Diet-induced adiposity alters the serum profile of inflammation in C57BL/6N mice as measured by antibody array

Morbid obesity is considered a systemic inflammatory state. The objective of this project was to characterize the adipokine, cytokine and chemokine protein profile in serum from control, lean and obese mice. We hypothesized that chemokines and cytokines are altered by caloric restriction and diet-induced obesity as a function of changes in body composition. Six-week-old female C57BL/6N mice (n = 12 per group) were randomized to one of three diets: control (fed ad libitum ); lean (30% calorie-restricted regimen relative to control) and diet-induced obese (DIO; high calorie diet, fed ad libitum ). Body weight, body composition and food intake were monitored throughout the study. After 10 weeks on the diets, blood samples were collected, and adipokine/cytokine/chemokine serum profiles were measured by antibody array. Lean mice, relative to the control group, displayed increased concentrations of insulin-like growth factor (IGF) binding protein-3, -5 and -6 and adiponectin and decreased IGF-1. These mice also showed increased concentrations of interleukin (IL)-10, IL-12 p40/p70, eotaxin, monocyte chemoattractant protein-5 and SDF-1. In contrast, DIO mice displayed increased leptin, IL-6 and LPS-induced chemokine and decreased concentrations of all chemokines/cytokines measured relative to control mice. As such, these data indicate that DIO may lead to an inflammatory state characterized as a shift towards a T helper lymphocyte type 1–skewed responsiveness. The demonstration of differential adipokine, cytokine and chemokine protein profile in control, lean and DIO mice may have implications for immune responsiveness and risk of disease.     

Obesity-induced inflammation: a metabolic dialogue in the language of inflammation

Obesity induces an inflammation state that is implicated in many clinically important complications, including insulin resistance, diabetes, atherosclerosis and non-alcoholic fatty liver disease. Although the cause and the molecular participants in this process remain incompletely defined, adipose tissue has a central role. Obesity-induced production of pro-inflammatory molecules, typified by TNF-alpha was recognized more than a dozen years ago, and since then more than two dozen other pro-inflammatory molecules induced by obesity have been identified. More recently a critical role for immune cells, specifically mononuclear phagocytes, in generating the obesity-induced inflammation has been identified. Defining the molecular and cellular components of obesity-induced inflammation offers the potential of identifying therapeutic targets that can ameliorate the complications associated with obesity.     

Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance

Aims: Obesity is associated with insulin resistance, liver steatosis and low‐grade inflammation. The role of oestrogen in sex differences in the above co‐morbidities is not fully understood. Our aim was to assess the role oestrogen has in modulating adipocyte size, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. Methods: To determine the role oestrogen has in the above co‐morbidities related to obesity, we randomized C57BL/6J mice into four groups (15 mice per group): (i) male, (ii) non‐ovariectomized female (novx), (iii) ovariectomized female (ovx) and (iv) ovariectomized female mice supplemented with 17β estradiol (ovx‐E). Mice received either a low‐fat (LF) or a high‐fat (HF) diet for 10 weeks. Outcomes measured were bodyweight, body fat, adipocyte diameter, adipose tissue lipolysis markers, adipose tissue oxidative stress, inflammation, insulin resistance and liver steatosis. Results: Male and ovx‐female mice consuming the HF diet had a higher propensity of gaining weight, specifically in the form of body fat. Oestrogen protected female mice from adipocyte hypertrophy and from developing adipose tissue oxidative stress and inflammation. Moreover, novx‐female and ovx‐female+E mice had higher phosphorylated levels of protein kinase A and hormone sensitive lipase, markers associated with lipolysis. Additionally, male and ovx female mice had a higher propensity of developing liver steatosis and insulin resistance. In contrast, oestrogen protected female mice from developing liver steatosis and from becoming insulin resistant. Conclusion: We show that oestrogen protects female mice from adipocyte hypertrophy and adipose tissue oxidative stress and inflammation. Furthermore, oestrogen prevented female mice from developing liver steatosis and from becoming insulin resistant.     

