PPARs信号通路参与肠道菌群和棕色脂肪组织的代谢调控肥胖

背景:肠道菌群与棕色脂肪组织之间存在着复杂的调控机制和广泛联系,但是目前机制尚未阐明。目的:揭示棕色脂肪组织与肠道菌群间的潜在关系,为接下来的研究提供实验思路。方法:由第一作者应用计算机以“brown adipose tissue,intestinal flora,obesity,peroxisome proliferator activated receptor family”为英文检索词,以“棕色脂肪组织,肠道菌群,肥胖,过氧化物酶体增殖物激活受体家族”为中文检索词在PubMed、万方、维普、知网数据库中检索1994-01-01/2020-06-01的相关文献,并对文献的相关内容进一步筛选、归纳分析与总结,最终纳入38篇相关文献进行综述。结果与结论:①肠道菌群失调会影响过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs),PPARs又可以影响棕色脂肪组织的代谢进而调控肥胖;PPARα、PPARβ和PPARγ都与脂肪代谢有关,可以被相应的激活剂激活促进棕色脂肪组织的表达,其中PPARγ在肠道菌群和棕色脂肪组织中的联系最为密切,肠道菌群代谢的变化可以上调PPARγ的表达,从而激活棕色脂肪组织达到减肥的目的;②调节肠道菌群与棕色脂肪组织的关系可以治疗肥胖症;③从棕色脂肪组织、PPARs信号通路两者中研究抵抗肥胖的相关药物前景可观。     

Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma

Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.     

The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis

Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear hormone receptor that serves as a trans factor to regulate lipid metabolism. Intense interest is focused on PPAR-gamma and its ligands owing to its putative role in adipocyte differentiation. Little is known, however, about the functions of PPAR-gamma in the immune system, especially in T lymphocytes. We demonstrate that both naive and activated ovalbumin-specific T cells from DO11.10-transgenic mice express PPAR-gamma mRNA and protein. In order to determine the function of PPAR-gamma, T cells were stimulated with phorbol 12-myristate 13-acetate and ionomycin or antigen and antigen-presenting cells. Simultaneous exposure to PPAR-gamma ligands (e. g. 15-deoxy-Delta(12, 14)-prostaglandin J(2), troglitazone) showed drastic inhibition of proliferation and significant decreases in cell viability. The decrease in cell viability was due to apoptosis of the T lymphocytes, and occurred only when cells were treated with PPAR-gamma, and not PPAR-alpha agonists, revealing specificity of this response for PPAR-gamma. These observations suggest that PPAR-gamma agonists play an important role in regulating T cell-mediated immune responses by inducing apoptosis. T cell death via PPAR-gamma ligation may act as a potent anti-inflammatory signal in the immune system, and ligands could possibly be used to control disorders in which excessive inflammation occurs.     

Adiponectin, a new hormone: its role in the pathogenesis of diabetes mellitus

Adiponectin is a hormone of adipose tissue, activating lipid metabolism and other physiological functions. Adiponectin deficiency induces obesity and decreases insulin-regulated carbohydrate metabolism, thus leading to insulin resistance. Blood level of adiponectin falls in type 2 diabetes. Adiponectin receptors--AdipoR1 and AdipoR2--are proteins with 7 transmembrane domains, which are synthesized mostly in muscles and the liver and function in a close connection with G proteins. Obesity and diabetes lower the tissue concentration of the receptors, thus impeding adiponectin regulation of lipid exchange and lowering the effectiveness of the insulin control of carbohydrate exchange. Adiponectin also influences cardiovascular functions and prevents atherosclerosis and some of the other kinds of vascular pathology.     

