Adipose Tissue Inflammation Research Articles

237 Spatial mapping of subcutaneous adipose tissue inflammation in panniculitis: Unveiling novel immune signatures

237 Spatial mapping of subcutaneous adipose tissue inflammation in panniculitis: Unveiling novel immune signatures

Periprostatic adipose tissue thromboinflammation triggers prostatic neoplasia in early metabolic impairment: Interruption by rivaroxaban

AimsProstate cancer is among the highest incidence malignancies in men with a prevalence rate increasing in parallel to the rising global trends in metabolic disorders. Whereas a sizeable body of evidence links metabolic impairment to negative prognosis of prostate cancer, the molecular mechanism underlying this connection has not been thoroughly examined. Our previous work showed that localized adipose tissue inflammation occurring in select adipose depots in early metabolic derangement instigated significant molecular, structural, and functional alterations in neighboring tissues underlying the complications observed at this stage. In this context, the periprostatic adipose tissue (PPAT) constitutes an understudied microenvironment with potential influence on the prostatic milieu. Main methods and resultsWe show that PPAT inflammation occurs in early prediabetes with signs of increased thrombogenic activity including enhanced expression and function of Factor X. This was mirrored by early neoplastic alterations in the prostate with fibrosis, increased epithelial thickness with marked luminal cellular proliferation and enhanced formation of intraepithelial neoplasia. Significantly, interruption of the procoagulant state in PPAT by a 10-day anticoagulant rivaroxaban treatment not only mitigated PPAT inflammation, but also reduced signs of prostatic neoplastic changes. Moreover, rivaroxaban decreased the murine PLum-AD epithelial prostatic cell viability, proliferation, migration, and colony forming capacity, while increasing oxidative stress. A protease-activated receptor-2 agonist reversed some of these effects. SignificanceWe provide some evidence of a molecular framework for the crosstalk between PPAT and prostatic tissue leading to early neoplastic changes in metabolic impairment mediated by upregulation of PPAT thromboinflammation.

Gestational Weight Gain Is Associated with the Expression of Genes Involved in Inflammation in Maternal Visceral Adipose Tissue and Offspring Anthropometric Measures

Background: Adequate gestational weight gain (GWG) is essential for maternal and fetal health. GWG may be a sign of higher visceral adipose tissue (VAT) accretion. A higher proportion of VAT is associated with an inflammatory process that may play a role in the fetal programming of obesity. This study aimed to (1) compare the expression of genes involved in inflammatory responses (TLR2, TLR4, NFκB, IKKβ, IL-1RA, IL-1β, IL-6, IL-10, TNF-α) in the VAT of pregnant women according to GWG and (2) explore whether VAT inflammation and GWG are related to offspring anthropometric measures. Material and methods: 50 women scheduled for cesarean section who delivered term infants were included in the study. We collected maternal omental VAT, and the expression of genes was examined with RT-qPCR. Results: Women with excessive and with adequate GWG had significantly higher expressions of most inflammatory genes than women with insufficient GWG. Neonates from mothers with excessive GWG had greater birth weight and chest circumference than those from mothers with insufficient GWG. GWG was positively correlated with fetal birth weight. Conclusions: The VAT expression of most genes associated with inflammatory pathways was higher in excessive and adequate GWG than in pregnant women with insufficient GWG. Moreover, GWG was found to be positively associated with newborn weight.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

With the prevalence of obesity and obesity-related metabolic syndrome, such as insulin resistance in recent years, it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome. Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources, mainly derived from marine products. Palmitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation. However, it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance. Here, we investigated the effects of palmitoleic acid on chow diet (CD)-fed and high-fat diet (HFD)-fed mice, which were fed CD or HFD for 12 weeks before administration. We administrated mice with BSA (control), oleic acid, or palmitoleic acid for 6 weeks on top of CD or HFD feeding. We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR. Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population. In colon, palmitoleic acid increased intestinal tight junction integrity and reduced inflammation. Moreover, palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue. Diacylglycerol (DAG) in tissue (for example, liver) is found to positively correlated with HOMA-IR. HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study. Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver. Therefore, in HFD-fed mice, palmitoleic acid reduced insulin resistance by an independent-manner of DAGs. It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition, improving of intestinal barrier function, and downregulating the inflammation in colon, liver, and adipose tissue.

Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis.

The adipose tissue-liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity-associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD. RARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarαfl/fl mice and adipocyte-specific Rarα-/- (RarαAdi-/- ) mice were fed a chow diet for 1 year or high-fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co-cultured. Metabolic regulation and inflammatory response were characterized. RARα expression was reduced in adipose tissue of db/db or ob/ob mice. RarαAdi-/- mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co-culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes. The data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.

CXCL13 promotes thermogenesis in mice via recruitment of M2 macrophage and inhibition of inflammation in brown adipose tissue.

Brown adipose tissue (BAT) is mainly responsible for mammalian non-shivering thermogenesis and promotes energy expenditure. Meanwhile, similar to white adipose tissue (WAT), BAT also secretes a variety of adipokines to regulate metabolism through paracrine, autocrine, or endocrine ways. The chemokine C-X-C motif chemokine ligand-13 (CXCL13), a canonical B cell chemokine, functions in inflammation and tumor-related diseases. However, the role of CXCL13 in the adipose tissues is unclear. The expression of CXCL13 in BAT and subcutaneous white adipose tissue (SWAT) of mice under cold stimulation were detected. Local injection of CXCL13 into BAT of normal-diet and high-fat-diet induced obese mice was used to detect thermogenesis and determine cold tolerance. The brown adipocytes were treated with CXCL13 alone or in the presence of macrophages to determine the effects of CXCL13 on thermogenic and inflammation related genes expression in vitro. In this study, we discovered that the expression of CXCL13 in the stromal cells of brown adipose tissue significantly elevated under cold stimulation. Overexpression of CXCL13 in the BAT via local injection could increase energy expenditure and promote thermogenesis in obese mice. Mechanically, CXCL13 could promote thermogenesis via recruiting M2 macrophages in the BAT and, in the meantime, inhibiting pro-inflammatory factor TNFα level. This study revealed the novel role of adipose chemokine CXCL13 in the regulation of BAT activity and thermogenesis.

Effects of Allium macrostemon Bunge Extract on Adipose Tissue Inflammation and Hepatic Endoplasmic Reticulum Stress in High-Fat Diet-Fed and Bisphenol A-Treated C57BL/6N Mice.

The simultaneous exposure to a high-fat (HF) diet and to bisphenol A (BPA) from delivered foods and food-delivery containers is on the rise in humans, according to the increased frequency of food delivery during the COVID-19 pandemic. This co-exposure could cause harmful tissue toxicity in the human body. Here, the preventive effect of Allium macrostemon Bunge (AM) extract against dysfunction in adipose tissue and the liver under co-exposure to BPA and an HF diet was examined using mice. C57BL/6N mice were divided into four groups (n = 6 or 7/group) according to diet and treatment: control diet with vehicle (CON), HF diet with vehicle (HF), HF diet with an oral injection of BPA (HF + BP), and HF diet with an oral injection of BPA and AM extract (HF + BP + AM). HF feeding increased body weight gain compared to CON feeding, while BP + HF and BP + HF + AM feeding suppressed body weight gain compared with HF feeding. The BP + HF group had lower body weight than the HF group, but the two groups had similar epididymal fat mass. The HF + BP + AM group showed lower pro-inflammatory gene expression levels in adipose tissue and epididymal fat mass compared to the HF + BP group. Altered endoplasmic reticulum (ER) stress response in the liver was partly observed in the HF + BP group, as shown by increased total phosphorylated Jun N-terminal kinase protein levels compared to those in the HF group. In addition, ecdysterone 25-O-β-D-glucopyranoside and 6-gingerol were identified in AM extract by mass spectrometry and molecular networking analysis. In summary, the AM extract diminished adipose tissue inflammation and hepatic ER stress in an HF diet and BPA co-exposure condition. To utilize AM as a potential food component to alleviate the harmful effect of an HF diet and BPA exposure, further research investigating the specific impact of AM extract supplementation using additional experimental groups or various treatment doses is warranted.

