肥胖治疗新希望：白色脂肪棕色化

哺乳动物体内有两种脂肪组织,白色脂肪和棕色脂肪。白色脂肪以储存能量为主,棕色脂肪则以消耗能量产热,维持体温恒定。棕色脂肪组织约占体重的2％以下,棕色脂肪细胞富含大量线粒体和解偶联蛋白1（UCP-1）,线粒体产生大量的ATP,通过UCP-1的解偶联作用,转换成热量释放。棕色脂肪细胞也有大量的脂滴,与白色脂肪细胞不同,它们以多房小脂滴形式存在,更方便于被氧化利用。     

白色脂肪棕色化研究进展

以往的观点认为,哺乳动物体内主要存在两种脂肪组织——白色脂肪（WAT）和棕色脂肪（BAT）。WAT的主要功能是以甘油三酯的形式储存能量,而BAT则通过产热来维持机体的能量代谢平衡。近年来,人们在WAT中发现了一种与BAT一样具有产热功能的所谓“米色脂肪”（beigecell）,这种现象也被认为是WAT棕色化。     

m6A甲基化修饰对脂肪组织代谢调控作用的研究进展

m6A修饰酶通过对相关因子表达进行m6A甲基化修饰,参与调控脂肪生成、脂肪细胞肥大、脂肪组织棕色化及产热。本文综述m6A甲基化修饰对脂肪组织代谢调控作用的研究进展。     

棕色脂肪组织的形成及其作用机制

人体内脂肪组织分为棕色脂肪组织(BAT)和白色脂肪组织(WAT).它们在组织形态和生理作用上存在较大差异,BAT主要在寒冷环境或交感神经兴奋下参与产热过程,而WAT主要以甘油三酯的形式储存多余能量.通过对BAT形成和作用机制的研究发现,两种脂肪组织的起源不同,并且揭示出部分细胞因子与BAT形成及活化之间的复杂关系,从而为肥胖及其相关疾病的防治提供了新的途径.     

脂肪组织棕色化与动脉粥样硬化的关系研究进展

脂肪组织棕色化会影响动脉粥样硬化的进展。本综述首先介绍环境温度改变对动脉粥样硬化的影响,接着介绍多种方法诱导脂肪组织棕色化对动脉粥样硬化的影响,最后介绍铁代谢在脂肪组织棕色化中的作用以及通过铁代谢调节脂肪组织棕色化治疗动脉粥样硬化的新思路,总结了脂肪组织棕色化与动脉粥样硬化的关系研究进展。     

一种新型脂肪细胞:beige细胞

最近的研究发现,与传统的白色和棕色脂肪细胞不同,脂肪组织中还存在另外一种新型的脂肪细胞,它们散在分布于白色脂肪组织中,受寒冷刺激或β3肾上腺素能受体激动剂激活后,表现出棕色脂肪细胞的特点,棕色脂肪细胞特异的解耦联蛋白1(UCP1)等基因的表达显著增高,产热和能量消耗能力增强.这一过程被称为“白色脂肪细胞棕色化”,这些细胞被命名为brite(brown to white)细胞或者beige(the intermediate color between white and brown)细胞.由于beige细胞在机体内分布广泛,并具有显著的消耗能量的功能,因此可能成为未来减肥药物开发的靶点.     

转录调控脂肪形成——代谢性疾病的新一代治疗

2012年第72届美国糖尿病协会(ADA)年会上,Bruce Soiegelman教授获得Banting科学成就奖.会上Soiegelman作了题为“转录调控脂肪形成——代谢性疾病的新一代治疗”的演讲.他报道了一种新发现的糖代谢关键调节激素——虹神素(Irisin)和第三类型脂肪——米色脂肪组织的脂肪细胞.其研究工作包括:(1 )PR域包含蛋白16(PRDM16)是控制棕色脂肪组织与骨骼肌组织相互转换的开关.(2) PRDM16决定小鼠皮下白色脂肪组织的产热方式.(3)米色脂肪细胞是小鼠和人类一种独特的产热脂肪细胞.(4)米色脂肪组织可用于减肥.(5)过氧化物酶体增殖物活化受体(PPAR)-γ协同刺激因子(PGC)-1α依赖的白色脂肪棕色样改变及产热作用与Irisin有关.     

