线粒体质量控制与米色脂肪之间的关系

近年来,肥胖患病率不断上升,肥胖已成为全球性公共卫生问题。肥胖能够增加高血压、冠心病等心血管疾病的发病风险,防治肥胖已经成为亟待解决的社会问题。米色脂肪是一种产热型脂肪细胞,可在受到寒冷、药物、运动等外界刺激下由白色脂肪细胞转化而来,但其形态和功能却与白色脂肪细胞不同,而与棕色脂肪细胞类似,即米色脂肪同样含有丰富的线粒体,可通过产热来消耗机体的能量,是预防和治疗肥胖的新靶点。线粒体是真核细胞中能量代谢的主要场所,其可为机体提供所需的能量。最近有研究显示,线粒体质量控制对米色脂肪的转化和产热功能具有关键作用。线粒体质量控制通过调控线粒体数量和质量的相对稳定来维持线粒体和细胞的正常活动。线粒体质量控制包括线粒体生成、线粒体自噬及线粒体融合/分裂。线粒体生成与线粒体自噬可以调控线粒体更新与降解,线粒体融合/分裂是线粒体修复的重要环节。有研究发现,线粒体数量、形态和功能的变化会对米色脂肪的生成、维持和产热造成影响,但是目前的研究还未完全阐明线粒体质量控制和米色脂肪之间的关系。本综述通过探讨线粒体生成、自噬及融合/分裂对米色脂肪的影响,探讨线粒体质量控制与米色脂肪的之间的关系,以期为预防和治疗肥胖提供新的思路。     

肥胖状态下脂肪组织线粒体功能紊乱与运动调控

线粒体在包括脂肪组织在内的新陈代谢器官中扮演重要角色。脂肪组织包括白色脂肪组织(white adipose tissue, WAT)和棕色脂肪组织(brown adipose tissue, BAT),这两种组织功能相反。白色脂肪组织储存多余的能量,棕色脂肪组织则通过线粒体进行非颤栗性产热来消耗能量。在受到寒冷时、β-肾上腺素能受体激动剂或运动刺激时,白色脂肪组织棕色化形成形态与功能类似棕色脂肪细胞的米色脂肪细胞。在脂肪细胞中,线粒体调节脂肪细胞分化、脂质稳态、支链氨基酸代谢、产热作用以及白色脂肪组织棕色化,因此高活性的线粒体对于脂肪细胞的功能至关重要。研究表明,脂肪组织线粒体功能障碍与肥胖和2型糖尿病等代谢性疾病高度相关。肥胖时线粒体功能紊乱,表现为线粒体生物合成和活性降低、活性氧产生过量以及自噬增加,从而对脂肪组织功能产生不利影响。因此,调节脂肪组织线粒体功能的干预措施将有助于治疗肥胖。研究发现,运动是预防和改善肥胖的重要方法,通过增加线粒体生物合成和活性,改善脂肪组织氧化应激并抑制自噬,从而促进机体代谢。本文深入探讨了脂肪组织线粒体的功能、线粒体紊乱的表现形式以及运动的调控效应,将加深对运动减肥的理解与认识,同时为肥胖症的治疗提供新的方向和思路。     

棕色和米色脂肪激活剂: 潜在的减肥靶标

全球性肥胖症及其代谢疾病已经严重影响人类健康。因此,对其进行治疗变得愈加重要。新近研究表明,激活棕色和米色脂肪可能成为对抗肥胖的有效途径。白色脂肪棕色化可使储存能量的白色脂肪转化为具有类似棕色脂肪产热特性的米色脂肪,来增加耗能,对抗肥胖。本文综述了棕色和米色脂肪激活剂及其作用机制的研究进展,并从纳米技术的角度展望了其在肥胖症治疗中的应用前景。     

