肥大细胞在脂肪组织中的生理与病理作用

脂肪组织可分为白色脂肪组织(white adipose tissue,WAT)与棕色脂肪组织(brown adipose tissue, BAT).WAT行使能量储存功能,将人体多余的能量以化学能形式储存,而BAT则具有产热功能,在寒冷等刺激下将化学能转化为热能,以维持体温.脂肪组织同时还具有内分泌功能,可分泌多种激素...     

棕色脂肪细胞因子的研究进展

<正>人体内存在着白色脂肪组织(white adipose tissue,WAT)、棕色脂肪组织(brown adipose tissue,BAT)和米色脂肪组织。WAT具有储能的作用,过量积聚可导致肥胖;棕色和米色脂肪为产热脂肪,具有潜在的抗肥胖作用^[1]。BAT能够通过利用葡萄糖和脂类产热,减少它们在循环中的过度沉积,起到预防肥胖性疾病和代谢异常的作用^[2]。BAT的产热过程     

敲除PAMM基因对小鼠白色和棕色脂肪组织基因表达的影响

目的：巨噬细胞集落刺激因子诱导单核细胞活化的类过氧化物酶2(peroxiredoxin-like 2 activated in M-CSF stimulated monocytes, PAMM)是一种具有抗炎、抗氧化功能的蛋白,在脂肪组织中高表达,本文拟利用基因敲除小鼠,探究PAMM对白色和棕色脂肪组织形态及基因表达等的影响,以期为其功能研究提供新思路。方法：利用CRISPR-Cas9等技术构建PAMM基因敲除（knockout, KO）小鼠,用野生型（wild-type, WT）小鼠作为对照。收集腹股沟皮下白色脂肪组织（inguinal adipose tissue, IAT）和背部棕色脂肪组织（brown adipose tissue, BAT）,通过HE染色观察组织形态,利用RNA-seq和RT-qPCR检测相关基因的表达。结果：通过基因组PCR及测序,证明基因敲除小鼠构建正确。敲除PAMM后IAT和BAT形态无明显变化,但E2F靶点、未折叠蛋白反应等基因集在IAT或BAT中富集。比较WT和KO小鼠组织,发现33个基因的变化趋势在IAT和BAT中保持一致;而仅在IAT中出现变化的...     

预防糖尿病新途径——将白色脂肪转化成燃烧能量的棕色脂肪

在我们人体内存在着两种型式的脂肪,即白色脂肪和棕色脂肪,通常棕色脂肪细胞能够通过特殊的方法燃烧能量,最近哈佛大学Joslin糖尿病研究中心的研究人员证实,小鼠白色脂肪组织和骨骼肌中存在祖细胞,它们能够被转化成棕色脂肪细胞。     

组蛋白脱乙酰酶在脂肪组织产热调控中的作用

<正>肥胖是由机体能量代谢失衡所引起的营养性疾病,是2型糖尿病、脂肪性肝病、冠状动脉粥样硬化等疾病的主要危险因素^[1-2]。脂肪是机体能量代谢的"调节中心"。除白色脂肪的储能作用外,棕色及米色脂肪还可以通过适应性非战栗性产热(adaptivenon-shivering thermogenesis)的方式将能量散失。     

