Le tissu adipeux : un acteur majeur du syndrome inflammatoire de l’obésité ?

The concept of the existence of a low grade chronic inflammation during human obesity, which can play a role in the physiopathology of the disease and its complications, has been the subject of intense investigations for a few years. The number of molecules linked to inflammation (acute phase inflammation proteins, interleukins, cytokines) whose circulating concentrations are increased in obese subjects, does not cease rising. Weight loss generally involves a reduction of these inflammatory factors in blood circulation. Recent work showed that white adipose tissue (WAT) expresses many pro and anti-inflammatory molecules and probably contributes to increasing their circulating levels in obese subjects. Cellular and histological studies showed that the genes of inflammation are expressed within WAT by cells that are not adipocytes but constitute the “stroma vascular fraction”, in particular by the macrophages infiltrating in a substantial way adipose tissue during obesity. This review aims at synthesizing the knowledge on the inflammation in human obesity and focuses on the mechanisms of macrophage infiltration in WAT and its local and systemic consequences.     

Tissu adipeux viscéral : rôle majeur dans le syndrome métabolique

The relationship between excess visceral fat and insulin resistance seems to play a central role in the development of the metabolic syndrome. The portal fat hypothesis is based on a unique venous drainage of visceral fat depot and its increased lipolytic activity, that could explain hepatic insulin resistance. On the other hand the offensives (visfatine, TNFα, PAI-1 and IL6) or defensives cytokines (adiponectine) secreted by visceral fat contribute to the pathogenesis of hepatic and systemic insulin resistance. Obesity can be considered as a low grade systemic inflammatory disease with a particular role for macrophage infiltration in omental adipose tissue. Numerous cross-sectional and a few longitudinal studies are in favour of this third paradigm. Nevertheless, intra abdominal obesity is not the only culprit. Increased subcutaneous abdominal fat and decreased leg fat mass have independent and opposite associations with metabolic abnormalities of the metabolic syndrome. The ectopic fat storage syndrome and the lipodystrophic adiposity hypothesis give a major role to the dysregulation of free fatty acid fluxes between white adipose tissue and other tissues, i.e. the muscle, the liver and probably the beta cell. As far as insulin resistance is concerned, increased visceral fat could have a dramatic effect at the beginning of abdominal obesity development or for patients with severe metabolic syndrome associated with partial lipodystrophy.     

Développement du tissu adipeux : importance des lipides alimentaires

A well-balanced development of white adipose tissue (WAT) is physiologically important. Longitudinal studies indicate that excess of adipose tissue at early age is predictive of subsequent overweight and obesity, emphasizing infancy as a critical period for WAT development. In this respect, in response to a positive energy balance, its expansion takes place from adipocyte precursor cells which remain present throughout life. Moreover, lipoatrophy and lipodystrophy on one hand, overweight and obesity on the other hand, lead to the metabolic syndrome. In obese patients, the earlier is the obesity onset, the higher is adipocyte size and even more so adipocyte number. As adipocytes do not divide, this observation indicates that excessive proliferation of adipocyte precursor cells is a critical issue, hampered by the lack of specific markers of these cells which represent the true potential of WAT development.In animals and humans, both cross-sectional and longitudinal studies have shown that a caloric excess, i.e. fat-enriched foods in most cases, is associated to enhanced fat mass. The role of dietary fat as a major player in adult human obesity remains controversial because the prevalence of overweight and obesity has increased dramatically over the last decades despite no recent major change in the amount of ingested fats. However the importance of qualitative changes in the fatty acid composition of fats has been largely disregarded despite a dramatic alteration over decades of the balance of essential polyunsaturated fatty acids (PUFAs). There is evidence from animal and human studies that changes in the balance of ω6 and ω3 PUFAs may alter the early stages of adipose tissue development. Under isonenergetic conditions, pups from wild-type mother mice fed a linoleic acid (LA)-enriched diet were 40% heavier 1 week after weaning than those from mothers fed a LA/α-linolinenic acid (LA/LNA) diet, and the weight difference is maintained at the adult age. The LA-induced enhancement of fat mass is abolished in mice invalidated for the cell surface prostacyclin receptor (ip ^-/- mice), demonstrating the critical role of arachidonic acid and prostacyclin in excessive adipose tissue development. Changes observed in the past decades in the fatty acid composition of dietary fats observed in breast milk and formula milk, i.e. an increase in LA with slight or no change in LNA content, acting in concert with a positive energy balance, may be responsible at least in part for the dramatic rise in the prevalence of childhood overweight and obesity. The significant change in the composition of PUFAs in most consumed foods can be traced to changes in human food habits but, quite importantly, also in the feeding pattern of breeding stock. Since prevention of obesity appears critical to avoid difficult if not insurmountable health problems in the future, and in addition to a better control of energy balance, the composition of dietary lipids should be reconsidered from the very beginning of the food chain.     