禁食及胰岛素水平对大鼠解偶联蛋白-1、2、3基因表达的影响

 为探讨禁食和胰岛素对解偶联蛋白 - 1、2、3基因 (UCP1 ,2 ,3)表达的影响 ,应用 RT- PCR方法观察了在不同禁食时间和应用胰岛素条件下大鼠白色脂肪组织、棕色脂肪组织和骨骼肌中 UCP1 ,2 ,3m RNA水平的变化 .UCP1基因只在大鼠棕色脂肪组织中表达 .UCP2 ,3基因在三种组织中均有表达 ,在白色脂肪组织中以 UCP2表达为主 ;在骨骼肌中以 UCP3表达为主 .过夜禁食使棕色脂肪组织 UCP1 ,3m RNA水平明显下降 (P<0 .0 1 ) ;UCP2 m RNA水平在三种组织中均呈上升反应 ,以白色脂肪组织中表现最为明显 (P<0 .0 5) ;而对白色脂肪组织和骨骼肌中 UCP3基因表达无明显影响 .禁食时间延长至 48h,除棕色脂肪组织中 UCP2 ,3基因有明显下降外 ,各组织中UCPs基因表达基本调节至正常或高于对照组水平 .胰岛素对 UCPs基因表达水平有一定的上调作用 ,这一作用对棕色脂肪组织 UCPs各基因及骨骼肌中 UCP3基因表现得尤为明显 (P<0 .0 5) .大鼠 UCPs基因表达有一定的组织特异性 ;禁食时间对三种组织中 UCPs各成员基因表达的影响有时相上的区别 ;胰岛素可以调 UCPs各成员基因的表达 .结果反映了 UCPs各成员在能量代谢调节上的不同作用 ,这为理解膳食 -产热与体重调节的关系 ,及其能量代谢平衡与疾病关系提供了实验依据     

β3肾上腺素能受体激动剂的减脂机制

肥胖症是一种由于机体能量过剩所导致的慢性代谢性疾病。β3肾上腺素能受体是β肾上腺素能受体的一种亚型,主要存在于棕色脂肪及白色脂肪组织中,参与棕色脂肪组织的产热和白色脂肪组织的脂质分解以及白色脂肪棕色化的过程,在脂肪代谢中起到减脂作用。β3肾上腺素能受体激动剂能与β3肾上腺素能受体结合,从而参与脂肪代谢的过程。本文对近年来β3肾上腺素能受体及其激动剂种类,包括其减脂机制进行了综述,旨在为β3肾上腺素能受体激动剂的进一步研究提供依据。     

外泌体调控白色脂肪棕色化的研究进展

白色脂肪和棕色脂肪是存在于哺乳动物体内的两种脂肪组织。在一定条件下,白色脂肪高表达线粒体解偶联蛋白1,耗能增加,表现出棕色脂肪的功能,称为白色脂肪棕色化。白色脂肪棕色化是正常机体能量消耗、脂肪减少的途径,也是患者恶病质形成的重要因素。外泌体是一类携带大量生物信息分子的细胞外囊泡,介导多种生理病理进程。现系统综述外泌体调控白色脂肪棕色化的研究进展及其在恶病质中的作用,以期为代谢性疾病的诊疗提供新思路。     

miRNAs调控褐色脂肪细胞功能和白色脂肪细胞米色化的研究进展

褐色脂肪细胞通过其线粒体内膜解偶联蛋白(uncoupling protein 1,UCP1)的解偶联作用,将能量以热量的形式释放出来,在维持机体的能量代谢平衡中发挥了关键作用。存在于皮下脂肪组织中的某些白色脂肪细胞也能够诱导UCP1的高表达,这种现象被称为"米色化"。miRNAs是一种小的非编码RNA,可通过直接降解mRNA或抑制其翻译来调控靶基因的表达,参与了多种生物学过程。miRNAs通过对褐色脂肪细胞分化和产热相关基因的表达调控,在褐色脂肪细胞的分化和功能维持上起了重要作用。同时,研究也发现了某些miRNAs在白色脂肪细胞的米色化中起到了重要作用。对miRNAs在褐色脂肪细胞的分化调控、功能维持以及在白色脂肪细胞米色化中的作用和机制的最新研究进展进行综述。     

