Adipose Tissue Infiltration Research Articles

Development of new bioabsorbable implants with de novo adipogenesis

Poly-L-lactic acid (PLLA) mesh implants containing collagen sponge (CS) were replaced with autologous adipose tissue regeneration in vivo. Herein, we investigated the optimal external frames and internal fillings using poly (lactic-co-ε-caprolactone) (P (LA/CL)), PLLA, and low-molecular-weight PLLA (LMW-PLLA) as the external frame and polyglycolic acid (PGA) nanosheets and CS as the internal filling. We prepared six implants: P (LA/CL) with PGA nano, PLLA with PGA nano, PLLA with CS, PLLA with 1/2 CS, PLLA with 1/4 CS, and LMW-PLLA with CS, and evaluated adipogenesis at 6 and 12 months using a rat inguinal model. The internal spaces in the P (LA/CL) and LMW-PLLA implants collapsed at 6 months, whereas those in the other four implants collapsed at 12 months. Adipose tissue regeneration was not significantly different between the PLLA-implanted groups at 6 and 12 months and was greater than that in the P (LA/CL) with PGA nano and LMW-PLLA with CS groups. The PGA nanosheet inside PLLA was comparable to the CS inside PLLA in the regeneration of adipose tissue and macrophage infiltration. In summary, PLLA is a promising external frame material in which the internal space can be replaced with adipose tissue. Thus, PGA nanosheets are an alternative internal filling material for adipose tissue regeneration.

Biventricular isolated apical hypoplasia: First-time description of a new cardiac abnormality by multimodality imaging

Left ventricular isolated hypoplasia is a seldom-described cardiac abnormality. Right ventricular hypoplasia is usually associated with congenital anomalies of the pulmonary or the tricuspid valve, whereas biventricular isolated apical hypoplasia has never been described. We report the case of a 48-year-old man with no history of known cardiac disease who was found to have a complex cardiac abnormality characterized by: 1) Deficiency of the myocardium within the biventricular apex with adipose tissue infiltration; 2) Truncated right ventricle because of an absent trabecular portion of the inflow tract; 3) Truncated and spherical left ventricular apex; 4) Origin of the mitral papillary muscle in the flattened anterior left ventricular apex. Multimodality imaging was performed to delineate the morphological and functional characteristics of this cardiomyopathy fully. To the best of our knowledge, this is the first description of a new cardiac abnormality characterized by the hypoplasia of the apical region of both ventricles in the absence of valvular or coronary artery disease.

Prevotella intermedia Aggravates Subclinical Hypothyroidism

Subclinical hypothyroidism (SCH) has been shown to be associated with microbiota. However, the association between SCH and oral microbiota has not yet been elucidated. The results of our previous clinical studies showed that Prevotella intermedia was abundant in the oral microbiota of SCH patients. This study aimed to investigate the relationship between SCH and oral microbiota, verify the pathogenicity of P. intermedia in SCH, and preliminarily explore the possible mechanism. The SCH mouse model with oral application of P. intermedia was established, and the variance in the mouse oral microbiota and changes in thyroid function and metabolism were detected in mice. Student’s t test and analysis of variance were used for statistical analysis. Oral application of P. intermedia changed the composition of the oral microbiota of SCH mice, which enhanced the damage to the thyroid and decreased the expression of functional genes of the thyroid. Moreover, P. intermedia decreased oxygen consumption and aggravated glucose and lipid metabolism disorders in SCH mice. Glucose tolerance and insulin tolerance decreased, and the triglyceride content of the liver and inflammatory infiltration in adipose tissue increased in SCH mice after P. intermedia stimulation. Mechanistically, P. intermedia increased the proportion of CD4+ T cells in cervical lymph nodes and thyroids in SCH mice. Th1 cells were suggested to play an important role in the pathogenesis of SCH involving P. intermedia. In conclusion, P. intermedia aggravated SCH manifestations, including thyroid dysfunction and glucose and lipid metabolism disorders, by causing immune imbalance in mice. This study sheds new light on the pathogenesis of SCH from the perspective of oral microbiota.