Le tissu adipeux : un donneur de cellules souches ?

Several laboratories have shown that the cells from the stroma-vascular fraction of the human adipose tissue express, depending on cell culture conditions, biochemical markers of multiple cell lineages including adipogenic, osteogenic, chondrogenic, myogenic, endothelial, neuronal and epithelial cell lineage. Furthermore, various in vivo approaches revealed the ability of the cells derived from the stroma-vacsular fraction of adipose tissue to repair ischemic or damaged tissues. Altogether these data strongly suggest that the stroma-vascular fraction of the human adipose tissue contains cells that exhibit properties like stem/progenitor cells. However, the exact nature of the cells, their potentiality to lead to differentiated cells in vivo as well as the mechanisms involved in their repair capability remain to be characterized to consider their use in regenerative and reparative medicine.     

Que devient le tissu adipeux dans l’obésité ?

Adipose tissue exerts multiples functions related to glucose and lipid homeostasis. The adipose tissue is a site of low-grade inflammation in obese subjects, evidenced by immune cells accumulation, mainly macrophages. Pro-inflammatory factors produced by macrophages alter adipocytes biology and may contribute to the severity of metabolic complications, including insulin resistance and hepatic diseases. However, macrophages might also be beneficial to tissue homeostasis through the elimination of deficient adipocytes or pro-angiogenic effects. The cellular and molecular mechanisms of macrophage infiltration are related, at least in part, to a dialogue among hypertrophied adipocytes, macrophages and other cell-types, including lymphocytes, pre-adipocytes and endothelial cells within adipose tissue. A newly discovered consequence of adipose tissue inflammation is fibrosis that is organized both in bundles and around adipocytes. These cellular and structural alterations are only partly reversible after weight loss and reflect the pathology of adipose tissue that may contribute to the chronicity of obesity. In this context, identification of pharmacological means to maintain adipose tissue integrity remains a major challenge in the field.     

Associations of abdominal intermuscular adipose tissue and inflammation: The Multi-Ethnic Study of Atherosclerosis

ObjectiveThis study examined the associations between abdominal IMAT area and density with inflammatory markers associated with cardiometabolic disease.Methods1897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis underwent computed tomography to quantify body composition and measurements of adiponectin, leptin, interleukin-6 (IL-6), C-reactive protein (CRP), and resistin.ResultsThe mean age and body mass index of participants was 65 years and 28 kg/m², respectively, and 50% were female. After adjustment for age, sex, and race/ethnicity, as IMAT area increased and density decreased from the first to fourth quartile, markers of inflammation increased linearly (p < 0.01). Using linear regression, and with adjustment for demographics, cardiovascular disease risk factors, and abdominal muscle area and density, a 1-standard deviation (SD) increase in total abdominal IMAT area was associated with a 21%, 36% and 20% higher IL-6, leptin, and CRP, respectively, and 19% lower adiponectin (p < 0.001). With similar adjustment, a 1-SD decrease in total abdominal IMAT density was associated with a 14%, 32%, and 15% higher IL-6, leptin, and CRP, respectively, and 22% lower adiponectin (p < 0.001). These associations were attenuated with the addition of visceral fat (p > 0.05).ConclusionsAbdominal IMAT area and density are associated with inflammatory markers, with these associations attenuated by central adiposity.     

Changes in metabolic parameters in growing male rats exposed to 10% and 30% sucrose drinking

Sucrose drink induced obesity and metabolic syndrome in human and animal models. However, age-specific metabolic effects of sucrose beverages are not clear yet. The purpose of this study was then to investigate changes in plasma biochemical parameters, oxidative stress markers, as well as lipid and redox contents and lipolytic activities in insulin target organs (liver, adipose tissue) in sucrose drinking rats at 10% and 30% during one month (day 30) and three months (day 90). Our results emphasized that sucrose drink induced obesity, adipose tissue accumulation with hyperinsulinemia, hyperglycemia, hyperlipidemia, liver steatosis, alterations in lipases activities and oxidative stress. These metabolic alterations were worsened by the amount of sucrose in the drink (30% versus 10%). The changes were apparent in young rats at day 30 and persisted until adulthood at day 90. Adult rats presented more sucrose-induced-metabolic abnormalities. In conclusion, sucrose drink induced an early increase in metabolic syndrome components. These data indicate the need of corrective nutritional intervention for young people and also for adults.     