Morphological signs of neurogenic inflammation in rat epicardial adipose tissue during aging

The aim of this work is to study the neuroinflammatory process in the epicardial adipose tissue (EAT) of the aorticpulmonary region of the rat heart during aging. The work was performed on Wistar rats aged 18-23 months (n=18). The adipose tissue of the pericardial region of rats was the object of study. Neuroimmunohistochemical markers (9.5 protein, tyrosine hydroxylase, synaptophysin) were used to study EAT innervation. The method of staining with toluidine blue and azure-eosin was used to study inflammation processes. Using histological and immunohistochemical methods, involutive and neurodegenerative changes in parasympathetic and sympathetic postganglionic nerve fibers were revealed in the white and brown adipose tissue of the heart of old rats (18-23 months old). A number of pathological changes were revealed in EAT: fibrosis, dystrophic changes and lysis of white adipocytes, disintegration of varicose axons of the terminal nerve plexus, as well as the formation of focal monocyticlymphoid infiltrates. It has been shown that the axons of the terminal nervous network are in close relationship with immune and inflammatory cells (lymphocytes, plasmablasts, monocyte-macrophage elements, mast cells). The noted morphological features indicate a neurogenic type of immune inflammation in the EAT of the heart. The identified changes may be the cause of chronic disorders of lipid metabolism during aging, leading to the development of pathological processes in the tissues of the main vessels of the aortic-pulmonary region of the heart, and also serve as prognostic indicators for clinical practice.

Angiotensin II type 1 receptor-associated protein in immune cells: a possible key factor in the pathogenesis of visceral obesity

Background and aimDysregulation of angiotensin II type 1 receptor-associated protein (ATRAP) expression in cardiovascular, kidney, and adipose tissues is involved in the pathology of hypertension, cardiac hypertrophy, atherosclerosis, kidney injury, and metabolic disorders. Furthermore, ATRAP is highly expressed in bone marrow-derived immune cells; however, the functional role of immune cell ATRAP in obesity-related pathology remains unclear. Thus, we sought to identify the pathophysiological significance of immune cell ATRAP in the development of visceral obesity and obesity-related metabolic disorders using a mouse model of diet-induced obesity. MethodsInitially, we examined the effect of high-fat diet (HFD)-induced obesity on the expression of immune cell ATRAP in wild-type mice. Subsequently, we conducted bone marrow transplantation to generate two types of chimeric mice: bone marrow wild-type chimeric (BM-WT) and bone marrow ATRAP knockout chimeric (BM-KO) mice. These chimeric mice were provided an HFD to induce visceral obesity, and then the effects of immune cell ATRAP deficiency on physiological parameters and adipose tissue in the chimeric mice were investigated. ResultsIn wild-type mice, body weight increase by HFD was associated with increased expression of immune cell ATRAP. In the bone marrow transplantation experiments, BM-KO mice exhibited amelioration of HFD-induced weight gain and visceral fat expansion with small adipocytes compared BM-WT mice. In addition, BM-KO mice on the HFD showed significant improvements in white adipose tissue metabolism, inflammation, glucose tolerance, and insulin resistance, compared with BM-WT mice on the HFD. Detailed analysis of white adipose tissue revealed significant suppression of HFD-induced activation of transforming growth factor-beta signaling, a key contributor to visceral obesity, via amelioration of CD206+ macrophage accumulation in the adipose tissue of BM-KO mice. This finding suggests a relevant mechanism for the anti-obesity phenotype in BM-KO mice on the HFD. Finally, transcriptome analysis of monocytes indicated the possibility of genetic changes, such as the enhancement of interferon-γ response at the monocyte level, affecting macrophage differentiation in BM-KO mice. ConclusionCollectively, our results indicate that ATRAP in bone marrow-derived immune cells plays a role in the pathogenesis of visceral obesity. The regulation of ATRAP expression in immune cells may be a key factor against visceral adipose obesity with metabolic disorders.

Short term effect of tetrahydrocurcumin on adipose angiogenesis in very high-fat diet-induced obesity mouse model.