Estimation of subvoxel fat infiltration in neurodegenerative muscle disorders using quantitative multi-T2 analysis.

MRI's T2 relaxation time is a valuable biomarker for neuromuscular disorders and muscle dystrophies. One of the hallmarks of these pathologies is the infiltration of adipose tissue and a loss of muscle volume. This leads to a mixture of two signal components, from fat and from water, to appear in each imaged voxel, each having a specific T2 relaxation time. In this proof-of-concept work, we present a technique that can separate the signals from water and from fat within each voxel, measure their separate T2 values, and calculate their relative fractions. The echo modulation curve (EMC) algorithm is a dictionary-based technique that offers accurate and reproducible mapping of T2 relaxation times. We present an extension of the EMC algorithm for estimating subvoxel fat and water fractions, alongside the T2 and proton-density values of each component. To facilitate data processing, calf and thigh anatomy were automatically segmented using a fully convolutional neural network and FSLeyes software. The preprocessing included creating two signal dictionaries, for water and for fat, using Bloch simulations of the prospective protocol. Postprocessing included voxelwise fitting for two components, by matching the experimental decay curve to a linear combination of the two simulated dictionaries. Subvoxel fat and water fractions and relaxation times were generated and used to calculate a new quantitative biomarker, termed viable muscle index, and reflecting disease severity. This biomarker indicates the fraction of remaining muscle out of the entire muscle region. The results were compared with those using the conventional Dixon technique, showing high agreement (R = 0.98, p< 0.001). It was concluded that the new extension of the EMC algorithm can be used to quantify abnormal fat infiltration as well as identify early inflammatory processes corresponding to elevation in the T2 value of the water (muscle) component. This new ability may improve the diagnostic accuracy of neuromuscular diseases, help stratification of patients according to disease severity, and offer an efficient tool for tracking disease progression.

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe?

CD40LG and GZMB were correlated with adipose tissue macrophage infiltration and involved in obstructive sleep apnea related metabolic dysregulation: Evidence from bioinformatics analysis.

Both obesity and obstructive sleep apnea (OSA) can lead to metabolic dysregulation and systemic inflammation. Similar to obesity, increasing evidence has revealed that immune infiltration in the visceral adipose tissue (VAT) is associated with obstructive sleep apnea-related morbidity. However, the pathological changes and potential molecular mechanisms in visceral adipose tissue of obstructive sleep apnea patients need to be further studied. Herein, by bioinformatics analysis and clinical validation methods, including the immune-related differentially expressed genes (IRDEGs) analysis, protein-protein interaction network (PPI), functional enrichment analysis, a devolution algorithm (CIBERSORT), spearman's correlation analysis, polymerase chain reaction (PCR), Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), we identified and validated 10 hub IRDEGs, the relative mRNA expression of four hub genes (CRP, CD40LG, CCL20, and GZMB), and the protein expression level of two hub genes (CD40LG and GZMB) were consistent with the bioinformatics analysis results. Immune infiltration results further revealed that obstructive sleep apnea patients contained a higher proportion of pro-inflammatory M1 macrophages and a lower proportion of M2 macrophages. Spearman's correlation analysis showed that CD40LG was positively correlated with M1 macrophages and GZMB was negatively correlated with M2 macrophages. CD40LG and GZMB might play a vital role in the visceral adipose tissue homeostasis of obstructive sleep apnea patients. Their interaction with macrophages and involved pathways not only provides new insights for understanding molecular mechanisms but also be of great significance in discovering novel small molecules or other promising candidates as immunotherapies of OSA-associated metabolic complications.