棕色脂肪基础研究进展

哺乳动物体内的脂肪组织按功能主要分为白色脂肪组织（WAT）和棕色脂肪组织（BAT）。WAT主要以甘油三酯的形式储存机体摄取的能量，当能量摄入超出脂肪细胞的存储能力时，机体就会产生肥胖。与WAT不同，BAT主要通过氧化脂肪酸消耗能量。BAT一方面通过非颤抖性产热维持动物体温，另一方面可以消耗机体过剩的能量，维持能量平衡。基于BAT在消耗能量方面的作用，     

Irisin——可否让代谢性疾病治疗进入新时代

由Bostr(o)m等于2012年初发现的肌肉因子irisin主要由运动诱导生成,能够促进白色脂肪组织棕色化,改善糖脂代谢,增加能量消耗、降低体脂量,改善胰岛素敏感性.鉴于肥胖、2型糖尿病患者irisin水平明显降低,增加irisin水平可能会预防代谢性疾病的发生.通过运动增加内源性irisin或外源性irisin替代来诱导皮下脂肪棕色化,可能起到防治肥胖、抗胰岛素抵抗等作用.但目前研究止步于动物的体内实验,在irisin成为代谢性疾病治疗的新靶点之前,仍需要大量深入细致的基础研究.     

棕色脂肪检测技术的研究进展

目前关于体内棕色脂肪的检测主要分为半定量检测和功能检测两大类.半定量检测方法主要包括正电子发射断层扫描(PET)/CT、MRI等影像学检查,功能检测方法主要包括间接热量测定法、交感神经张力测定法、测温法等.此外,还可以通过称重法、检测棕色脂肪经典标志物表达来评估.对棕色脂肪组织的检测有助于进一步探讨肥胖的发生机制,从而为其治疗提供新的靶点.     

棕色脂肪组织与糖代谢的关系

研究证实成人体内存在有活性的棕色脂肪组织(BAT).BAT是非颤栗产热和饮食诱导产热的主要器官,其产热作用依赖线粒体内膜的解耦联蛋白1(UCP1).UCP1可使物质氧化与ATP生成解耦联(解耦联呼吸),减少ATP的生成,使能量以热量的形式释放,维持体温与能量的平衡.寒冷暴露、胰岛素、去甲肾上腺素、甲状腺激素等均可诱导UCP1表达使BAT活化,进而促进BAT摄取循环中的葡萄糖,加速循环中葡萄糖的清除.饮食因素以及可诱导BAT活化的因素均可影响BAT对葡萄糖的摄取.     

Polycystic ovary syndrome and adipose tissue

Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder in women of reproductive age. Typically, it is associated with ovulatory dysfunction: dysovulation or anovulation, and symptoms of hyperandrogenism. It incurs risk of metabolic disorders such as diabetes, dyslipidemia and fatty liver. As a key endocrine organ in metabolic homeostasis, adipose tissue is often implicated in these complications. Studies of white adipose tissue (WAT) in PCOS have focused on the mechanism of insulin resistance in this tissue. Clinically, abnormalities in WAT distribution are seen, with decreased waist-to-hip ratio and increased ratio of adipose to lean mass. Such abnormalities are greater when total circulating androgens are elevated. At tissue level, white adipocyte hyperplasia occurs, along with infiltration of macrophages. Secretion of adipokines, cytokines and chemo-attractant proteins is increased in a pro-inflammatory manner, leading to reduced insulin sensitivity via alteration of glucose transporters, and hence decreased glucose uptake. The kinetics of non-esterified fatty acids (or free fatty acids) is also altered, leading to lipotoxicity. In recent years, brown adipose tissue (BAT) has been studied in women with PCOS. Although abundance is low in the body, BAT appears to play a significant role in energy expenditure and metabolic parameters. Both supra-clavicular skin temperature, which reflects BAT activity, and BAT mass are reduced in women with PCOS. Moreover, BAT mass and body mass index (BMI) are inversely correlated in patients. In the adipocyte, increased total circulating androgen levels reduce expression of uncoupling protein 1 (UCP1), a key protein in the brown adipocyte, leading to reduced biogenesis and mitochondrial respiration and hence a reduction in post-prandial thermogenesis. BAT is currently being investigated as a possible new therapeutic application.     