Tetrahydrocurcumin (THC) has been shown to possess anti-angiogenic activities. This study aims to investigate the effects of THC on adipose angiogenesis and expression of angiogenic factors that occurs in 60% high-fat diet-induced obese mice. Male ICR mice were randomly divided into 3 groups: mice fed with a low-fat diet (LFD group); mice fed with very high fat diet (VHFD group), and mice fed with VHFD supplemented with THC (300 mg/kg/day orally) (VHFD+THC treated group) for 6 weeks. Body weight (BW), food intake, fasting blood sugar (FBS), lipid profiles and visceral fats weight (VF) were measured. The microvascular density (MVD), TNF-α, VEGF, MMP-2, and MMP-9 expressions were evaluated. The VHFD group had significantly increased total cholesterol, triglyceride, food intake, BW, VF, VF/BW ratio, adipocyte size and the number of crown-liked structures as compared to LFD group. THC supplementation markedly reduced these parameters and adipocyte hypertrophy and inflammation in white adipose tissues. MVD, TNF-α, VEGF, MMP-2, and MMP-9 were over-expressed in the VHFD group. However, THC supplementation decreased MVD and reduced expression of TNF-α, VEGF, MMP-2, and MMP-9. In conclusion, THC suppressed angiogenesis in adipose tissue by the downregulation of TNF-α, VEGF, MMP-2, and MMP-9. With its effects on lipid metabolism as well as on food consumption, THC could contribute to lower visceral fat and body weight. Overall, our study demonstrated the potential benefit of THC in mitigating obesity and associated metabolic disorders along with elucidated the suppression of adipose angiogenesis as one of its underlying mechanisms.

A protein kinase C α and β inhibitor blunts hyperphagia to halt renal function decline and reduces adiposity in a rat model of obesity-driven type 2 diabetes

Type 2 diabetes (T2D) and its complications can have debilitating, sometimes fatal consequences for afflicted individuals. The disease can be difficult to control, and therapeutic strategies to prevent T2D-induced tissue and organ damage are needed. Here we describe the results of administering a potent and selective inhibitor of Protein Kinase C (PKC) family members PKCα and PKCβ, Cmpd 1, in the ZSF1 obese rat model of hyperphagia-induced, obesity-driven T2D. Although our initial intent was to evaluate the effect of PKCα/β inhibition on renal damage in this model setting, Cmpd 1 unexpectedly caused a marked reduction in the hyperphagic response of ZSF1 obese animals. This halted renal function decline but did so indirectly and indistinguishably from a pair feeding comparator group. However, above and beyond this food intake effect, Cmpd 1 lowered overall animal body weights, reduced liver vacuolation, and reduced inguinal adipose tissue (iWAT) mass, inflammation, and adipocyte size. Taken together, Cmpd 1 had strong effects on multiple disease parameters in this obesity-driven rodent model of T2D. Further evaluation for potential translation of PKCα/β inhibition to T2D and obesity in humans is warranted.

SAT671 SGLT2 Inhibition Decreases Adipose Tissue And Global Inflammaging Profile Of Older Obese Adults With Pre-Diabetes