The Role of Omega-3 Polyunsaturated Fatty Acids and Their Lipid Mediators on Skeletal Muscle Regeneration: A Narrative Review

Skeletal muscle is the largest tissue in the human body, comprising approximately 40% of body mass. After damage or injury, a healthy skeletal muscle is often fully regenerated; however, with aging and chronic diseases, the regeneration process is usually incomplete, resulting in the formation of fibrotic tissue, infiltration of intermuscular adipose tissue, and loss of muscle mass and strength, leading to a reduction in functional performance and quality of life. Accumulating evidence has shown that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and their lipid mediators (i.e., oxylipins and endocannabinoids) have the potential to enhance muscle regeneration by positively modulating the local and systemic inflammatory response to muscle injury. This review explores the process of muscle regeneration and how it is affected by acute and chronic inflammatory conditions, focusing on the potential role of n-3 PUFAs and their derivatives as positive modulators of skeletal muscle healing and regeneration.

Human epicardial adipose tissue inflammation correlates with coronary artery disease.

This study investigates the expression of novel adipocytokines and inflammatory cells infiltration in epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) between 27 coronary artery disease (CAD) and 21 non-CAD (NCAD) patients enrolled from September 2020 to September 2021. Serum, gene, and protein expression levels of the novel adipocytokines were determined using ELISA, RT-qPCR, and western blot analyses. The number of blood vessels and adipocytes morphology were measured via hematoxylin-eosin staining, and inflammatory cells infiltration was examined via immunohistochemistry. Serum ANGPTL8, CTRP5, and Wnt5a levels were higher in the CAD than in the NCAD group, while serum CTRP3, Sfrp5, and ZAG levels were lower in the CAD than in the NCAD group. Compared to the EAT of NCAD and SAT of CAD patients, the EAT of CAD patients had higher mRNA levels of ANGPTL8, CTRP5, and Wnt5a while lower levels of CTRP3, Sfrp5, and ZAG; higher protein expression levels of ANGPTL8 and CTRP5 but lower levels of CTRP3; more blood vessels; and higher infiltration rates of macrophages (CD68+), pro-inflammatory M1 macrophages (CD11c+), mast cells (Tryptase+), T lymphocytes (CD3+), and B lymphocytes (CD20+) but lower infiltration rates of anti-inflammatory M2 macrophages (CD206+). Novel adipocytokines and inflammatory cells infiltration are dysregulated in human EAT, and could be important pathophysiological mechanisms and novelly promising medicating targets of CAD.

Antiobesity Effect of Lacticaseibacillus paracasei LM-141 on High-Fat Diet-Induced Rats through Alleviation of Inflammation and Insulin Resistance.

In this study, we set out to evaluate the antiobesity activities of our newly isolated Lacticaseibacillus paracasei LM-141 (LPLM141) using a high-fat diet (HFD)-fed rat model. Male Sprague-Dawley rats were fed with a HFD with or without low-dosage (2 × 107 CFU/day per rat) or high-dosage (2 × 109 CFU/day per rat) LPLM141 for 14 weeks. The results showed that administration of LPLM141 significantly decreased body weight gain, liver weight, adipose tissue weight, and epididymal white adipocyte size increased by HFD feeding. The abnormal serum lipid profile induced by HFD feeding was normalized by administration of LPLM141. The enhanced chronic low-grade inflammation in HFD-fed rats was reduced by LPLM141 supplementation, as reflected by decreased serum lipopolysaccharide (LPS) and monocyte chemoattractant protein-1 (MCP-1) levels, reduced macrophage infiltration in adipose tissue, and increased serum adiponectin concentration. In addition, the elevations of proinflammatory cytokine genes and suppression of PPAR-γ mRNA in adipose tissues of rats fed with a HFD were markedly reversed by LPLM141 administration. Oral administration of LPLM141 induced browning of epididymal white adipose tissue (eWAT) and activation of interscapular brown adipose tissue (iBAT) in rats fed with HFD. Consumption of LPLM141 exhibited a significant amelioration in insulin resistance, which were mechanistically caused by downregulation of the serum leptin level and upregulation of hepatic IRS-1 and p-Akt protein expressions, in HFD treated rats. LPLM141 consumption significantly decreased hepatic lipogenic gene expressions and preserved liver function stimulated by HFD treatment. Administration of LPLM141 obviously mitigated hepatic steatosis observed in HFD feeding rats. Our current findings shed light on LPLM141 supplementation that exhibited an antiobesity effect in HFD-fed rats by alleviating inflammation and insulin resistance, which further highlighted the potential of utilizing LPLM141 as a preventive/therapeutic probiotic agent for obesity.