Visualized macrophage dynamics and significance of S100A8 in obese fat

Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysM^EGFP) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysM^EGFP-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-α and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysM^EGFP-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ.Obesity, especially visceral fat obesity, is a central player in the development of metabolic syndrome and in its clinical consequences (1–4). Chronic low-grade inflammation of adipose tissue has been demonstrated to be critical in the pathogenesis of obesity (5, 6). In terms of innate immune cells, the defining feature of adipose tissue inflammation in obesity is a marked increase of macrophage infiltration into adipose tissue (6, 7). The macrophages in inflamed adipose tissue are predominantly inflammatory M1 macrophages producing proinflammatory cytokines such as TNF-α (8). The other immune cells, such as T/B lymphocytes (9, 10), neutrophils (11), and eosinophils (12), have also been shown to play significant roles in adipose tissue inflammation and consequent metabolic disorders. However, most of these observations are based on immunohistological and flow cytometric analyses. The dynamic nature of immune cells has not been fully elucidated in adipose tissue during the progression of obesity. Adipose tissue is considered to be a key site of interaction between adipocytes and other immune system effectors, which may highlight the necessity to analyze immune cell dynamics in obese adipose tissue in vivo.Chemokines and other inflammatory mediators have been proposed to be involved in adipose tissue inflammation in obesity. Several potential targets of modulation of inflammatory response have been demonstrated. Among them, there is considerable evidence for the pathophysiological role of the chemokine (C-C motif) ligand 2 [CCL2; monocyte chemoattractant protein-1 (MCP-1)]/chemokine (C-C motif) receptor 2 (CCR2) pathway in monocyte/macrophage infiltration into obese adipose tissues (13, 14). In addition, danger-associated molecular patterns, also called alarmins, which are released from damaged tissues and stressed cells, have caused sterile immune responses such as obesity-induced chronic inflammation. Pattern-recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors are involved in binding and responding to alarmins, including high-mobility group box chromosomal protein 1 (HMGB1) (15), S100 proteins (16, 17), saturated fatty acid (18, 19), oxidized LDL (20), and degradation products of extracellular matrices (21). Furthermore, adipose-derived saturated fatty acids have been shown to directly activate TLR4 and TLR2, not only of macrophages but also of adipocytes themselves, as endogenous ligands, resulting in the production of proinflammatory cytokines and chemokines and the dysregulation of adipocytokines (18, 19).Chronic inflammation is a complex phenomenon, and multiple factors have been shown to be intricately involved in the progression of adipose tissue inflammation when it has happened. However, the early events triggering the chronic inflammatory cascades in adipose tissues have not been understood. Here, by means of intravital multiphoton microscopy of adipose tissues, we visualized time-dependent changes of immune cell dynamics during the development of obesity, and succeeded in identifying the early triggering event of chronic inflammation in obese adipose tissue.     

Alterations in cyclic nucleotide phosphodiesterase activities in omental and subcutaneous adipose tissues in human obesity

Objective: To elucidate the activity and expression of cyclic nucleotide phosphodiesterase (PDE) families in omental (OM) and subcutaneous (SC) adipose tissue and adipocytes, and to study alterations in their activity in human obesity.Design: Cross-sectional, translational research study.Patients: In total, 25 obese and 9 non-obese subjects undergoing gastrointestinal surgery participated in the study.Results: Inverse correlations between PDE activities and body mass index (BMI) were seen in both SC and OM adipose tissue. Inverse correlations between total PDE and PDE3 activity and BMI were seen in OM adipocytes but not in SC adipocytes. In both SC and OM adipose tissue of obese patients, total PDE and PDE3 activities were decreased compared with the controls. In SC adipose tissue of Type 2 diabetes (T2D) patients, the PDE activity not inhibitable by PDE3 or PDE4 inhibitors (PDEn) was increased compared with obese non-diabetic patients. In addition to PDE3 and 4 isoforms, PDE7B, PDE9A and PDE10A proteins were also detected in adipose tissue or adipocytes.Conclusions: Multiple PDE families are present in human adipose tissue and their activities are differentially affected by obesity and T2D.     

Common mechanisms of dysfunctional adipose tissue and obesity‐related cancers

The relation between cancer and metabolic disorders was recognized several decades ago, but the underlying mechanisms involved in cancer development and progression remain obscure. In the last years, many groups have been studying systemic adipose tissue markers in cancer patients. However, few consistent results were obtained. On the other hand, several studies revealed many aspects of adipose tissue physiology in obesity. Nowadays, it is recognized that excessive lipid uptake in adipocytes leads to hypertrophy and consequently to metabolic dysregulation, hypoxia, inflammation, impaired adipocytokine expression and angiogenesis, insulin resistance and macrophage recruitment. In obese patients, tumours commonly colocalize with excessive adipose tissue accumulation, and most of the features of hypertrophic adipose tissue are observed in cancer patients, namely breast and colon. This review aimed to summarize pathological adipose tissue alterations that may contribute to cancer aetiology and development. Copyright © 2013 John Wiley & Sons, Ltd.     