Abstract Disclosure: J. Nie: None. M.K. Semwal: None. F.M. Acosta: None. A.R. Stepanenko: None. M. Brown: None. A.J. Moody: None. N. Sanchez: None. T.M. Cortes: None. Y. Qin: None. C. Triplitt: None. G. Clarke: None. S.E. Espinoza: None. N. Musi: None. C. Solis-Herrera: None. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are drugs for treating T2D. Through their glucosuric effect, you see a reduced HbA1c, weight loss, and improved insulin sensitivity/ β-cell function. Beyond their glycemic properties, SGLT2i provide substantial cardio-renal benefits. Given their multiple therapeutic advantages and established safety profile, there is the presupposition that SGLT2i may have various beneficial possibilities in medical practice. An area of interest for SGLT2i is their use as agents for late-aging and longevity. SGLT2i are known to promote a calorie restriction (CR) state by promoting glucosuria and fatty acid-oxidation/ketogenesis and reducing insulin levels. CR activates a myriad of anti-aging-related pathways, including senescence-associated “inflammaging,” which can be triggered by obesity and states of overnutrition. However, clinical research in this area remains largely unexplored. A single-center, open-label, randomized-controlled clinical trial was designed to determine the effect of SGLT2i on the aging-related processes of global and adipose tissue inflammation and senescence. Twenty older, obese, pre-diabetic subjects (Age=70±1.5, BMI=33.7±0.6, A1c=5.9±0.03) were randomized dapagliflozin 10mg/day (SGLT2i) vs. nutritional counseling for weight loss (control) in a 1:1 fashion for 12 weeks. Healthspan and clinical evaluation were performed at baseline and weeks 10-12 of the study. The SGLT2i group showed a significant decrease (-5.4±1.7, p=0.01) in weight loss, downward trend in HbA1c (-0.02±0.06 vs. +0.06±0.04), and significant loss in %Fat vs. control (-1%, p=0.05 vs. -0.5%, p=0.1). Given adiposity changes observed with SGLT2i, in a subset of subjects (n=10), subcutaneous fat biopsies were performed, and single nuclei (sn)RNA-seq done to map changes in adipose cellular populations (mature adipocytes, immune, endothelial, and adipogenic progenitor cells) and molecular profiling. Notably, with SGLT2i, the mature adipocyte, immune, and adipogenic progenitor cells, saw a significant (p≤0.05) decrease in senescent score. Globally, plasma-measured inflammaging-associated factors in the IL8 and TNFα families, also saw a significant decrease (p≤0.05) with SGLT2i.Aging and metabolic homeostasis are bidirectional processes. As you age, adiposity tends to increase, associated with an upsurge in the development of metabolic syndrome-related diseases in older adults. Here we demonstrate that in the high-risk population of older obese adults with pre-diabetes, SGLT2i targets multiple points in the spectrum that delay the aging process. In particular, we show evidence that SGLT2i treatment improves the global and adipose senescent and inflammatory profile, alongside glycemic and weight control. These findings support the notion that SGLT2i may contribute to the increase of both healthspan and lifespan. Presentation: Saturday, June 17, 2023

FRI021 Adipocyte Subpopulations Regulate The Lipolytic Response And Inflammatory Cytokine Action In Obesity

Abstract Disclosure: J. Huang: None. R. Sharma: None. K.Y. Lee: None. Previously, our lab has utilized gene expression profiling and lineage tracing analysis to uncover three developmentally and functionally distinct subpopulations of white adipocytes with stable and unique gene expression profiles, which were termed Type 1, 2, and 3 adipocytes, respectively. This study extends these findings to investigate the role of Type 2 adipocytes in obesity. We found that the proportion of Type 2 preadipocytes and adipocytes in each adipose tissue was stable through time, but was dynamically regulated by high-fat diet (HFD) induced obesity in a depot-specific manner with a 59.34% increase in the perigonadal fat depots. Histological examination of fat depots after HFD-induced obesity revealed that over 80% of recruited macrophages, organized into crown-like structures, were found in direct contact with Type 2 adipocytes indicating increased necrosis or apoptosis of this adipocyte subpopulation. In addition, treatment of macrophage-derived inflammatory cytokine TNFα increased lipolysis specifically in Type 2 adipocytes by 11.9%, with no effects on other adipocytes. As previous studies have shown that inflammatory cytokines promote lipolysis in adipose tissue, at least in part, through the reduction of FSP27 (fat specific protein 27), we assessed the contribution of Type 2 adipocytes by overexpressing FSP27 specifically in this population (Type2Ad-hFSP27tg mice) during the development of obesity. We found that HFD-fed male Type2Ad-hFSP27tg mice had improved glucose tolerance and insulin sensitivity, with no change in body weight. These metabolic changes may, at least in part, be explained by the reduced basal and stimulated lipolysis rate in the visceral fat of Type2Ad-hFSP27tg mice compared with control mice. Although over-expression of FSP27 in primary Type 2 adipocytes is sufficient to acutely reduce TNFα-induced apoptosis, no reduction of macrophage infiltration was found in HFD-fed Type2Ad-hFSP27tg visceral fat after 18 weeks of HFD. Taken together, these results strongly suggest that adipocyte subpopulations contribute to the regulation of obesity-associated inflammation and lipolytic response in adipose tissue. Presentation: Friday, June 16, 2023

Immune profile of adipose tissue from youth with obesity and asthma.

