Carbohydrate and fat have different effects on plasma leptin concentrations and adipose tissue leptin production

Leptin is secreted by adipocytes and plays a role in the regulation of food intake. However, the regulation of leptin production by adipose tissue is unclear. We have investigated whether a mixed meal or a high-fat load given orally, or a pure fat load given intravenously, stimulates adipose tissue leptin production. Six volunteers were studied on two occasions following an overnight fast. On one occasion they consumed tomato soup containing 40 g of triacylglycerol (as Intralipid) and 9.6 g of carbohydrate; on the other occasion Intralipid was infused intravenously over 4 h to give the same fat load. A further eight subjects consumed a mixed meal (containing 37 g of fat and 100 g of carbohydrate) after an overnight fast. Paired blood samples were obtained from an arterialized hand vein and a vein draining subcutaneous adipose tissue at baseline and for 6 h following the meals or the start of the infusion. After both the intravenous and oral fat loads, the arterialized and adipose venous plasma leptin concentrations decreased over 6 h (both P<0.001), as did the leptin veno--arterial difference (P=0.01). Following the mixed meal, there was a slight increase in the arterialized plasma leptin concentration (P=0.02) and a more marked increase in the adipose venous plasma leptin concentration (P=0.03) and in the adipose tissue leptin veno--arterial difference (P=0.01), all peaking at 240 min. We conclude that the increase in plasma leptin concentration observed after meals is not simply a result of an energy load, but is in response to a signal that is not present following a fat load without carbohydrate.     

Activation of brown adipose tissue in hypothyroidism

Abstract

Background Brown adipose tissue (BAT) attracts growing interest as a potential therapeutic target for obesity and diabetes. Hyperthyroidism is well-known to increase BAT activity, but the role of hypothyroidism is controversial. We aimed to investigate the association between different thyroid hormone (TH) states and BAT activity.

Methods FDG-PET studies were retrospectively evaluated in thyroid cancer patients after total thyroidectomy both at euthyroidism during TH replacement or at hypothyroidism after TH cessation. Serum TH levels were compared between patients with active BAT and control patients with non-active BAT matched for age, gender, and body mass index. Additionally, animal experiments with controls (n?=?5) and hypothyroid rats (n?=?5) were performed.

Results Out of 124 patients, 6 patients with active BAT were identified. These patients showed significantly higher thyroid-stimulating hormone (TSH) levels than matched controls (P?<?0.05). In animal experiments, all hypothyroid animals showed BAT activation at room temperature (24?°C), whereas controls did not (P?<?0.001). Increased BAT activity was also confirmed by increased expression of UCP-1 and D2.

Conclusions Increased BAT metabolism appears to be related with hypothyroidism, which might be the result of a feedback mechanism to maintain body temperature in a state of reduced basal thermogenesis. Future research needs to explore the underlying mechanistic and biological implications.

• Key Messages

• Increased brown adipose tissue (BAT) metabolism appears to be related with hypothyroidism, which might be the result of a feedback mechanism to maintain body core temperature in a state of reduced basal thermogenesis.

     

Imaging and identification of brown adipose tissue on CT scan

Two types of adipose tissue (AT) have been described in the field of physiology: white (W) and brown (B) AT. Although WAT is well identified on human imaging, BAT imaging aspect remains to be further explored. The aim of this study was to investigate imaging aspect of BAT and its identification on CT (computed tomography) with iodine‐based contrast media injection. We retrospectively reviewed 464 positron emission tomography (PET)/CT, performed during 21 months on adults younger than 37 years. In 39 cases only, the PET revealed the presence of activated BAT. ROI was placed on both white and brown adipose tissue simultaneously on both PET and CT. Several patients’ characteristics (blood sugar level, gender, age, body mass index) as well as BAT and WAT parameters were assessed. Mean CT densities for WAT and BAT were ?99·5 HU versus ?32·6, mean SUV were 1·38 versus 13·2 and SUVmax were 1·79 versus 16·57, respectively. We found a statistically significant inverse relation between BMI and BAT density. BAT has a higher density than WAT. In this manner, BAT can be misinterpreted as an infiltration of adipose tissue in neoplasic and inflammatory context. Contrast‐enhanced CT scan allows visualization and identification of BAT.     

