood draw; secondary endpoint is sarcopenic obesity; and exploratory endpoints are physical fitness and function and patient reported outcomes. Participants randomized to the exercise groups participate in three weekly supervised exercise sessions for 16-weeks. Participants randomized to the attention control group are offered the CARE intervention after the 16-week period of observation. Discussion: This is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Results will contribute to a better understanding of exercise modality on adipose tissue inflammation that can potentially improve patient prognosis. Clinical trial information: NCT03091842.

Adipose tissue macrophage-derived exosomes induce ferroptosis via glutathione synthesis inhibition by targeting SLC7A11 in obesity-induced cardiac injury

Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of reactive oxygen species (ROS). Long-term high fat diet (HFD) was found to be associated with ferroptosis and cardiac injury. HFD-induced obesity is characterized by sustained, low-grade inflammation in adipose tissue, while macrophage infiltration plays a crucial role in inflammation. Exosomes (Exos) derived from adipose tissue macrophages (ATMs) participate in the physiological processes of recipient cells. In this study, we investigated the role of ATM-Exos in obesity-induced ferroptosis and cardiac injury. We found that HFD-induced obesity resulted in higher mRNA expression levels of specific markers, e.g., prostaglandin endoperoxide synthase 2 (PTGS2), and increased the levels of lipid peroxides, including malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Macrophages infiltrated the adipose tissues, as examined by flow cytometry. Exosomes derived from ATM-Exos were analyzed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Obese ATM-Exos administration induced higher levels of PTGS2, MDA, 4-HNE, lipid ROS, and mitochondrial injury. Obese ATM-Exos further provoked obvious cardiac injury, demonstrated by abnormal levels of cardiac enzymes and inflammatory factors. Systolic left ventricle (LV) function anomalies were induced by ATM-Exos in obese mice. miR-140-5p is abundant in obese ATM-Exos and promotes ferroptosis in cardiomyocytes. Solute carrier family 7 member 11 (SLC7A11) is a downstream target of miR-140-5p, which induces ferroptosis via inhibition of GSH synthesis by targeting SLC7A11. Attenuating exosomal-miR-140-5p expression alleviates ferroptosis and cardiac injury induced by obese ATM exosomes by alleviating GSH inhibition. In summary, the current study provides evidence that obese ATM-exosomal miR-140-5p promotes ferroptosis by regulating GSH synthesis and provides a novel therapeutic strategy for targeting obese ATM-Exos in obesity-induced cardiac injury.

A Straightforward Method for Adipocyte Size and Count Analysis Using Open-source Software QuPath

ABSTRACT Changes in adipose tissue morphology, depicted by cell morphology alterations such as enlargement of fat cells, always accompany over-weight and obesity. The variables related to cell size have been shown to associate with low-grade inflammation of adipose tissue and common obesity-related comorbidities including metabolic syndrome and type 2 diabetes. Quantifying fat cell morphology from images of histological specimens can be tedious. Here, we present a straightforward method for the task using the free open-source software QuPath with its inbuilt tools only. Measurements of human adipose tissue samples with the described protocol showed an excellent correlation with those obtained with ImageJ software with Adipocyte Tools plugin combined with manual correction of misdetections. Intraclass correlation between the two methods was at good to excellent level. The method described here can be applied to considerably large tissue areas, even whole-slide analysis.

꾸지뽕 열매 발효식초의 3T3-L1 세포에서 항염증 및 인슐린 저항성 개선 효과

Obesity is associated with chronic low-grade adipose tissue inflammation, leading to insulin resistance. Inflammation associated with insulin resistance is an interesting area of biomedical research and is expected to affect insulin signaling pathways via the downregulation of glucose transporters. In the present study, we investigated the inhibitory effects of Maclura tricuspidata fruit vinegar (MFV) against TNF-α-induced inflammation and insulin resistance in 3T3-L1 adipocytes. Differentiated 3T3-L1 adipocytes were pretreated with MFV at various concentrations and then cultured with TNF-α to induce insulin resistance. Then, lipid droplets, inflammatory cytokine and glucose uptake, PPARγ and GLUT4 expression, and IRS-1 phosphorylation were analyzed. MFV attenuated the TNF-α-induced decrease in lipid droplets and glucose uptake and inhibited TNF-α-induced inflammatory cytokine, IL-6, and MCP-1 production. MFV reversed the decrease in adiponectin produced by TNF-α. Furthermore, MFV upregulated the TNF-α-induced suppression of PPARγ and GLUT4 protein expression and reduced the TNF-α-induced phosphorylation of IRS-1. These findings suggest that MFV effectively ameliorates TNF-α-induced insulin resistance; accordingly, we recommend the use of MFV for the control and management of insulin resistance and its associated complications.