Central obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: Role of nutrition and insulin challenge

ObjectiveInsulin resistance (IR) and white adipose tissue (WAT) dysfunction frequently are associated with nonalcoholic fatty liver disease (NAFLD); however, the pathogenic mechanisms contributing to their clustering are not well defined. The aim of this study was to define some nutritional, anthropometric, metabolic, and genetic mechanisms contributing to their clustering.MethodsForty-five (20 men, 25 women) patients (age 45.7 ± 11.1 y) with recent diagnosis of NAFLD were grouped according to IR state. Energy balance was assessed using a food questionnaire and indirect calorimetry, and body composition with anthropometry and dual-energy x-ray absorptiometry. Biochemical and hormonal parameters combined with adipose tissue gene expression were determined. Microarray analysis of gene expression was performed in a subset of WAT samples from IR patients (n = 9), in the fasted state, after specific test meals (monounsaturated fatty acid [MUFA], saturated fat [SAT], and carbohydrate-rich) and after being challenged with insulin.ResultsIR patients exhibited higher trunk fat to leg fat ratio (P < 0.05) and had a higher ratio of SAT/MUFA fat intake (P < 0.05) than insulin-sensitive (IS) individuals. Deposition of fat in the trunk but not in the leg was directly related to liver enzyme levels (P < 0.05). IR patients also had lower adiponectin serum levels and leptin (LEP) mRNA expression in WAT compared with IS patients (P < 0.01 and P < 0.05, respectively). Microarray analysis after insulin challenge confirmed that insulin treatment induces the expression of PPARG gene and LEP and decreases GCGR gene (P < 0.05 for all) in WAT. No changes in these genes were observed in the postprandial state induced after the acute effect of specific diets.ConclusionsPatients exhibiting NAFLD and IR had preferential central fat deposition directly related to their serum alanine aminotransferase levels. These patients showed peripheral adipose tissue dysfunction and exhibited inappropriately low LEP biosynthesis that could be partially restored after anabolic conditions induced by insulin signaling.     

芦丁抑制3T3-L1前脂肪细胞分化并促进米色脂肪细胞形成

  目的  探讨芦丁对米色脂肪细胞形成的影响。  方法  用不同浓度芦丁处理3T3-L1前脂肪细胞;细胞计数盒（CCK8）检测不同浓度芦丁对细胞活性影响,油红O染色观察脂滴大小;Western blot检测过氧化物酶增殖物激活受体 – γ（PPAR-γ）、aP2及解偶联蛋白1（UCP1）表达;RT-qPCR检测UCP1、PRDM16、Dio2表达;细胞免疫荧光检测线粒体变化。  结果  芦丁在0～250 μmol/L范围内对细胞活性无明显影响,且以药物依赖性方式减少脂滴生成;与对照组[aP2（1.12 ± 0.03）]、[PPAR-γ（0.87 ± 0.02）]比较,50、100、250 μmol/L芦丁使aP2[分别为（0.87 ± 0.03）、（0.64 ± 0.01）、（0.64 ± 0.05）]、PPAR-γ[分别为（0.73 ± 0.02）、（0.46 ± 0.02）、（0.43 ± 0.05）]蛋白表达降低,使UCP1蛋白表达[分别为（0.58 ± 0.03）、（0.42 ± 0.02）、（0.34 ± 0.01）]增加;与对照组比较,50 μmol/L芦丁可使UCP1、PRDM16、Dio2表达[分别为（7.02 ± 0.24）、（2.09 ± 0.06）、（10.40 ± 0.93）]升高;细胞免疫荧光显示,3T3-L1前脂肪细胞内线粒体含量增加。  结论  芦丁可减少3T3-L1前脂肪细胞脂滴生成,并促进米色脂肪细胞形成。     

环境内分泌干扰物对哮喘发生影响研究进展

环境内分泌干扰物对全球环境和生物方面的影响越来越受到重视,其可能通过影响神经中枢和免疫系统及激活相关丝裂原活化蛋白激酶通路而增加哮喘发生。本文以近年来各类内分泌干扰物相关毒理学研究资料为依据,综述其可能对哮喘产生的影响。     

Obesity,insulin resistance,adipocytokines and breast cancer: New biomarkers and attractive therapeutic targets