多巴胺D2受体基因敲除导致体重减轻以及棕色脂肪PRDM16、UCP1、FAS和ACC的表达变化

目的以多巴胺D2受体基因敲除(D2KO)小鼠为动物模型,研究D2KO小鼠体重减轻后,棕色脂肪组织(brown adipose tissue,BAT)重量,白色脂肪重量,BAT中含PR结构域蛋白16(PRD1-BF1-RIZ1 homologous domain containing 16,PRDM16)、解偶联蛋白1(uncoupling protein 1,UCP1)、脂肪酸合酶(fatty acid synthase,FAS)以及乙酰辅酶A羧化酶(acetyl Coenzyme A carboxylase,ACC)的mRNA和蛋白表达变化,以期为肥胖机制研究提供线索。方法 8周龄野生型小鼠组(wild type,WT)和D2KO小鼠组各10只。分别称量各小鼠体重及其白色脂肪、棕色脂肪重量。Real-time quantitative RT-PCR方法检测棕色脂肪中PRDM16、UCP1、FAS、ACC的m RNA表达水平,Western blotting方法检测棕色脂肪中PRDM16、UCP1、FAS、ACC的蛋白表达水平。结果 WT组动物体重为(23.78±0.54)g,D2KO组动物体重为(20.54±1.15)g,P0.05。WT组动物附睾脂肪(epididymal adipose tissue,eAT)重量为(1.083±0.02)g,D2KO组动物e AT重量为(0.978±0.03)g,P0.05。WT组动物皮下脂肪(subcutaneous adipose tissue,sAT)重量为(1.85±0.05)g,D2KO组动物sAT重量为(1.72±0.03)g,P0.05。WT组动物BAT重量为(31.38±4.22)mg,D2KO组动物BAT重量为(42.44±2.47)mg,P0.05。半定量PCR与Western blotting检测结果显示,相对于WT组,D2KO组小鼠棕色脂肪中PRDM16、FAS、ACC的mRNA与蛋白的表达均显著增加,UCP1的mRNA与蛋白表达显著减少。结论 D2KO小鼠的体重减轻与棕色脂肪中的PRDM16、UCP1、FAS以及ACC存在一定关联。     

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。     

代谢型谷氨酸受体5(mGluR5)调控白色脂肪细胞棕色化

目的 探讨代谢型谷氨酸受体5(mGluR5)对白色脂肪细胞棕色化的调控作用.方法 Western blot检测mGluR5是否在白色及棕色脂肪组织中表达.用mGluR5拮抗剂处理分化的小鼠白色脂肪前体细胞系3T3L1,BODIPY荧光染色观察脂肪细胞脂滴形态,实时荧光定量聚合酶链反应(RT-qPCR)检测棕色脂肪细胞特...     

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。     

大鼠白色和棕色脂肪来源的间充质干细胞成脂分化特性的比较

目的探讨白色脂肪组织(WAT)和棕色脂肪组织(BAT)来源的间充质干细胞成脂分化特性的差异。方法雄性SD大鼠15只,3只用于细胞分离培养,12只用于细胞移植。体外分离培养WAT和BAT两种来源的脂肪干细胞,用油红O染色检测两种干细胞的成脂分化率,用免疫荧光技术检测成脂诱导、分化后的细胞是棕色脂肪细胞还是白色脂肪细胞。4’6-二脒基-2-苯基吲哚(DAPI)标记两种来源的干细胞后移植至腹股沟区,分别在第1、2、3周取材,免疫荧光技术检测植入细胞的分化趋向。结果 WAT来源的干细胞增殖速度明显快于BAT来源的干细胞,前者成脂分化率为0.205±0.069,后者为0.165±0.053,两种干细胞的成脂诱导率差异无统计学意义(P0.05)。两种干细胞分别植入体内后,在第1、2、3周发现,两种干细胞均表达棕色脂肪特异性蛋白解耦联蛋白1(UCP1)。结论 WAT和BAT来源的干细胞在体外及体内诱导成脂后均分化为棕色脂肪细胞。     

Evaluation of brown adipose tissue with intermolecular double-quantum coherence magnetic resonance spectroscopy at 3.0 T