Increased fat:carbohydrate oxidation ratio in <Emphasis Type="Italic">Il1ra</Emphasis><Superscript>−/−</Superscript> mice on a high-fat diet is associated with increased sympathetic tone

AIMS/HYPOTHESIS: Proinflammatory cytokines, including IL-1, exert pleiotropic effects on the neuro-immuno-endocrine system. Previously, we showed that mice with knockout of the gene encoding IL-1 receptor antagonist (Il1ra (-/-), also known as Il1rn (-/-)) have a lean phenotype. The present study was designed to analyse the mechanisms leading to this lean phenotype. METHODS: Il1ra (-/-) mice were fed a high-fat diet following weaning. Energy expenditure, body temperature, heart rate, blood parameters, urinary catecholamines and adipose tissue were analysed. RESULTS: Il1ra (-/-) mice exhibited resistance to obesity induced by a high-fat diet; this resistance was associated with increased energy expenditure and a decreased respiratory quotient, indicating that the ratio of fat:carbohydrate metabolism in Il1ra (-/-) mice is greater than in controls. Activity level in Il1ra (-/-) mice was significantly decreased and body temperature was significantly increased, compared with wild-type (WT) mice. Inguinal white adipose tissues in Il1ra (-/-) mice express increased levels of Ucp1 and mitochondrial respiratory chain genes compared with WT mice. Histological analysis of adipose tissue in Il1ra (-/-) mice revealed that brown adipose tissue is hyperactive and inguinal white adipose tissue contains smaller cells, which exhibit the distinctive multilocular appearance of brown adipocytes. Urinary epinephrine and norepinephrine excretion in Il1ra (-/-) mice was significantly increased compared with WT mice, suggesting that Il1ra (-/-) mice have increased sympathetic tone. Consistent with this, heart rate in Il1ra (-/-) mice was also significantly increased. CONCLUSIONS/INTERPRETATION: Our results show that Il1ra (-/-) mice have increased energy expenditure, fat:carbohydrate oxidation ratio, body temperature, heart rate and catecholamine production. All of these observations are consistent with an enhanced sympathetic tone.     

Stearic acid content of abdominal adipose tissues in obese women

Objective:

Subcutaneous (SC) adipose tissue stearic acid (18:0) content and stearoyl-CoA desaturase-1 (SCD1)-mediated production of oleic acid (18:1) have been suggested to be altered in obesity. The objective of our study was to examine abdominal adipose tissue fatty acid content and SCD1 mRNA/protein level in women.

Subjects and methods:

Fatty acid content was determined by capillary gas chromatography in SC and omental (OM) fat tissues from two subgroups of 10 women with either small or large OM adipocytes. Samples from 10 additional women were used to measure SCD1 mRNA and protein expression, total extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 protein as well as insulin receptor (IR) expression levels.

Results:

OM fat 18:0 content was significantly lower in women with large OM adipocytes compared with women who had similar adiposity, but small OM adipocytes (2.37±0.45 vs 2.75±0.30 mg per 100 g adipose tissue, respectively, P⩽0.05). OM fat 18:0 content was negatively related to the visceral adipose tissue area (r=−0.44, P=0.05) and serum triglyceride levels (r=−0.56, P<0.05), while SC fat 18:0 content was negatively correlated with total body fat mass (BFM) (r=−0.48, P<0.05) and fasting insulin concentration (r=−0.73, P<0.005). SC adipose tissue desaturation index (18:1/18:0), SCD1 expression and protein levels were positively correlated with BFM. Moreover, obese women were characterized by a reduced OM/SC ratio of SCD1 mRNA and protein levels. A similar pattern was observed for ERK1/2 and IR expression.