Worldwide, breast cancer (BC) represents the most common type of non-skin human malignancy and the second leading cause of cancer-related deaths amid women in Western countries. Obesity and its metabolic complications have rapidly become major global health issues and are associated with increased risk for cancer, especially BC in postmenopausal women. Adipose tissue is considered as a genuine endocrine organ secreting a variety of bioactive adipokines, such as leptin, adiponectin, resistin and nicotinamide phosphoribosyl-transferase/visfatin. Recent evidence has indicated that the constellation of obesity, insulin resistance and adipokines is associated with the risk and prognosis of postmenopausal BC. Direct evidence is growing rapidly supporting the stimulating and/or inhibiting role of adipokines in the process of development and progression of BC. Adipokines could exert their effects on the normal and neoplastic mammary tissue by endocrine, paracrine and autocrine mechanisms. Recent studies support a role of adipokines as novel risk factors and potential diagnostic and prognostic biomarkers in BC. This editorial aims at providing important insights into the potential pathophysiological mechanisms linking adipokines to the etiopathogenesis of BC in the context of a dysfunctional adipose tissue and insulin resistance in obesity. A better understanding of these mechanisms may be important for the development of attractive preventive and therapeutic strategies against obesity-related breast malignancy.     

Genetic test in multiple endocrine neoplasia type 1 syndrome: An evolving story

Multiple endocrine neoplasia type 1(MEN1) is an autosomal dominant inherited tumour syndrome expressing various endocrine and non-endocrine lesions and tumours. Since the identification of the causative gene, the oncosuppressor gene MEN1, in 1997, genetic testing has revealed an important approach for the early and differential diagnosis of the disease. The finding of a MEN1 mutation in a patient has important clinical implications for relatives since it allows very early disease diagnosis and identification of carriers, even before biochemical and/or clinical manifestation, permitting their inclusion in a specific program of surveillance and subsequent praecox therapy. Currently, genetic testing for MEN1 consists principally of the sequencing of coding regions and intron-exon junctions of the MEN1 gene. However, the recent acquisition of novel high throughput technologies will allow the design of innovative, accurate, complete and rapid genetic diagnosis. These new tools are able to increase the strength of the analysis and almost completely eliminate the possibility of false negative results. This review aims to give an overview on genetic testing of MEN1 syndrome, reporting the positive aspects of performing the analysis and the future perspectives for improving the performance of the test, as well as its application in clinical practice.     

Genetic mechanisms of fetal male undermasculinization: a background to the role of endocrine disruptors

Fetal male sex development proceeds along an orderly sequence of events coordinated by an interplay of genetic and hormonal events. These operate in a time- and concentration-dependent manner. Once a testis is formed (the female sex being constitutive in nature), differentiation of the internal and external male genitalia is androgen dependent. A number of genetic syndromes of sex reversal are well characterized at the biochemical and molecular levels. They fall into three principal categories: defects in formation of the testis, defects in production of androgens, and defects in the action of androgens. In many instances, the precise cause is not established, although the investigative evidence points in the direction of one of the three stated classifications. Polymorphic variants in several of the genes involved in male development are associated with certain degrees of male undermasculinization. While the genetic background is essentially static, it is plausible that the effect of endocrine disruptors during fetal life acting through epigenetic mechanisms may partly explain the observed changing trends in male reproductive tract disorders.     

Multi-factorial influences on sex ratio: a spatio-temporal investigation of endocrine disruptor pollution and neighborhood stress

Abstract

Background:

It is suggested the declining male birth proportion in some industrialized countries is linked to ubiquitous endocrine disruptor exposure. Stress and advanced parental age are determinants which frequently present positive findings. Multi-factorial influences on population sex ratio are rarely explored or tested in research.

Objectives:

To test the hypothesis that dual factors of pollution and population stress affects sex proportion at birth through geographical analysis of Central Scotland.

Methods:

The study incorporates the use of Geographical Information Systems (GIS) tools to overlay modeled point source endocrine disruptor air emissions with “small-area” data on multiple deprivation (a proxy measurement of stress) and birth sex. Historical review of regional sex ratio trends presents additional data on sex ratio in Scotland to consider.

Results:

There was no overall concentration in Central Scotland of low sex ratio neighborhoods with areas where endocrine disruptor air pollution and deprivation or economic stress were high. Historical regional trends in Scotland (from 1973), however, do show significantly lower sex ratio values for populations where industrial air pollution is highest (i.e. Eastern Central Scotland).

Conclusions:

Use of small area data sets and pollution inventories is a potential new method of inquiry for reproductive environmental and health protection monitoring and has produced interesting findings.