Endogenous ways to stimulate brown adipose tissue in humans

Abstract

Obesity is the result of disequilibrium between energy intake and energy expenditure (EE). Successful long-term weight loss is difficult to achieve with current strategies for the correction of this caloric imbalance. Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is a possible therapeutic target for the prevention and treatment of obesity and associated metabolic diseases. In recent years, more knowledge about the function and stimulation of bat has been obtained. The sympathetic nervous system (SNS) is currently seen as the main effector for brown fat function. Also, interplay between the thyroid axis and SNS plays an important role in BAT thermogenesis. Almost daily new pathways for the induction of BAT thermogenesis and ‘browning’ of white adipose tissue (WAT) are identified. Especially the activation of BAT via endogenous pathways has received strong scientific attention. Here we will discuss the relevance of several pathways in activating BAT and their implications for the treatment of obesity. In this review we will focus on the discussion of the most promising endocrine and paracrine pathways to stimulate BAT, by factors and pathways that naturally occur in the human body.     

Lipogenic activity and brown fat content of human perirenal adipose tissue

The incorporation of 3H2O and/or 14C-glycerol into lipids and the specific activities of the enzymes acetyl CoA carboxylase and lipoprotein lipase were measured in the perirenal and subcutaneous adipose tissue of human subjects. The perirenal adipose tissue of younger subjects with higher brown adipocyte content had higher rates of lipogenesis and enzyme activities per gram tissue than the corresponding subcutaneous tissue. However, in individual specimens, the perirenal/subcutaneous ratios of all but one of the above parameters failed to show a correlation with the brown adipocyte content of the perirenal adipose tissue. One parameter, namely 3H2O incorporation into fatty acids per adipocyte, did relate to the brown adipocyte content of the perirenal adipose tissue in four normal-weight patients only.     

The characterization and energetic potential of brown adipose tissue in man

In adult man, brown fat can be detected in perinephric fat depots by visual inspection, electron microscopy and nucleotide binding to the tissue-specific uncoupling protein. The 32 kDa uncoupling protein is functionally active, showing a nucleotide-sensitive conductance to protons and an uncoupling response to fatty acids. The amount of uncoupling protein in human mitochondria is equivalent to that in a partially cold-adapted guinea pig, indicating some potential for thermogenesis. Respiratory capacity measurements indicate that the total perinephric fat in adult man can only account for one-fivehundredth of the whole-body response to infused noradrenaline. Thus, although brown fat has been found to be quantitatively important in animal studies, considerable caution must be exercised in extrapolating its significance to adult man.     

Neural control of adenylate cyclase responsiveness in brown adipose tissue

The level of prior adrenergic stimulation is known to affect the responsiveness of tissue to subsequent stimulation. We investigated the effects of cold exposure on sympathetic nerve activity in interscapular brown adipose tissue (IBAT) and the impact of those changes on the responsiveness of the adenylate cyclase system. Exposing rats to 4 degrees C for 3 days increased norepinephrine turnover in IBAT and increased the ability of norepinephrine to stimulate adenylate cyclase activity. This 2- to 3-fold increase in adenylate cyclase activity appeared to result from increased nerve transmission because it was abolished by prior surgical denervation of IBAT. Additional studies indicated that cold exposure did not affect the number of beta adrenergic receptors in IBAT. Moreover, cold exposure increased the maximal response of adenylate cyclase to fluoride and guanosine-5--(beta-gamma-imino)triphosphate stimulation by 2- to 3-fold. We conclude that increased nerve transmission produces supersensitivity of IBAT adenylate cyclase and this effect is mediated by a postreceptor modification of the adenylate cyclase system.     