组胺刺激棕色和米色脂肪产热

3-肾上腺素受体激动剂能够刺激棕色脂肪适应性产热,并能促进白色脂肪米色化。然而到目前为止,有哪些代谢产物参与介导β3-肾上腺素受体激动剂促进脂肪产热作用尚不清楚。本研究通过给予8周龄C57/BL6J雄性小鼠腹腔注射β3-肾上腺素受体激动剂CL316,243,分离提取小鼠脂肪组织进行RNA-Seq检测,结果显示组胺合成限速酶组氨酸脱羧酶(histidine decarboxylase, HDC)在脂肪中被CL316,243强烈诱导,因此推测HDC的代谢产物组胺可能参与了脂肪组织的产热过程。通过给予正常饮食与高脂饮食C57BL/6J小鼠静脉注射组胺,以明确组胺促进脂肪产热的生理作用和机制。结果显示,组胺可刺激正常饮食小鼠棕色脂肪和皮下白色脂肪中产热基因的表达,包括过氧化物酶体增殖物激活受体γ-辅活化因子-1α(peroxisome proliferator-activated receptor gamma coactivator-1α, PGC-1α)和解耦联蛋白1 (uncoupling protein 1, UCP1)。HE染色表明,组胺处理降低了脂肪细胞中脂滴的大小。此外,组胺还可以促进高脂饮食诱导的肥胖小鼠脂肪产热,改善糖耐量和脂肪肝表型。最后,我们通过脂肪原代前体细胞实验验证了组胺促进产热是细胞的自主特性。本研究结果表明,组胺可能参与介导了β3-肾上腺素受体激动剂促进脂肪的产热。     

钙循环——米色脂肪产热新机制

正线粒体氧化磷酸化(mitochondrial oxidative phosphorylation)是指将线粒体内物质氧化所得的能量合成ATP的化学偶联反应;相对而言,"解偶联反应",则指该过程不合成ATP,而是将能量以热能形式释放。褐色脂肪细胞富含线粒体,由此成为重要的产热细胞。目前认为,褐色脂肪细胞的线粒体解偶联反应主要由"解偶联蛋白1"(uncoupling protein 1,UCP1)参与介导。米色脂肪细胞(beige adipocytes)散在于白色脂肪细胞之间,在低温、过氧化物酶体增殖物活化受体γ(PPARγ)激动剂、β3肾上腺素受体激动剂等刺激下,可向褐色脂肪细胞转化,表现为颜色由米色变为褐色,并获得产热能力;此过程被称为"褐变"。然     

棕色脂肪的产热及其调控机制

棕色脂肪组织是小型哺乳动物重要的兼性产热器官,位于棕色脂肪细胞线粒体内膜的解偶联蛋白是此种产热机制的关键物质.产热刺激激活解偶联蛋白构成的质子通道,在线粒体内膜形成质子短路,从而解除ATP合成偶联对氧化呼吸速率的控制,使产热高速进行.去甲肾上腺素、甲状腺激素、胰岛素、pH值以及食物、环境温度等因素综合调控着棕色脂肪组织的结构与功能状态.     