In the current study, we propose a single-voxel (SV) magnetic resonance spectroscopy (MRS) pulse sequence, based on intermolecular double-quantum coherence (iDQC), for in vivo specific assessment of brown adipose tissue (BAT) at 3 T. The multilocular adipocyte, present in BAT, typically contains a large number of small lipid droplets surrounded by abundant intracellular water, while the monolocular adipocyte, present in white adipose tissue (WAT), accommodates only a single large lipid droplet with much less water content. The SV-iDQC sequence probes the spatial correlation between water and fat spins at a distance of about the size of an adipocyte, thus can be used for assessment of BAT, even when mixed with WAT and/or muscle tissues. This sequence for measurement of water-to-fat (water-fat) iDQC signals was tested on phantoms and mouse BAT and WAT tissues. It was then used to differentiate adipose tissues in the supraclavicular and subcutaneous regions of healthy youth human volunteers (n = 6). Phantom results with water-fat emulsions demonstrated enhanced water-fat iDQC signal with increased voxel size, increased energy level of emulsification, or increased distribution balance of water and fat spins. The animal tissue experiments resulted in obvious water-fat iDQC signal in mouse BAT, while this signal was almost absent in the WAT spectrum. The optimal choice of the dipolar coupling distance for the observation was approximately 100 μm, as tested on both emulsion phantom and animal tissue. The water-fat iDQC signals observed in the supraclavicular adipose tissues were higher than in the subcutaneous adipose tissues in healthy young volunteers (0.43 ± 0.36 vs. 0.10 ± 0.06, p = 0.06). It was concluded that the iDQC-based sequence has potential for assessment of mouse and human BAT at 3 T, which is of interest for clinical research and the diagnosis of obesity and associated diseases.     

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.     

Comparison of DNA synthesis in white and brown adipose tissue in rats with ventromedial hypothalamic lesions

Ventromedial hypothalamic (VMH) lesions cause excessive fat accumulation in white adipose tissue (WAT), and brown adipose tissue (BAT); however, little information is available on whether or not cell proliferation occurs in WAT and BAT after VMH lesioning. In this study, we determined the DNA content and thymidine incorporation in unilateral parametrial WAT and interscapular BAT 0, 1, 3, and 7 days after VMH lesioning, and examined the mechanism of increased DNA content in WAT. In rats with VMH lesions, the weight of WAT and BAT had increased significantly at 7 days, and the DNA content and thymidine incorporation of WAT had increased significantly at 3 days and continued to increase for up to 7 days, while those of BAT did not increase for as long as 7 days after VMH lesioning. Restricted food intake according to the pair-feeding method partially inhibited the increased DNA content in WAT. The increased DNA content in WAT was mostly restored but not completely by the administration of anti-insulin antibody, and by administration of propranolol, a -adrenergic blocker. The results demonstrated that VMH lesions induced DNA synthesis in WAT early after VMH lesioning, but did not induce DNA synthesis in BAT, and suggested that either hyperinsulinemia or a -adrenergic receptor mechanism or both may be responsible for the increased DNA content in WAT.     

Chronic l-menthol-induced browning of white adipose tissue hypothesis: A putative therapeutic regime for combating obesity and improving metabolic health

IntroductionObesity constitutes a serious global health concern reaching pandemic prevalence rates. The existence of functional brown adipose tissue (BAT) in adult humans has provoked intense research interest in the role of this metabolically active tissue in whole-body energy balance and body weight regulation. A number of environmental, physiological, pathological, and pharmacological stimuli have been proposed to induce BAT-mediated thermogenesis and functional thermogenic BAT-like activity in white adipose tissue (WAT), opening new avenues for therapeutic strategies based on enhancing the number of beige adipocytes in WAT.HypothesisRecent evidence support a role of l-menthol cooling, mediated by TRPM8 receptor, on UCP1-dependent thermogenesis and BAT-like activity in classical WAT depots along with the recruitment of BAT at specific anatomical sites. l-Menthol-induced BAT thermogenesis has been suggested to occur by a β-adrenergic-independent mechanism, avoiding potential side-effects due to extensive β-adrenergic stimulation mediated by available beta receptor agonists. l-Menthol has been also linked to the activation of the cold-gated ion channel TRPA1. However, its role in l-menthol-induced UCP1-dependent thermogenic activity in BAT and WAT remains undetermined. White adipose tissue plasticity has important clinical implications for obesity prevention and/or treatment because higher levels of UCP1-dependent thermogenesis can lead to enhanced energy expenditure at a considerable extent. We hypothesize that chronic dietary l-menthol treatment could induce TRPM8- and TRPA1-dependent WAT adaptations, resembling BAT-like activity, and overall improve whole-body metabolic health in obese and overweight individuals.ConclusionsThe putative impact of chronic l-menthol dietary treatment on the stimulation of BAT-like activity in classical WAT depots in humans remains unknown. A detailed experimental design has been proposed to investigate the hypothesized l-menthol-induced browning of WAT. If our hypothesis was to be confirmed, TRPM8/TRPA1-induced metabolic adaptations of WAT to BAT-like activity could provide a promising novel therapeutic approach for increasing energy expenditure, regulating body weight, and preventing obesity and its related co-morbidities in humans.     