肠缺血再灌注损伤对血清及脂肪组织Leptin水平的影响

背景近年来的研究发现脂肪组织不仅仅是脂肪的储存库,还是一种能够分泌多种功能性细胞因子的多潜能内分泌器官.Leptin是一种由脂肪组织特异性分泌的蛋白质,主要功能是抑制摄食和增加能量消耗.目的研究肠缺血再灌注损伤对血清及脂肪组织Leptin水平的影响,探讨Leptin在急性炎症反应中的作用.设计完全随机设计,自身及组间对照.地点和材料本实验于解放军总医院生化研究室完成.3只雄性新西兰白兔及54只雄性SD大鼠作为实验动物.干预免疫新西兰白兔获得Leptin抗体,采用氯胺-T法碘标记Leptin抗原,由此建立一种简便的鼠Leptin放射免疫分析法.建立大鼠肠缺血再灌注损伤模型,实验大鼠随机分为6组假手术组(sham)、缺血60min-再灌注30 min组(I60-R30),I60-R90,I60-R150,I60-R240及I60-R360组,每组9只.主要观察指标采用放射免疫分析法测量血清及脂肪组织Leptin浓度变化.结果与损伤前自身对照组的血清Leptin水平相比,肠缺血60min再灌注损伤30min(I60-B30)组显著降低(t=2.389 1, P＜0.05),I60-R150组呈现增高的趋势,而I60-R360组显著增高(t=-2.343 7,P＜0.05);与损伤后sham组的血清Leptin水平(9.88±1.87)βg/L相比,I60-R240组呈现增高的趋势,而I60-R360组(19.43±2.84)μg/L显著增高(t=-2.808 5,P＜0.05);与损伤后sham组的脂肪组织Leptin水平(11.12±1.27)ng相比,I60-R30(4.46±2.63)ng、I60-R90组(3.45±2.77)ng显著降低(t=2.280 4,2.517 0,两者P均＜0.05),而I60-R360组(17.54±1.87)ng显著增高(t=-2.840 1,P＜0.05).结论Leptin对肠缺血-再灌注损伤等急性炎症刺激具有时间依赖效应,并在急性炎症反应的能量代谢障碍中发挥一定作用.     

Beta-1 receptor is the predominant beta-adrenoreceptor on rat brown adipose tissue

A new in vitro radioligand binding assay is described for brown adipose tissue using the beta adrenergic antagonist [3H]CGP 12177 (4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidazol-2-one). Binding was saturable and stereoselectively inhibited by propranolol. There was 60 to 80% specific binding using either 30 microM l-isoproterenol or 10 microM l-propranolol to define nonsaturable binding. [3H]CGP 12177 was bound to partially purified membranes from collagenase-separated brown adipocytes with a Kd of 0.84 nM, as determined from kinetic studies, and 1.24 +/- 0.13 nM as found by equilibrium binding studies; maximum binding was 14.2 +/- 0.9 fmol/mg of protein. Membranes from whole-pad homogenates had a similar Kd of 1.17 +/- 0.14 nM but twice the maximum number of binding sites (28.5 +/- 4.4 fmol/mg of protein). Intact brown adipocytes had a Kd of 0.55 nM and a maximum binding of 29.4 +/- 1.5 fmol X 10(-6)/cell or 17,700 sites per cell. Competitive binding studies showed about 80% of the binding sites to be of the beta-1 and 20% of the beta-2 subtype. The pA2 values derived from inhibition of isoproterenol-stimulated in vitro oxygen consumption in intact brown adipocytes by the beta-1 selective antagonist metoprolol and beta-2 selective lCl 118551 were in close agreement with their respective K1 values at the beta-1 receptor as derived from competitive binding studies. These data strongly suggest that the beta-1 adrenoreceptor on brown adipose tissue is primarily responsible for the initiation of thermogenesis in this tissue.     

Recruited brown adipose tissue as an antiobesity agent in humans

Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.     

Norepinephrine infusions increase adenylate cyclase responsiveness in brown adipose tissue

Previous work from our laboratory demonstrated that exposing rats to cold increases interscapular brown adipose tissue (IBAT) adenylate cyclase activity through a postreceptor modification of the adenylate cyclase system. The cold-induced sensitization is correlated with an increase in the activity of the sympathetic innervation of IBAT, and is prevented by prior surgical denervation of this tissue. The present experiments were aimed at identifying the neurogenic signal that mediates cold-induced sensitization. We found that, like cold exposure, infusions of norepinephrine increased adenylate cyclase activity and enhanced the ability of cholera toxin to ADP-ribosylate the stimulatory regulatory protein of adenylate cyclase (Gs) in warm-adapted rats whose IBAT had been denervated surgically. Infusions of isoproterenol increased adenylate cyclase responsiveness more potently than norepinephrine; however, the maximal effect achieved by isoproterenol was less than that produced by norepinephrine. Infusions of phenylephrine and clonidine had no effect on adenylate cyclase responsiveness. The effects of low doses of isoproterenol, however, were greatly potentiated by coinfusion of phenylephrine. Furthermore, the sensitizing effects of norepinephrine could be blocked by either propranolol or prazosin, indicating that the effects of norepinephrine require simultaneous stimulation of beta and alpha-1 adrenergic receptors.     