Abstract P065: Effects of metformin on breast tissue inflammation in premenopausal women with components of metabolic syndrome

Abstract Background: Obesity, with increasing worldwide prevalence, is associated with increased breast cancer burden. The association is attributed to multiple metabolic disturbances including chronic inflammation due to dysfunctional adipose tissue. Features of local breast adipose tissue inflammation such as macrophage infiltration and an enriched pro-inflammatory gene signature were recently reported in mouse models of obesity and in women with high adiposity or metabolic disorders. Strategies that can reduce obesity-induced chronic inflammation may lead to reduction of breast cancer risk. Metformin, a widely used anti-diabetic drug, exerts favorable effects on multiple metabolic disturbances. This study aims to evaluate the clinical effects of metformin on breast tissue inflammation. Methods: Macrophage infiltration and polarization were determined in breast core needle biopsies collected at baseline and 6 months after agent intervention from a Phase II randomized, double-blind, placebo-controlled trial of metformin in premenopausal women with components of metabolic syndrome. Macrophage infiltration was assessed using a pan macrophage marker (CD68) by immunohistochemistry (IHC). M1 and M2 macrophages were assessed using CD40 and CD206 surface markers, respectively, by IHC. The primary endpoint is the change in macrophage density in breast adipose tissue. Secondary endpoints include the change in macrophage density in breast stroma and epithelium tissues, the proportion of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages in breast adipose, stroma, and epithelium tissues. Results: Baseline biopsies from 76 participants (40 in the metformin arm and 36 in the placebo arm) were available for CD68 analysis. The baseline CD68 density was 22.48 ± 3.25, 67.26 ± 9.68, 418.81± 71.02 (mean±SE) per mm2 in breast adipose, stroma, and epithelium tissues, respectively. Biopsies from 71 participants (34 in the metformin arm and 37 in the placebo arm) were available for CD68 analysis at 6 months. Comparing to placebo, metformin intervention led to a significant reduction in CD68 density in breast adipose tissue (p = 0.01) but did not change the CD68 density in breast epithelium and stroma tissues. Conclusion: Metformin intervention resulted in favorable changes in macrophage infiltration in breast adipose tissue in premenopausal women with component of metabolic syndrome. Studies are ongoing to evaluate the effects of metformin on macrophage polarization. Citation Format: Liane E. Pinto, Sara Centuori, Jose Guillen-Rodriguez, Denise J. Roe, Edgar Tapia, Pavani Chalasani, H-H. Sherry Chow. Effects of metformin on breast tissue inflammation in premenopausal women with components of metabolic syndrome. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P065.

PS-BPB04-2: P2RX7 DEFICIENCY OR P2RX7 ANTAGONISM BLUNTS ANGIOTENSIN II-INDUCED HYPERTENSION, VASCULAR INJURY AND CD8+ T CELL ACTIVATION