冷驯化条件下中缅树鼩脂肪组织代谢产物的变化

为探究冷驯化条件下中缅树鼩（Tupaia belangeri）白色脂肪组织（WAT）和褐色脂肪组织（BAT）的差异代谢物变化,本研究采集对照组和冷驯化28天组中缅树鼩的WAT和BAT,采用非靶向代谢组液相色谱—质谱联用检测技术分析其差异代谢物含量变化。结果表明,冷驯化组较对照组WAT中有7种差异代谢物显著上调;BAT中有25种差异代谢物,其中23种差异代谢物显著上调,2种差异代谢物显著下调,主要参与三羧酸循环、脂类代谢、氨基酸代谢和糖代谢等。以上结果说明中缅树鼩通过利用脂肪组织的不同差异代谢物来抵御低温环境,提高生存率。     

Translocator Protein 18 kDa (TSPO) Is Regulated in White and Brown Adipose Tissue by Obesity

Translocator protein 18 kDa (TSPO) is an outer-mitochondrial membrane transporter which has many functions including participation in the mitochondrial permeability transition pore, regulation of reactive oxygen species (ROS), production of cellular energy, and is the rate-limiting step in the uptake of cholesterol. TSPO expression is dysregulated during disease pathologies involving changes in tissue energy demands such as cancer, and is up-regulated in activated macrophages during the inflammatory response. Obesity is associated with decreased energy expenditure, mitochondrial dysfunction, and chronic low-grade inflammation which collectively contribute to the development of the Metabolic Syndrome. Therefore, we hypothesized that dysregulation of TSPO in adipose tissue may be a feature of disease pathology in obesity. Radioligand binding studies revealed a significant reduction in TSPO ligand binding sites in mitochondrial extracts from both white (WAT) and brown adipose tissue (BAT) in mouse models of obesity (diet-induced and genetic) compared to control animals. We also confirmed a reduction in TSPO gene expression in whole tissue extracts from WAT and BAT. Immunohistochemistry in WAT confirmed TSPO expression in adipocytes but also revealed high-levels of TSPO expression in WAT macrophages in obese animals. No changes in TSPO expression were observed in WAT or BAT after a 17 hour fast or 4 hour cold exposure. Treatment of mice with the TSPO ligand PK11195 resulted in regulation of metabolic genes in WAT. Together, these results suggest a potential role for TSPO in mediating adipose tissue homeostasis.     

Different metabolic responses of human brown adipose tissue to activation by cold and insulin

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner.     

Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice

Exposure of humans and rodents to cold activates thermogenic activity in brown adipose tissue (BAT). This protocol describes a mouse model to study the activation of BAT and angiogenesis in adipose tissues by cold acclimation. After a 1-week exposure to 4 °C, adult C57BL/6 mice show an obvious transition from subcutaneous white adipose tissue (WAT) into brown-like adipose tissue (BRITE). The BRITE phenotype persists after continuous cold exposure, and by the end of week 5 BRITE contains a high number of uncoupling protein-1-positive mitochondria, a characteristic feature of BAT. During the transition from WAT into BRITE, the vascular density is markedly increased owing to the activation of angiogenesis. In BAT, cold exposure stimulates thermogenesis by increasing the mitochondrial content and metabolic rate. BAT and the increased metabolic rate result in a lean phenotype. This protocol provides an outstanding opportunity to study the molecular mechanisms that control adipose mass.     

Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis

Triiodothyroacetic acid (TRIAC) is a physiological product of triiodothyronine (T(3)) metabolism, with high affinity for T(3) nuclear receptors. Its interest stems from its potential thermogenic effects. Thus this work aimed 1) to clarify these thermogenic effects mediated by TRIAC vs. T(3) in vivo and 2) to determine whether they occurred predominantly in adipose tissues. To examine this, control rats were infused with equimolar T(3) or TRIAC doses (0.8 or 4 nmolx100 g body wt(-1) x day(-1)) or exposed for 48 h to cold. Both T(3) doses and only the highest TRIAC dose inhibited plasma and pituitary thyroid-stimulating hormone (TSH) and thyroxine (T(4)) in plasma and tissues. Interestingly, the lower TRIAC dose marginally inhibited plasma T(4). T(3) infusion increased plasma and tissue T(3) in a tissue-specific manner. The highest TRIAC dose increased TRIAC concentrations in plasma and tissues, decreasing plasma T(3). TRIAC concentrations in tissues were <10% those of T(3). Under cold exposure or high T(3) doses, TRIAC increased only in white adipose tissue (WAT). Remarkably, only the lower TRIAC dose activated thermogenesis, inducing ectopic uncoupling protein (UCP)-1 expression in WAT and maximal increases in UCP-1, UCP-2, and lipoprotein lipase (LPL) expression in brown adipose tissue (BAT), inhibiting UCP-2 in muscle and LPL in WAT. TRIAC, T(3), and cold exposure inhibited leptin secretion and mRNA in WAT. In summary, TRIAC, at low doses, induces thermogenic effects in adipose tissues without concomitant inhibition of TSH or hypothyroxinemia, suggesting a specific role regulating energy balance. This selective effect of TRIAC in adipose tissues might be considered a potential tool to increase energy metabolism.     