棕色脂肪MRI定量研究现状及进展

随着人们生活水平的提升和生活方式的改变,成人和儿童肥胖的发生率逐年上升,肥胖及其并发症已经成为危害人类健康的主要因素.棕色脂肪组织(brown adipose tissue,BAT)通过特征性高表达的解偶联蛋白1(uncoupling protein 1,UCP1)使线粒体内发生氧化磷酸化解偶联将化学能转化为热能,近些...     

追赶肥胖大鼠血清瘦素水平及脂肪组织瘦素受体mRNA的表达变化

目的:通过观察大鼠追赶肥胖过程中瘦素水平及瘦素受体mRNA(OBRb-mRNA)表达变化进一步揭示追赶肥胖发生机制.方法:5周龄Wistar雄性大鼠适应性喂养1周后随机分为对照组(NC)和追赶肥胖组(RN),NC组持续开放饮食,RN组给予半量饮食喂养4周(S4)后自由开放饮食8周.在造模过程中检测大鼠进食量、体重变化.分别于实验第0、4、6、8、12周采集血液并剥离内脏脂肪,测内脏脂肪(以两侧肾周及附睾脂肪为代表)重量/体重比值(以两侧肾周及附睾脂肪为代表);用ELISA法测血清瘦素水平及RT-PCR检测内脏脂肪OBRb-mRNA表达.结果:实验第4周,与NC组比较,RN组血清瘦素水平、内脏脂肪/体重比值明显降低(P＜0.05),内脏脂肪OBRb-mRNA表达增强,但无统计学意义.开放喂养后RN组血清瘦素水平、内脏脂肪/体重比值呈时间依赖性升高,于第8周时显著高于NC组(P＜0.05);而脂肪组织OBRb-mRNA表达逐渐降低,于第6周时明显低于NC组(P＜0.05).结论:在追赶生长过程中内脏脂肪组织OBRb-mRNA表达下降导致瘦素抵抗可能是造成内脏脂肪堆积的因素之一.     

针刺对肥胖大鼠褐色脂肪组织产热作用的影响

目的:探讨针刺对肥胖机体褐色脂肪组织(brownadiposetissue,BAT)解偶联蛋白1(uncouplingprotein1,UCP1)和肾上腺素能受体(β-adrenergicreceptor,β-AR)基因表达的作用。方法:采用反转录聚合酶链反应(RT-PCR)和RNA印迹试验(NorthernBlot)测定UCP1和β-AR的基因表达水平,观察针刺治疗前后肥胖大鼠(SD大鼠,n=18)体质量、Lee's指数、体脂,BATUCP1和β-AR的基因表达变化。结果:肥胖大鼠体质量、Lee's指数、体脂均显著高于正常大鼠(t=7.51,9.15,8.20;P<0.01),而BATUCP1和β-AR的基因表达水平明显低于正常大鼠(RT-PCR分析:t=-5.66,-4.66;NorthernBlot分析:t=-4.25,-4.925;P均<0.01)。相关分析显示,肥胖指标与BATUCP1和β-AR的基因表达水平呈负相关(RT-PCR或NorthernBlot分析P<0.05～0.01)。针刺治疗取得良好减肥疗效同时,肥胖大鼠BATUCP1和β-AR的基因表达水平明显回升(RT-PCR分析:t=2.20,6.72;NorthernBlot分析:t=2.33,2.35;P均<0.05)。结论:BATUCP1和β-AR的基因表达异常低下可能是产生肥胖的重要因素之一。针刺促进肥胖机体BATUCP1和β-AR的基因表达可能是针刺减肥的细胞分子机制之一。