Differential responses of white adipose tissue and brown adipose tissue to caloric restriction in rats

Caloric restriction (CR) slows the aging process and extends longevity, but the exact underlying mechanisms remain debatable. It has recently been suggested that the beneficial action of CR may be mediated in part by adipose tissue remodeling. Mammals have two types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). In this study, proteome analysis using two-dimensional gel electrophoresis combined with MALDI-TOF MS, and subsequent analyses were performed on both WAT and BAT from 9-month-old male rats fed ad libitum or subjected to CR for 6 months. Our findings suggest that CR activates mitochondrial energy metabolism and fatty acid biosynthesis in WAT. It is likely that in CR animals WAT functions as an energy transducer from glucose to energy-dense lipid. In contrast, in BAT CR either had no effect on, or down-regulated, the mitochondrial electron transport chain, but enhanced fatty acid biosynthesis. This suggests that in CR animals BAT may change its function from an energy consuming system to an energy reservoir system. Based on our findings, we conclude that WAT and BAT cooperate to use energy effectively via a differential response of mitochondrial function to CR.     

Resistin increases islet blood flow and decreases subcutaneous adipose tissue blood flow in anaesthetized rats

Aim: Resistin is an adipokine which has been suggested to participate in the induction of insulin resistance associated with type 2 diabetes. The aim of the present study was to investigate whether acute administration of resistin influences tissue blood perfusion in rats. Methods: Resistin was administered as an intravenous infusion of 7.5 μg h^?1 (1.5 mL h^?1) for 30 min to rats anaesthetized with thiobutabarbital. A microsphere technique was used to estimate the blood flow to six different depots of white adipose tissue (WAT), brown adipose tissue (BAT), as well as to the pancreas, islets, duodenum, colon, kidneys, adrenal glands and liver. Results: Resistin administration led to an increased blood flow to the pancreas and islets and a decrease in subcutaneous WAT and BAT. Intra‐abdominal white adipose tissue blood flow and that to other organs were not affected. Conclusion: Acute administration of resistin markedly affects the blood perfusion of both the pancreas and subcutaneous white adipose tissue depots. At present it is unknown whether resistin exerts a direct effect on the vasculature, or works through local or systemic activation of endothelial cells and/or macrophages. The extent to which this might contribute to the insulin resistance caused by resistin is yet unknown.     

Orexin receptor type 2 agonism inhibits thermogenesis in brown adipose tissue by attenuating afferent innervation

Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.     

Molecular determinants of brown adipocyte formation and function

Humans contain essentially two types of adipose tissue: brown adipose tissue (BAT) and white adipose tissue (WAT). The function of WAT is to store fat while that of BAT is to burn fat for heat production. A potential strategy to combat obesity and its related disorders is to induce the conversion of WAT into BAT. In this issue of Genes & Development, Kajimura and colleagues (pp. 1397-1409) have identified a mechanism by which PRDM16, the principal regulator of brown adipocyte formation and function, can simultaneously induce BAT gene expression, while suppressing WAT gene expression. The studies suggest that PRDM16 and its associated coregulators PPARgamma coactivator-1alpha (PGC-1alpha) and C-terminal-binding protein 1/2 (CtBP1/2), which control the switch from WAT to BAT, are potential targets for development of obesity-related therapeutics.