Abstract 10233: Interruption of Perirenal Adipose Tissue Thromboinflammation Reverses Prediabetic Kidney Impairment

Introduction: Mounting evidence suggests that micro- and macrovascular complications typically seen in diabetic patients commence in prediabetes. In absence of protracted hyperglycemia and its downstream pathological pathways, alternative mechanisms contribute to the observed cardiorenal involvement. Recent work from our laboratory implicated localized adipose inflammation in the detrimental phenotype in early metabolic deterioration, where inflammatory changes in perirenal adipose tissue triggered kidney functional and vascular deterioration. Significantly, thromboinflammatory processes involving increased factor Xa activity contribute to the low-grade adipose tissue inflammation resulting in vascular remodeling, vascular injury, atherosclerosis and organ damage, acting in a positive feedback loop further exacerbating tissue damage. Hypothesis: As such, we hypothesize factor Xa inhibition in a non-obese prediabetic rat model of localized perirenal adipose inflammation will mitigate the functional and renovascular derangements associated with metabolic dysfunction. Methods: Our rat model is induced by twelve weeks of high-caloric diet feeding to evoke a non-obese normoglycemic prediabetic phenotype. Prediabetic rats received daily oral rivaroxaban (20 mg/Kg) for the last two weeks of feeding. Renal function was assessed by measuring urinary protein excretion and glomerular filtration rate. Renovascular reactivity was examined in isolated perfused kidney preparations. Markers of inflammation, oxidative stress, and structural damage were studied in perirenal adipose and renal cortices. Results: High-calorie diet induced local adipose tissue inflammation and subsequent renovascular deterioration evident by an impaired renovasular endothelial feedback. This was associated with augmented oxidative stress and interstitial fibrosis. Rivaroxaban treatment decreased markers of perirenal adipose inflammation, oxidative stress and improved kidney structure and function. Conclusion: Our results highlight a pleotropic effect of the factor Xa inhibitor, rivaroxaban, in decreasing perirenal adipose tissue inflammation and subsequent amelioration of the deteriorated kidney function in prediabetes.

GPNMB protects against obesity-related metabolic disorders by attenuating macrophage-derived inflammation in white adipose tissue through CD44 receptor-dependent mechanism

Abstract Introduction Obesity is a worldwide health issue frequently linked to cardiovascular disease. Obesity is closely associated with chronic low-grade inflammation in adipose tissue caused by macrophage infiltration and activation, which leads to metabolic disorders. We discovered glycoprotein non-metastatic melanoma protein B (GPNMB) as a gene that is robustly expressed in white adipose tissue of obese mice. Purpose We aim to elucidate the role of GPNMB in obesity and its related metabolic disorders. Methods We generated GPNMB-knockout (KO) mice and assessed body weight, insulin sensitivity, and inflammation-related phenotypes after 12 weeks of high fat-diet (HFD) feeding. For in vitro experiment, we isolated peritoneal macrophages from wild-type (WT) and GPNMB-KO mice to explore their inflammatory phenotypes. Results After HFD feeding, obesity-related metabolic disorders were markedly worsened in GPNMB-KO mice, assessed by insulin and glucose tolerance test, although the weight gain and adiposity were similar between WT and GPNMB-KO mice. Expression of inflammatory cytokines was significantly increased in WAT of GPNMB-KO mice, in addition to a remarkable increase in crown-like structures. Peritoneal macrophages isolated from GPNMB-KO mice exhibited higher inflammatory cytokine levels, and significantly impaired the adipocytes insulin sensitivity in an endocrine manner. Recombinant soluble GPNMB attenuated the inflammatory capabilities in peritoneal macrophages isolated from GPNMB-KO mice. We identified that GPNMB inhibits the NF-κB signaling through binding to the CD44 receptor, and therefore negatively regulates inflammatory responses in macrophages. Conclusion Our study demonstrates GPNMB as an adipokine that protects against obesity-related metabolic disorders by reducing macrophage-derived inflammation, which in turn improves adipocytes functions and consequently preserves systemic metabolic health. Therefore, GPNMB is an attractive therapeutic target for the treatment of obesity-related metabolic disorders. Funding Acknowledgement Type of funding sources: None.

Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling

ObjectiveObesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. MethodsProtein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. ResultsInguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = −0.413, p < 0.001, n = 66). ConclusionsOur data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.

Effects of Des-acyl Ghrelin on Insulin Sensitivity and Macrophage Polarization in Adipose Tissue.