Quantitative image analysis in adipose tissue using an automated image analysis system: differential effects of peroxisome proliferator-activated receptor-alpha and -gamma agonist on white and brown adipose tissue morphology in AKR obese and db/db diabetic mice

Morphometric analysis of adipocytes is widely used to demonstrate the effects of antiobesity drugs or anti-diabetic drugs on adipose tissues. However, adipocyte morphometry has been quantitatively performed by manual object extraction using conventional image analysis systems. The authors have developed an automated quantitative image analysis method for adipose tissues using an innovative object-based quantitative image analysis system (eCognition). Using this system, it has been shown quantitatively that morphological features of adipose tissues of mice treated with peroxisome proliferator-activated receptor (PPAR) agonists differ dramatically depending on the type of PPAR agonist. Marked alteration of morphological characteristics of brown adipose tissue (BAT) treated with GI259578A, a PPAR-alpha agonist, was observed in AKR/J (AKR) obese mice. Furthermore, there was a 22.8% decrease in the mean size of adipocytes in white adipose tissue (WAT) compared with vehicle. In diabetic db/db mice, the PPAR-gamma agonist GW347845X decreased the mean size of adipocytes in WAT by 15.4% compared with vehicle. In contrast to changes in WAT, GW347845X increased the mean size of adipocytes in BAT greatly by 96.1% compared with vehicle. These findings suggest that GI259578A may activate fatty acid oxidation in BAT and that GW347845X may cause adipocyte differentiation in WAT and enhancement of lipid storage in BAT.     

Development of adipose tissues

Studies on the development of brown and white adipose tissues and their relationship to ordinary connective tissue are the subject of the present review, which is updated to the fall of 1985. Primordial entities described as "primitive organs" have been noted at sites of adipose tissue development by numerous investigators. These "primitive organs" are clearly delineated from surrounding connective tissue and possess a well-defined vascular network in the interstices of which cellular organization takes place. The precursor cells of brown and white adipocytes appear to acquire their distinctive cytogenetic properties at a very early stage in the embryo. These progenitor cells temporarily exhibit structural similarities to fibroblasts and endothelial cells. This resemblance has led to speculation that fibroblasts and/or endothelial cells may be ancestral to adipocytes. However, recent in vivo and in vitro observations suggest that the brown adipose precursor cell is morphogenetically distinct from the white adipose precursor cell on one hand, and from fibroblasts and endothelial cells on the other. In vitro studies have also shown that the pericytic elements present in both brown and white adipose tissue depots in the adult are quiescent precursor cells that may be recruited under certain circumstances. Areas for further inquiry by means of recently developed techniques are indicated.     

Cross-talk between adipose tissue and vasculature: role of adiponectin

Adipose tissue is a highly dynamic endocrine organ, secreting a number of bioactive substances (adipokines) regulating insulin sensitivity, energy metabolism and vascular homeostasis. Dysfunctional adipose tissue is a key mediator that links obesity with insulin resistance, hypertension and cardiovascular disease. Obese adipose tissue is characterized by adipocyte hypertrophy and infiltration of inflammatory macrophages and lymphocytes, leading to the augmented production of pro-inflammatory adipokines and vasoconstrictors that induce endothelial dysfunction and vascular inflammation through their paracrine and endocrine actions. By contrast, the secretion of adiponectin, an adipokine with insulin sensitizing and anti-inflammatory activities, is decreased in obesity and its related pathologies. Emerging evidence suggests that adiponectin is protective against vascular dysfunction induced by obesity and diabetes, through its multiple favourable effects on glucose and lipid metabolism as well as on vascular function. Adiponectin improves insulin sensitivity and metabolic profiles, thus reducing the classical risk factors for cardiovascular disease. Furthermore, adiponectin protects the vasculature through its pleiotropic actions on endothelial cells, endothelial progenitor cells, smooth muscle cells and macrophages. Data from both animal and human investigations demonstrate that adiponectin is an important component of the adipo-vascular axis that mediates the cross-talk between adipose tissue and vasculature. This review highlights recent work on the vascular protective activities of adiponectin and discusses the molecular pathways underlying the vascular actions of this adipokine.     

Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model

BACKGROUND: Allergic asthma is associated with persistent functional and structural changes in the airways and involves many different cell types. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is predominantly expressed in adipose tissue and plays a major role in regulating adipocyte differentiation and glucose metabolism. Recently, PPAR-gamma has been shown to play an important role in the control of inflammatory responses, including within the lung, acting on both immune and nonimmune cells. OBJECTIVE: Our aim was to assess the anti-inflammatory potential of a PPAR-gamma agonist locally delivered by means of nebulization. METHODS: We used a mouse model of asthma induced by sensitization and airway challenge with ovalbumin. Ciglitazone, a PPAR-gamma agonist, was administered by means of nebulization alone at the time of antigen challenge or by means of gavage and nebulization. Treatments with both ciglitazone and GW9662, a specific antagonist, were also performed to verify that ciglitazone's effects were mediated through PPAR-gamma activation. RESULTS: Our results show that PPAR-gamma is mainly expressed in airway epithelium on antigen sensitization. Treatment with ciglitazone reduced PPAR-gamma levels in the lung, whereas combined treatment with GW9662 abrogated this inhibition. Importantly, nebulization with ciglitazone decreased airway hyperresponsiveness, basement membrane thickness, mucus production, collagen deposition, and TGF-beta synthesis. A significant correlation was also found between airway hyperresponsiveness, basement membrane thickness, and TGF-beta levels. CONCLUSION: These results demonstrate that inhaled agonistic ligands of PPAR-gamma might have new therapeutic potential for airway asthmatic inflammation.     

Brown adipocyte precursor cells: a morphological study

The origin of brown adipocyte precursor cells is to date unknown. Some authors believe they arise from vascular cells, others from interstitial cells. The purpose of the present ultrastructural study was to find markers in rat fetal and perinatal adipose tissue that can be used to identify brown adipose precursor cells. The study was carried out on the interscapular brown adipose tissue of fetal (fetuses of 19 and 21 days) and perinatal rats (pups of 4 and 12 hours and of 1, 3, 5, 7, 9, 11, 13, and 15 days). The analysis focused on stem cells and showed the characteristic presence of typical mitochondria which make their identification as brown adipocyte precursor cells inequivocal. These cells were frequently observed in a pericytic position. Also some endothelial cells were characterised by typical mitochondria and abundant glycogen. These data seem to support the hypothesis that brown adipocytes originate from vascular cells.     

Vascular effects of GI262570X (PPAR-gamma agonist) in the brown adipose tissue of Han Wistar rats: a review of 1-month, 13-week, 27-week and 2-year oral toxicity studies

We describe and discuss microscopic findings in the brown adipose tissue (BAT) blood vessels of Han Wistar rats treated with GI262570X, a peroxisome proliferator-activated receptor-gamma agonist (PPAR-gamma agonist) by oral gavage for 28 days, 13 weeks, 27 weeks, and 2 years. Review of these studies revealed a consistent vascular change, consisting of multifocal fatty infiltration in the BAT of treated rats. A similar vascular change was not seen in other vessels or organs. Microscopically, fatty infiltration was characterized primarily by round, clear vacuoles within the tunica media and/or tunica adventitia of small and medium-sized arteries and arterioles. Occasionally, these vacuoles had peripherally located nuclei and morphologically resembled adipocytes, suggesting a well-characterized PPAR effect (ie, differentiation of stem cells or preadipocytes into mature adipocytes). However, administration of GI262570X up to 2 years failed to induce more severe or progressive lesions in the blood vessels of rat BAT and, in particular, did not result in induction of any atherosclerotic-like lesions or foam cell infiltration. At the longer exposure, there was an apparent reduction of severity and/or incidence, indicating a possible adaptive response. These results suggest that the possibility of generating atherosclerotic-like lesions through prolonged treatment of GI262570X (PPAR-gamma agonist) is highly unlikely in rats.     

Resident and migratory adipose immune cells control systemic metabolism and thermogenesis

Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.     