Obesity is a risk factor for paediatric asthma. Obesity-mediated systemic inflammation correlates with metabolic dysregulation; both are associated with asthma burden. However, adipose tissue inflammation is not defined in obesity-related asthma. Define adipose tissue inflammation and its association with metabolic measures in paediatric obesity-related asthma. Cellular profile of stromal vascular fraction from visceral adipose tissue (VAT) from youth with obesity-related asthma (n = 14) and obesity without asthma (n = 23) was analyzed using flow cytometry and correlated with metabolic measures. Compared to youth without asthma, VAT from youth with obesity-related asthma was enriched for leukocytes and macrophages, including M1 and dual M1M2 cells, but did not differ for CD4+ lymphocytes, and endothelial cells, their progenitors, and preadipocytes. M1 macrophage counts positively correlated with glucose, while M1M2 cells, CD4+ lymphocytes, and their subsets negatively correlated with high-density lipoprotein, in youth with obesity without asthma, but not among those with obesity-related asthma. Enrichment of macrophage-mediated inflammation in VAT from youth with obesity-related asthma supports its role in systemic inflammation linked with asthma morbidity. Lack of correlation of VAT cells with metabolic dysregulation in youth with obesity-related asthma identifies a need to define distinguishing factors associated with VAT inflammation in obesity-related asthma.

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.

OC 28.2 Neutrophil-Derived Factor XIII-A Transglutaminase Contributes to Adipose Tissue Fibrosis and Inflammation in Mouse-Obesity Model

OC 28.2 Neutrophil-Derived Factor XIII-A Transglutaminase Contributes to Adipose Tissue Fibrosis and Inflammation in Mouse-Obesity Model

Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

BackgroundThe gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition.ResultsIn this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo.ConclusionsOur findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue.7MrSGPEkxmDTc41cVX6rPoVideo

Adipocyte Glucocorticoid Receptor Inhibits Immune Regulatory Genes to Maintain Immune Cell Homeostasis in Adipose Tissue.

Glucocorticoids acting via the glucocorticoid receptors (GR) are key regulators of metabolism and the stress response. However, uncontrolled or excessive GR signaling adversely affects adipose tissue, including endocrine, immune, and metabolic functions. Inflammation of the adipose tissue promotes systemic metabolic dysfunction; however, the molecular mechanisms underlying the role of adipocyte GR in regulating genes associated with adipose tissue inflammation are poorly understood. We performed in vivo studies using adipocyte-specific GR knockout mice in conjunction with in vitro studies to understand the contribution of adipocyte GR in regulating adipose tissue immune homeostasis. Our findings show that adipocyte-specific GR signaling regulates adipokines at both mRNA and plasma levels and immune regulatory (Coch, Pdcd1, Cemip, and Cxcr2) mRNA gene expression, which affects myeloid immune cell presence in white adipose tissue. We found that, in adipocytes, GR directly influences Cxcr2. This chemokine receptor promotes immune cell migration, indirectly affecting Pdcd1 and Cemip gene expression in nonadipocyte or stromal cells. Our findings suggest that GR adipocyte signaling suppresses inflammatory signals, maintaining immune homeostasis. We also found that GR signaling in adipose tissue in response to stress is sexually dimorphic. Understanding the molecular relationship between GR signaling and adipose tissue inflammation could help develop potential targets to improve local and systemic inflammation, insulin sensitivity, and metabolic health.

Study the Effect of Some Adipokines and Interleukins in Hypo and Hyperthyroidism Patients

Introduction: Thyroid diseases have effects on metabolism and inflammation. Adipocytokines have autocrine, paracrine, and endocrine functions on several organs which have a central role in subclinical inflammation of adipose tissue, and obese adipose tiss

Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD.

This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individualswith obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. In humanswith obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1)polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.