What are the mechanisms of action of anti-inflammatory agents in adipose tissue?: A protocol for systematic review and meta-analysis

Background:Obesity is a disease characterized by the abnormal accumulation of adipose tissue in the body, triggering a chronic subclinical state of inflammation. Bioactive compounds, given their anti-inflammatory properties, are a safe and promising alternative in controlling the inflammatory condition of obesity. This study describes a systematic review protocol aiming to analyze the anti-inflammatory molecules mechanisms and compounds action on adipocytes.Methods:Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) will outline the protocol and PRISMA to the systematic review. The databases used for research will be PubMed, Science Direct, Scopus, Web of Science, BVS, and EMBASE. Experimental studies performed on rats and mice with a control group that describes treatment with anti-inflammatory agents (drugs, nutraceuticals, bio active compounds, among others) at any frequency, time, and dose will be included. Three independent reviewers will select studies and extract data. The evaluation of the methodological quality of each research will be performed using the SYRCLE tool. If at least 2 studies show clinical and/or methodological and/or statistical homogeneity, a meta-analysis will be performed, using the RevMan Analyzes statistical package in Review Manager v.5.3.Results:In this study, we hope to find a considerable number of articles presenting mechanisms involved in the action of anti-inflammatory molecules and compounds on adipocytes.Conclusion:The systematic review produced from this protocol will present evidence on the mechanisms involved in the action of anti-inflammatory molecules and compounds in adipocytes. It will also contribute to developing new research and new insights about anti-inflammatory therapies with a future application view.Record of systematic review:This review was registered with the International Register of Prospective Systematic Reviews on May 18, 2020 (registration: CRD42020182897). Available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020182897.     

In humans the adiponectin receptor R2 is expressed predominantly in adipose tissue and linked to the adipose tissue expression of MMIF‐1

In this study, the regional adipose tissue‐adiponectin (AT‐ADN) and adiponectin receptor (R1 and R2) expression and their relation with metabolic parameters, circulating and AT‐derived cytokine expressions were compared. Paired subcutaneous adipose tissue (SCAT) and visceral adipose tissue (VAT) were taken from 18 lean and 39 obese humans, AT‐mRNA expression of adipokines analysed by RT‐PCR and corresponding serum levels by enzyme‐linked immunosorbent assay (ELISA). R1 and R2 adipocyte expression was compared with 17 other human tissues. ADN‐gene expression was lower in VAT than SCAT [mean (SD) 1.54 (1.1) vs. 2.84 (0.87); p < 0.001], and lower in obese subjects (VAT : p = 0.01;SCAT : p < 0.001). SCAT‐ADN correlated positively with serum ADN (r = 0.33;p = 0.036) but not VAT‐ADN. AT expressions of ADN and macrophage migration inhibiting factor (MMIF), IL18 and cluster of differentiation factor 14 (CD14) in both depots showed inverse correlations. R1 and R2 were expressed ubiquitously and R2 highest in SCAT, and this is much higher (×100) than R1 (×100). R expression was similar in lean and obese subjects and unrelated to the metabolic syndrome, however, receptors correlated with VAT‐MMIF (R 1: r = 0.4;p = 0.008;R 2: r = 0.35,p = 0.02) and SCAT‐MMIF expression (R 2: r = 0.43;p = 0.004). Unlike ADN, its receptors are expressed in many human tissues. Human R2 expression is not highest in the liver but in AT where it is associated with MMIF expression. The adiponectin‐dependent insulin‐sensitizing action of thiazolidinediones is thus probably to differ amongst species with weaker effects on the human liver.     

Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis

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C1q/肿瘤坏死因子相关蛋白6在肥胖及胰岛素抵抗中的研究进展

C1q/肿瘤坏死因子相关蛋白6(CTRP6)是CTRP超家族中的一员,诸多研究证明,CTRP在胰岛素抵抗及肥胖的形成中起到重要作用,因而研究其参与的作用及具体机制,有助于为胰岛素抵抗及肥胖的治疗指明方向。文章主要对CTRP6的结构、分布及其促进胰岛素抵抗与肥胖的相关生理功能的研究进展进行综述。