Objectives: Innate and adaptive immune cells contribute to hypertension and end-organ damage. High blood pressure (BP) causes cardiovascular injury and the release of damage-associated molecule patterns such as adenosine triphosphate (ATP). ATP can bind to the purinergic receptor P2X7 (P2RX7) on innate immune cells triggering interleukin-1β; release, which drives further immune activation. Elevated plasma ATP levels was observed in hypertensive patients. We hypothesized that P2rx7 knockout or P2RX7 antagonism would blunt angiotensin II (AngII)-induced BP elevation and cardiovascular injury through decreased immune activation. Design and method: Ten-to-12-week-old male C57BL/6J wild-type (WT) and P2rx7-/- mice were infused or not with AngII (1000 ng/kg/min) for 14 days. A second group of AngII-infused WT mice was also infused with the P2RX7 antagonist AZ10606120 (694 ng/kg/min) or vehicle. BP was determined by telemetry, plasma ATP using a bioluminescence assay, mesenteric artery function using pressurized myography, cardiac left ventricle (LV) function and mass by ultrasound and activated immune T cell infiltration in aortic perivascular adipose tissue (PVAT) by flow cytometry. Results: Plasma ATP was 2.2 fold higher in AngII-infused compared to sham-treated mice (P &lt; 0.05). AngII-induced systolic BP elevation was reduced by P2rx7 deficiency (12 mm Hg, P &lt; 0.05) or P2RX7 antagonism (27 mm Hg, P &lt; 0.01). AngII induced a 26% decrease in LV fractional shortening (FS, P &lt; 0.05) and a 1.5 fold increase in LV mass/body weight (BW) in WT mice (P &lt; 0.001), which were exaggerated in P2rx7-/- mice (FS: 38% lower and LVmass/BW: 1.14 fold higher, P &lt; 0.05), but not in mice receiving AZ10606120. AngII treatment caused a 26% reduction in the dilatation response of mesenteric arteries to acetylcholine in WT mice (P &lt; 0.05), but not in P2rx7-/- or AZ10606120-treated mice. AngII promoted a 3.8 fold increase in CD69+CD8+ T cell infiltration in aortic PVAT of WT mice (P &lt; 0.001), but not in P2rx7-/- or AZ10606120-treated mice. Conclusion: P2rx7 knockout or antagonism attenuates AngII-induced BP elevation, vascular injury, and infiltration of activated CD8+ T cells into aortic PVAT. P2rx7 knockout exacerbated AngII-induced cardiac dysfunction and hypertrophy, whereas P2RX7 antagonism did not.

Acne Scars: Multimodal Treatment with Surgical Subdermal Plane Dissection, Microfragmented Adipose Tissue Infiltration and Deep CO2 Laser Resurfacing. Our Clinical Experience in 15 Clinical Cases Treated

Acne vulgaris is a common dermatological condition with an estimated prevalence of 70 to 87% in the general population; post-acne scars are equally common conditions with an estimated prevalence of 11 to 14% in the general population and cause a major impact on patients' quality of life with an important negative psychological impact.

Supplemental wheat germ modulates phosphorylation of STAT3 in the gut and NF-κBp65 in the adipose tissue of mice fed a Western diet

BackgroundCommensal gut bacteria, including Lactobacillus, can produce metabolites that stimulate the release of gut antimicrobial peptides (AMPs) via the signal transducer and activator of transcription (STAT)3 pathway and prevent obesity-associated leaky gut and chronic inflammation. We have previously reported that wheat germ (WG) selectively increased cecal Lactobacillus in obese mice. ObjectivesThis study investigated the effects of WG on gut STAT3 activation and AMPs (Reg3γ and Reg3β) as well as the potential of WG to inhibit nuclear Nf-κB–activation and immune cell infiltration in the visceral adipose tissue (VAT) of mice fed a Western diet (i.e., high-fat and sucrose diet [HFS]). MethodsSix-wk-old male C57BL/6 mice were randomly assigned to 4 groups (n = 12/group): control (C, 10% fat and sucrose kcal) or HFS (45% fat and 26% sucrose kcal) diet with or without 10% WG (wt/wt) for 12 wk. Assessments include serum metabolic parameters jejunal AMPs genes, inflammatory markers, and phosphorylation of STAT3 as well as VAT NF-κBp65. Independent and interaction effects of HFS and WG were analyzed with a 2-factor ANOVA. ResultsWG significantly improved markers of insulin resistance and upregulated jejunal Il10 and Il22 genes. The HFS + WG group had a 15-fold increase in jejunal pSTAT3 compared with the HFS group. Consequently, WG significantly upregulated jejunal mRNA expression of Reg3γ and Reg3β. The HFS group had a significantly higher VAT NF-κBp65 phosphorylation than the C group, while the HFS + WG group suppressed this to the level of C. Moreover, VAT Il6 and Lbp genes were downregulated in the HFS + WG group compared with HFS. Genes related to macrophage infiltration in the VAT were repressed in the WG-fed mice. ConclusionThese findings show the potential of WG to influence vital regulatory pathways in the gut and adipose tissue which may reduce the chronic inflammatory burden on these tissues that are important targets in obesity and insulin resistance.