Background and ObjectivesObesity is the accumulation of adipose tissue caused by excess energy in the body, accompanied by long-term chronic low-grade inflammation of adipose tissue. More than 50% of interstitial cells in adipose tissue are macrophages, which produce cytokines closely related to insulin resistance. Macrophage biology is driven by two polarization phenotypes, M1 (proinflammatory) and M2 (anti-inflammatory). This study aimed to investigate the effect of gastric hormone des-acyl ghrelin (DAG) on the polarization phenotype of macrophages and elucidate the role of macrophages in adipose tissue inflammation and insulin sensitivity and its molecular mechanism.MethodsMice were subcutaneously administrated with DAG in osmotic minipumps. The mice were fed a normal diet or a high-fat diet (HFD). Different macrophage markers were detected by real-time revere transcription polymerase chain reaction.ResultsExogenous administration of DAG significantly inhibited the increase of adipocyte volume caused by HFD and reduced the number of rosette-like structures in adipose tissue. HFD in the control group significantly increased M1 macrophage markers, tumor necrosis factor α (TNFα), and inducible NO synthase (iNOS). However, these increases were reduced or even reversed after DAG administration in vitro. The M2 markers, macrophage galactose type C-type Lectin-1 (MGL1), arginase 1 (Arg1), and macrophage mannose receptor 1 (MRC1) were decreased by HFD, and the downward trend was inhibited or reversed after DAG administration. Although Arg1 was elevated after HFD, the fold increase after DAG administration in vitro was much greater than that in the control group.ConclusionDAG inhibits adipose tissue inflammation caused by HFD, reduces infiltration of macrophages in adipose tissue, and promotes polarization of macrophages to M2, thus alleviating obesity and improving insulin sensitivity.

Pro-inflammatory effects of DEHP in SGBS-derived adipocytes and THP-1 macrophages

In the member countries of the Organization for Economic Co-operation and Development (OECD), overweight and obesity affect the majority of the population. The use of environmental chemicals, such as the plasticizer DEHP, has largely increased simultaneously with this development. DEHP is an "obesogen" that interferes with normal adipocyte differentiation and energy homeostasis. Obesity in turn is accompanied by chronic low-grade adipose tissue inflammation, leading to metabolic disorders such as type II diabetes. The main actors in adipose tissue inflammation are adipocytes and macrophages. However, the impact of DEHP on adipose tissue inflammation and the crosstalk between adipocytes and macrophages are unknown and the subjects of the current study. The influence of DEHP on inflammation was investigated in human Simpson–Golabi–Behmel syndrome (SGBS)-derived adipocytes and human THP-1 macrophages. The proinflammatory markers IL8, MCP1, IL1β, TNFα and others were measured (qRT-PCR, ELISA) in SGBS-derived adipocytes treated with DEHP [day 0 (d0)–d4; 50 µg/ml] and THP-1 macrophages cultured with conditioned medium (CM) from DEHP-treated adipocytes (SGBS-CM) (from d4 and d8). DEHP exposure led to a proinflammatory state in SGBS-derived adipocytes (e.g., increased secretion of IL8 and MCP1). Surprisingly, exposure of THP-1 macrophages to SGBS-CM did not show DEHP-induced effects. However, we demonstrated that medium containing (pre)adipocyte-secreted factors had a significant impact on the expression and secretion of macrophage and inflammatory markers in THP-1 macrophages in general and led to the significantly increased accumulation of intracellular lipid droplets.

Adipose tissue inflammation and metabolic dysfunction in obesity.

Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.

1941-P: Aging Disturbs the Inflammatory Balance in Adipose Tissue

Background: Aging (middle age) is usually associated with obesity and progressive low-grade inflammation in adipose tissue. However, how immune components in adipose tissue respond to aging is still not fully uncovered. Here, we sought to examine immune cells and inflammation in adipose tissue in aging mice. Methods: Bodyweight and insulin sensitivity were measured in 12-month-old (aging) and 3-month-old (young) C57BL/6J mice on a low-fat normal diet. UCP1 expression was examined in white adipose tissue after stimulation. The immune-cell composition and phenotypes in adipose tissue were analyzed by flow cytometry. The suppressive functions of adipose tissue-resident T regulatory cells (aTregs) for conventional T cell proliferation were evaluated by CFSE-labeling proliferation assay in vitro. Results: Compared to young mice, aging mice exhibited adipose tissue expansion and insulin resistance. UCP1 was reduced in adipose tissue, indicating impaired adipose tissue browning, in aging mice compared to young mice. The frequency of resident T cells and macrophages was increased in adipose tissue of aging mice compared to those of young mice. Moreover, the Th1 subset of T cells and the M1 subset of macrophages dominated in their parent population in adipose tissue of aging mice. In contrast to diet-induced obesity that reduced aTregs, the frequency of aTregs was increased in old mice compared to young mice. However, the anti-inflammatory cytokines IL10 and inflammation-inhibitory marker CTLA4 were reduced on aTregs in aging mice than young mice. The proliferative assay showed that the suppressive capacity of Treg cell on conventional T cell proliferation was impaired in aging mice. Conclusion: Aging in mice is associated with increased aTregs, which have reduced anti-inflammatory functions and may, therefore, contribute to increased Th1 and M1 inflammation in adipose tissue, leading to metabolic disorders in aging mice. Disclosure Z. Lian: None. X. Perrard: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Corvidia, Denka-Seiken Co., Ltd., Esperion Therapeutics, Inc., Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Matinas BioPharma, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amgen, Esperion Therapeutics, Inc., Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA. H. Wu: None. Funding American Diabetes Association (1-17-IBS-082 to H.W.); National Institutes of Health (R01HL098839); American Heart Association (16GRNT30410012)

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.