棕色脂肪形成的内分泌及环境影响因素研究

本文主要研究白色脂肪棕色化的内分泌调控及影响棕色脂肪变化的环境因素的最新研究成果,为其在代谢疾病中的治疗潜力提供证据。截至目前,对棕色脂肪的内分泌调控,低温及低氧环境暴露对棕色脂肪的影响,以及脂肪组织在高原上维持能量、代谢和热平衡的相互转化的研究依然较少。深入地了解BAT的潜在能力,能够更好地控制这些细胞,以改善系统能量代谢和葡萄糖稳态,为对抗人类肥胖和相关代谢紊乱提供新的治疗策略。     

钙敏感受体在动脉粥样硬化中的作用研究进展

钙敏感受体(CaSR)是G蛋白偶联受体C家族的成员之一,广泛表达于体内不同组织细胞,参与机体多种病理生理过程。CaSR能够通过调控血管内皮细胞损伤、炎性反应、血管平滑肌细胞增殖和迁移及血管钙化过程,参与动脉粥样硬化的发生发展。     

The insulin resistance syndrome: implications for thrombosis and cardiovascular disease

The insulin resistance syndrome (IRS) with obesity is large-word wide-spread and represents a strong risk factor for vascular disease. Atherothrombotic complications in IRS are partly attributed to a dysregulation of hemostasis inducing a prothrombotic state which includes endothelial activation, hyperactivity of platelets, hypercoagulability and hypofibrinolysis. This latter, due to elevated PAI-1 levels, is a core feature of the IRS. Most of the prothrombotic modifications can be reversed by loosing weight. Low grade inflammation with prolonged cytokines mediated acute phase reaction is actually considered as strongly related to the IRS and is involved in the dysregulation of hemostasis. TNF pathway and TGFb play an important role in the regulation of PAI-1 synthesis in the adipose tissue and the liver with steatosis. Interestingly, modulation of PAI-1 expression in adipose tissue influences adipose tissue growth, increasing once more the spectrum of the non hemostatic functions of coagulation/fibrinolysis parameters.     

Complement-endothelial cell interactions: pathophysiological implications.

The function of the endothelial cells can be modulated by humoral factors present in the circulation and in the extravascular fluid, including proteins of the complement system. This review examines the multiple interactions between the complement system and the endothelial cells and their functional consequences on inflammation, coagulation and regulation of vascular tone. The implications of these interactions in the induction and progression of the vascular lesions occurring in atherosclerosis, ischemia/reperfusion and xenotransplantation and the possible therapeutic approaches in terms of complement regulation are also discussed.     

Endocrine and signalling role of adipose tissue: new perspectives on fat

White adipose tissue (WAT) is now recognized as a major endocrine and secretory organ, releasing a wide range of protein factors and signals termed adipokines - in addition to fatty acids and other lipid moieties. A paradigm shift came with the discovery of leptin, a pleiotropic hormone which is a critical signal to the hypothalamus in the control of appetite and energy balance. A number of adipokines, including adiponectin, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, vascular endothelial growth factor, plasminogen activator inhibitor-1 and haptoglobin, are linked to inflammation and the inflammatory response. Obesity is characterized by a state of mild inflammation, and the expression and release of inflammation-related adipokines generally rises as adipose tissue expands; a notable exception is adiponectin, with its anti-inflammatory action, the levels of which fall. WAT may be the main site of inflammation in obesity, increased circulating levels of inflammatory markers reflecting spillover from an 'inflamed' tissue, leading to the obesity-associated pathologies of type 2 diabetes and the metabolic syndrome. From the wide range of adipokines now identified, it is evident that WAT is highly integrated into overall physiological regulation, involving extensive crosstalk with other organs and multiple metabolic systems. Whether major changes in adipokine production in obesity, particularly of those factors linked to inflammation, are unique to this condition, or are a feature of all situations in which there are substantial increases in adipose mass (such as pregnancy, and pre-hibernatory and pre-migratory fattening) requires consideration.