Gene Expression Profiling of Peripheral Blood Mononuclear Cells in Type 2 Diabetes: An Exploratory Study.

Background and Objectives: Visceral obesity is associated with chronic low-grade inflammation that predisposes to metabolic syndrome. Indeed, infiltration of adipose tissue with immune-inflammatory cells, including 'classical' inflammatory M1 and anti-inflammatory 'alternative' M2 macrophages, causes the release of a variety of bioactive molecules, resulting in the metabolic complications of obesity. This study examined the relative expression of macrophage phenotypic surface markers, cholesterol efflux proteins, scavenger receptors, and adenosine receptors in human circulating peripheral blood mononuclear cells (PBMCs), isolated from patients with type 2 diabetes mellitus (T2DM), with the aim to phenotypically characterize and identify biomarkers for these ill-defined cells. Materials and Methodology: PBMCs were isolated from four groups of adults: Normal-weight non-diabetic, obese non-diabetic, newly diagnosed with T2DM, and T2DM on metformin. The mRNA expression levels of macrophage phenotypic surface markers (interleukin-12 (IL-12), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 17 (CCL17), and C-C motif receptor 7 (CCR7)), cholesterol efflux proteins (ATP-binding cassette transporter-1 (ABCA1), ATP binding cassette subfamily G member 1 (ABCG1), and sterol 27-hydroxylase (CYP27A)), scavenger receptors (scavenger receptor-A (SR-A), C-X-C motif ligand 16 (CXCL16), and lectin-like oxidized LDL receptor-1 (LOX-1)), and adenosine receptors (adenosine A2A receptor (A2AR) and adenosine A3 receptor (A3R)) were measured using qRT-PCR. Results: In PBMCs from T2DM patients, the expression of IL-12, CCR7, ABCA1, and SR-A1 was increased, whereas the expression of CXCL10, CCL17, ABCG1,27-hydroxylase, LOX-1, A2AR and A3R was decreased. On the other hand, treatment with the antidiabetic drug, metformin, reduced the expression of IL-12 and increased the expression of 27-hydroxylase, LOX-1, CXCL16 and A2AR. Conclusions: PBMCs in the circulation of patients with T2DM express phenotypic markers that are different from those typically present in adipose tissue M1 and M2 macrophages and could be representative of metabolically activated macrophages (MMe)-like cells. Our findings suggest that metformin alters phenotypic markers of MMe-like cells in circulation.

Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice

Multiple genome-wide association studies (GWAS) have identified specific genetic variants in the coiled-coil domain containing 92 (CCDC92) locus that is associated with obesity and type 2 diabetes in humans. However, the biological function of CCDC92 in obesity and insulin resistance remains to be explored. Utilizing wild-type (WT) and Ccdc92 whole-body knockout (KO) mice, we found that Ccdc92 KO reduced obesity and increased insulin sensitivity under high-fat diet (HFD) conditions. Ccdc92 KO inhibited macrophage infiltration and fibrosis in white adipose tissue (WAT), suggesting Ccdc92 ablation protects against adipose tissue dysfunction. Ccdc92 deletion also increased energy expenditure and further attenuated hepatic steatosis in mice on an HFD. Ccdc92 KO significantly inhibited the inflammatory response and suppressed the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome in WAT. Altogether, we demonstrated the critical role of CCDC92 in metabolism, constituting a potential target for treating obesity and insulin resistance.

Dynamics of adipose tissue macrophage populations after gastric bypass surgery.