Up-regulation of uterine UCP2 and UCP3 in pregnant rats.

Pregnancy produces profound changes in hormone dynamics, thermoregulation and energy metabolism. Uncoupling proteins (UCPs) have been identified in a variety of tissues and UCP1 is known to play important roles in energy homeostasis, while the regulation of UCP2 and UCP3 is still unclear. The present study aimed to investigate the effects of the changes during pregnancy on UCP gene expression in the uterus, as well as in brown adipose tissue (BAT), white adipose tissue (WAT), soleus muscle (Muscle), and liver, throughout the estrus and metestrus periods, at early, middle and late stages in pregnancy, and during post-gestational stages. The expression of uterine UCP2 and UCP3 were up-regulated by 3.2- and 1. 5-fold, respectively, during the late stage of pregnancy with an increase of WAT leptin mRNA expression and exogenous administration of leptin resulted in induction of the uterine UCP2 and UCP3 levels. Contrary to uterine UCPs, UCP1 mRNA expression in BAT was down-regulated by 0.5-fold and there were no remarkable changes in WAT or liver UCP2, or Muscle UCP3 expression throughout the periods. These results indicate that UCP gene expressions during pregnancy are regulated tissue-dependently, and up-regulation of uterine UCP2 and UCP3 mRNA may be due to increased leptin levels.     

Differential sympathetic drive to adipose tissues after food deprivation, cold exposure or glucoprivation

Surplus energy is principally stored in white adipose tissue (WAT) as triacylglycerol and mobilized via lipolysis through norepinephrine (NE) released from sympathetic nervous system terminals innervating WAT. We demonstrated that central melanocortin receptor agonism provokes differential sympathetic drives across WAT pads and interscapular brown adipose tissue (IBAT). Here we tested for differential WAT and IBAT sympathetic drive to known lipolytic stimuli {glucoprivation [2-deoxy-D-glucose (2-DG)], cold exposure (5 degrees C), food deprivation (16 h), or both cold exposure and food deprivation} by measuring NE turnover (NETO). Only inguinal WAT NETO significantly increased across all stimuli. Dorsal subcutaneous WAT NETO only increased with glucoprivation. Retroperitoneal WAT NETO increased with glucoprivation, cold and cold + food deprivation, but not by food deprivation. Epididymal WAT NETO was unaffected by glucoprivation but increased with cold, cold + food deprivation or food deprivation, but to a small significant degree. IBAT NETO was unaffected by glucoprivation or food deprivation, but increased with cold and cold + food deprivation. Plasma glucose decreased with food deprivation and increased with 2-DG administration or cold exposure. Plasma glycerol was increased with food deprivation, cold, and their combination but not with 2-DG, whereas plasma free fatty acids increased with food deprivation, cold + food deprivation, and 2-DG. These data show differential sympathetic drive to WAT and BAT for four different lipolytic stimuli, exemplifying the fat pad-specific pattern of WAT sympathetic drive across lipid-mobilizing conditions and emphasizing the need to analyze multiple adipose depots for measures of NETO and likely most measures.