Conclusion:

The presence of large adipocytes and increased adipose mass in a given fat compartment is related to reduced 18:0 content and increased desaturation index in women, independently of dietary fat intake. The depot-specific difference in ERK1/2 expression and activation, as well as in SCD1 and IR expression in obese women is consistent with the hypothesis that they may predominantly develop SC fat, which could in turn help protect from metabolic disorders.     

Effects of carotid baroreceptor stimulation on aortic remodeling in obese rats

Background and aimOur previous study found carotid baroreceptor stimulation (CBS) reduces body weight and white adipose tissue (WAT) weight, restores abnormal secretion of adipocytokines and inflammation factors, decreases systolic blood pressure (SBP) by inhibiting activation of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in obese rats. In this study, we explore effects of CBS on aortic remodeling in obese rats.Methods and resultsRats were fed high-fat diet (HFD) for 16 weeks to induce obesity and underwent either CBS device implantation and stimulation or sham operation at 8 weeks. BP and body weight were measured weekly. RAS activity of WAT, histological, biochemical and functional profiles of aortas were detected after 16 weeks. CBS effectively decreased BP in obese rats, downregulated mRNA expression of angiotensinogen (AGT) and renin in WAT, concentrations of AGT, renin, angiotensin II (Ang II), protein levels of Ang II receptor 1 (AT1R) and Ang II receptor 2 (AT2R) in WAT were declined. CBS inhibited reactive oxygen species (ROS) generation, inflammatory response and endoplasmic reticulum (ER) stress in aortas of obese rats, restrained vascular wall thickening and vascular smooth muscle cells (VSMCs) phenotypic switching, increased nitric oxide (NO) synthesis, promoted endothelium-dependent vasodilatation by decreasing protein expression of AT1R and leptin receptor (LepR), increasing protein expression of adiponectin receptor 1 (AdipoR1) in aortic VSMCs.ConclusionCBS reduced BP and reversed aortic remodeling in obese rats, the underlying mechanism might be related to the suppressed SNS activity, restored adipocytokine secretion and restrained RAS activity of WAT.     

Aged garlic extract with supplement is associated with increase in brown adipose,decrease in white adipose tissue and predict lack of progression in coronary atherosclerosis

Background

Aged garlic extract with supplement (AGE-S) significantly reduces coronary artery calcium (CAC). We evaluated the effects of AGE-S on change in white (wEAT) and brown (bEAT) epicardial adipose tissue, homocysteine and CAC.

Methods

Sixty subjects, randomized to a daily capsule of placebo vs. AGE-S inclusive of aged garlic-extract (250 mg) plus vitamin-B12 (100 μg), folic-acid (300 μg), vitamin-B6 (12.5 mg) and l-arginine (100 mg) underwent CAC, wEAT and bEAT measurements at baseline and 12 months. The postcuff deflation temperature-rebound index of vascular function was assessed using a reactive-hyperemia procedure. Vascular dysfunction was defined according to the tertiles of temperature-rebound at 1 year of follow-up. CAC progression was defined as an annual-increase in CAC > 15%.

Results

From baseline to 12 months, there was a strong correlation between increase in wEAT and CAC (r² = 0.54, p = 0.0001). At 1 year, the risks of CAC progression and increased wEAT and homocysteine were significantly lower in AGE-S to placebo (p < 0.05). Similarly, bEAT and temperature-rebound were significantly higher in AGE-S as compared to placebo (p < 0.05). Strong association between increase in temperature-rebound and bEAT/wEAT ratio (r² = 0.80, p = 0.001) was noted, which was more robust in AGE-S. Maximum beneficial effect of AGE-S was noted with increase in bEAT/wEAT ratio, temperature-rebound, and lack of progression of homocysteine and CAC.

Conclusions

AGE-S is associated with increase in bEAT/wEAT ratio, reduction of homocysteine and lack of progression of CAC. Increases in bEAT/wEAT ratio correlated strongly with increases in vascular function measured by temperature-rebound and predicted a lack of CAC progression and plaque stabilization in response to AGE-S.