This case-control study aimed to analyze the dynamics of macrophage infiltration in subcutaneous adipose tissue following bariatric surgery or conservative treatment of obesity and to clarify whether these features predict the weight loss outcome after the surgery. Subcutaneous tissue samples taken before and 12 months after laparoscopic Roux-en-Y gastric bypass surgery (n=39) or conservative (n=43) treatment for obesity were analyzed. Fat cell size was determined, and with CD68 immunohistochemistry, crown-like structures (CLS) were counted and single macrophages were quantitated. A major decline in CLS density from 4.1 (SD 3.5) to 1.1 (SD 0.8) per 1000 fat cells (p < 0.000) was found, regardless of the degree of weight loss after the surgery. Surgery had no effect on the fraction of infiltrating single-cell macrophages in subcutaneous adipose tissue. The abundance of these macrophage populations before the intervention did not predict the degree of postsurgery weight loss or suboptimal response to the surgery. The effect of gastric bypass on adipose tissue inflammatory status associates closely with CLS density even in subjects with suboptimal weight loss. The study suggests that factors related to bypass surgery other than weight loss modify the inflammatory response in adipose tissue.

Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity.

Obesity is characterized by chronic, low-grade inflammation, which is driven by macrophage infiltration of adipose tissue. PPARγ is well established to have an anti-inflammatory function in macrophages, but the mechanism that regulates its function in these cells remains to be fully elucidated. PPARγ undergoes post-translational modifications (PTMs), including acetylation, to mediate ligand responses, including on metabolic functions. Here, we report that PPARγ acetylation in macrophages promotes their infiltration into adipose tissue, exacerbating metabolic dysregulation. We generated a mouse line that expresses a macrophage-specific, constitutive acetylation-mimetic form of PPARγ (K293Qflox/flox:LysM-cre, mK293Q) to dissect the role of PPARγ acetylation in macrophages. Upon high-fat diet feeding to stimulate macrophage infiltration into adipose tissue, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice, including responses to the PPARγ agonist Rosiglitazone. Macrophage-specific PPARγ K293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue, but not in subcutaneous or brown adipose tissue, leading to decreased energy expenditure, insulin sensitivity, glucose tolerance, and adipose tissue function. Furthermore, mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling. Our study reveals that acetylation is a new layer of PPARγ regulation in macrophage activation, and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.

RF04 | PSUN313 A Natural Antibody Against Oxidized Phospholipids Improves Glucose Metabolism in Aging Mice

Abstract Oxidative stress-induced lipid peroxidation generates oxidized phospholipids (OxPL), such as oxidized phosphatidylcholine, that are pro-inflammatory moieties present on oxidized low density lipoproteins and apoptotic cells. OxPL have been implicated in the pathogenesis of cardiovascular, neurological, autoimmune, liver, and lung diseases. It has been shown earlier that OxPL decrease bone formation. Natural antibodies (NAb) produced by B-1 lymphocytes, bind OxPL and prevent their inflammatory activity. The NAb E06 blocks oxidized phosphatidylcholine, and transgenic expression of a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv) prevents many age-associated diseases, such as atherosclerosis, non-alcoholic steatohepatitis and age-related bone loss. OxPL are also implicated in the pathogenesis of the metabolic syndrome and diabetes by either causing insulin resistance, increasing macrophage infiltration and inflammation in white adipose tissue, decreasing insulin gene expression, and/or causing death of pancreatic beta cells through induction of oxidative stress and amyloid protein misfolding. Consistent with this evidence, NAb produced by B-1b lymphocytes are protective against obesity associated inflammation, glucose intolerance, and insulin resistance. In the work reported here, we have investigated the impact of oxidized phosphatidylcholine on glucose metabolism and age–related glucose intolerance. To this end, we aged chow-fed female and male C57BL/6 E06-scFv transgenic mice (and their WT littermates) up to 22 and 24 months. Both male and female E06-scFv transgenic mice accumulated less fat mass than WT littermates during aging, as determined by sequential body composition measurements by DXA. Intraperitoneal glucose tolerance test, performed at 10 and at 15 months of age, showed that glucose tolerance was greater in both male and female E06-ScFv transgenic mice than WT littermates and did not differ from the glucose tolerance of young mice. Insulin sensitivity, measured by insulin tolerance test, was increased in 4- and 10-month-old old transgenic females and in 15-month-old transgenic males. There was no difference in food consumption calculated over 5 days or the production of glucose after pyruvate infusion, indicating similar liver gluconeogenesis in both strains. Physical activity or energy expenditure, measured by indirect calorimetry in 11-month-old females, was indistinguishable between transgenic and WT mice. However, E06-scFv transgenic mice exhibited a significant increase in the respiratory exchange ratio, indicating that utilization of glucose was the main metabolic source under basal conditions. Collectively, these results show that blocking oxidized phosphatidylcholine improves age–related glucose intolerance in mice fed a normal diet; hence, OxPL are major culprits of the aging-associated glucose intolerance. Therefore, targeting OxPL with a neutralizing antibody represents a novel therapeutic intervention that may simultaneously ameliorate several age-associated diseases, including the metabolic syndrome and diabetes. Presentation: Saturday, June 11, 2022 1:42 p.m. - 1:47 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Fat infiltration in the infarcted heart as a paradigm for ventricular arrhythmias

Infiltrating adipose tissue (inFAT) has been recently found to co-localize with scar in infarcted hearts and may contribute to ventricular arrhythmias (VAs), a life-threatening heart rhythm disorder. However, the contribution of inFAT to VA has not been well-established. We investigated the role of inFAT versus scar in VA through a combined prospective clinical and mechanistic computational study. Using personalized computational heart models and comparing the results from simulations of VA dynamics with measured electrophysiological abnormalities during the clinical procedure, we demonstrate that inFAT, rather than scar, is a primary driver of arrhythmogenic propensity and is frequently present in critical regions of the VA circuit. We determined that, within the VA circuitry, inFAT, as opposed to scar, is primarily responsible for conduction slowing in critical sites, mechanistically promoting VA. Our findings implicate inFAT as a dominant player in infarct-related VA, challenging existing paradigms and opening the door for unexplored anti-arrhythmic strategies.

Identification of a biomarker and immune infiltration in perivascular adipose tissue of abdominal aortic aneurysm.

Objective: Abdominal aortic aneurysm (AAA) refers to unusual permanent dilation of the abdominal aorta, and gradual AAA expansion can lead to fatal rupture. However, we lack clear understanding of the pathogenesis of this disease. The effect of perivascular adipose tissue (PVAT) on vascular functional status has attracted increasing attention. Here, we try to identify the potential mechanisms linking AAA and PVAT. Methods: We downloaded dataset GSE119717, including 30 dilated AAA PVAT samples and 30 non-dilated aorta PVAT samples from AAA cases, from Gene Expression Omnibus to identify differentially expressed genes (DEGs). We performed pathway enrichment analysis by Metascape, ClueGo and DAVID to annotate PVAT functional status according to the DEGs. A protein-protein interaction network, the support vector machine (SVM)-recursive feature elimination and the least absolute shrinkage and selection operator regression model were constructed to identify feature genes. Immune infiltration analysis was explored by CIBERSORT. And the correlation between feature gene and immune cells was also calculated. Finally, we used the angiotensin II (Ang II)-ApoE−/− mouse model of AAA to verify the effect of feature gene expression by confirming protein expression using immunohistochemistry and western blot. Results: We identified 22 DEGs, including 21 upregulated genes and 1 downregulated gene. The DEGs were mainly enriched in neutrophil chemotaxis and IL-17 signaling pathway. FOS was identified as a good diagnostic feature gene (AUC = 0.964). Immune infiltration analysis showed a higher level of T cells follicular helper, activated NK cells, Monocytes, activated Mast cells in AAA group. And FOS was correlated with immune cells. Immunohistochemistry and western blot confirmed higher FOS expression in PVAT of the AAA mouse model compared to control group. Conclusion: The differentially expressed genes and pathways identified in this study provide further understanding of how PVAT affects AAA development. FOS was identified as the diagnostic gene. There was an obvious difference in immune cells infiltration between normal and AAA groups.