褐色脂肪组织代谢与肥胖

肥胖是由于机体能量储存与消耗的失衡而产生的.褐色脂肪组织通过产热的形式,能够将体内过多的能量释放出来,以减少能量积累,避免造成肥胖.现从褐色脂肪组织的结构、分布、功能以及调控机制等方面,对褐色脂肪组织与肥胖症的关系作一综述,旨在为防治肥胖症及相关疾病寻找理论基础和实验依据.     

Genetic Regulation of SN-Glycerol-3-Phosphate Dehydrogenase in Brown Adipose Tissue

The levels of sn-glycerol-3-phosphate dehydrogenase (GPDH) were determined in the brown adipose tissue (BAT) of different inbred strains of mice. The BAT of the BALB/cJ strain contains twice as much enzyme activity per milligram protein as do other strains. The appearance of this difference is developmentally dependent, since it is not detected in BAT until 25-30 days postpartum. Genetic analysis of this strain difference has shown that the mechanism of inheritance involves at least two genes, one of which is linked to the Gdc-1 structural locus on chromosome 15. Determinations of GPDH synthesis by immunoprecipitation of GPDH protein labeled in vivo with [3H]leucine, and of GPDH mRNA by Northern blot analysis, establish that in BALB/cJ mice higher rates of enzyme synthesis are determined by elevated levels of GPDH mRNA. It was also found that cold stress increases GPDH mRNA levels in all the strains examined.     

Brown Adipose Tissue in Cetacean Blubber

Brown adipose tissue (BAT) plays an important role in thermoregulation in species living in cold environments, given heat can be generated from its chemical energy reserves. Here we investigate the existence of BAT in blubber in four species of delphinoid cetacean, the Pacific white-sided and bottlenose dolphins, Lagenorhynchus obliquidens and Tursiops truncates, and Dall’s and harbour porpoises, Phocoenoides dalli and Phocoena phocoena. Histology revealed adipocytes with small unilocular fat droplets and a large eosinophilic cytoplasm intermingled with connective tissue in the innermost layers of blubber. Chemistry revealed a brown adipocyte-specific mitochondrial protein, uncoupling protein 1 (UCP1), within these same adipocytes, but not those distributed elsewhere throughout the blubber. Western blot analysis of extracts from the inner blubber layer confirmed that the immunohistochemical positive reaction was specific to UCP1 and that this adipose tissue was BAT. To better understand the distribution of BAT throughout the entire cetacean body, cadavers were subjected to computed tomography (CT) scanning. Resulting imagery, coupled with histological corroboration of fine tissue structure, revealed adipocytes intermingled with connective tissue in the lowest layer of blubber were distributed within a thin, highly dense layer that extended the length of the body, with the exception of the rostrum, fin and fluke regions. As such, we describe BAT effectively enveloping the cetacean body. Our results suggest that delphinoid blubber could serve a role additional to those frequently attributed to it: simple insulation blanket, energy storage, hydrodynamic streamlining or contributor to positive buoyancy. We believe delphinoid BAT might also function like an electric blanket, enabling animals to frequent waters cooler than blubber as an insulator alone might otherwise allow an animal to withstand, or allow animals to maintain body temperature in cool waters during sustained periods of physical inactivity.     

Refeeding-Induced Brown Adipose Tissue Glycogen Hyper-Accumulation in Mice Is Mediated by Insulin and Catecholamines

Brown adipose tissue (BAT) generates heat during adaptive thermogenesis through a combination of oxidative metabolism and uncoupling protein 1-mediated electron transport chain uncoupling, using both free-fatty acids and glucose as substrate. Previous rat-based work in 1942 showed that prolonged partial fasting followed by refeeding led to a dramatic, transient increase in glycogen stores in multiple fat depots. In the present study, the protocol was replicated in male CD1 mice, resulting in a 2000-fold increase in interscapular BAT (IBAT) glycogen levels within 4–12 hours (hr) of refeeding, with IBAT glycogen stores reaching levels comparable to fed liver glycogen. Lesser effects occurred in white adipose tissues (WAT). Over the next 36 hr, glycogen levels dissipated and histological analysis revealed an over-accumulation of lipid droplets, suggesting a potential metabolic connection between glycogenolysis and lipid synthesis. 24 hr of total starvation followed by refeeding induced a robust and consistent glycogen over-accumulation similar in magnitude and time course to the prolonged partial fast. Experimentation demonstrated that hyperglycemia was not sufficient to drive glycogen accumulation in IBAT, but that elevated circulating insulin was sufficient. Additionally, pharmacological inhibition of catecholamine production reduced refeeding-induced IBAT glycogen storage, providing evidence of a contribution from the central nervous system. These findings highlight IBAT as a tissue that integrates both canonically-anabolic and catabolic stimulation for the promotion of glycogen storage during recovery from caloric deficit. The preservation of this robust response through many generations of animals not subjected to food deprivation suggests that the over-accumulation phenomenon plays a critical role in IBAT physiology.     

Altered Brown Adipose Tissue and Na,K Pump Activities During Diet-Induced Obesity and Weight Loss in Rats

Brown adipose tissue (BAT) thermogenesis is an uncoupled ATPase-independent thermogenic mechanism. Ion transport by the Na,K pump is an ATPase- dependent thermogenic mechanism. Both have been proposed as mechanisms of altered energy expenditure during states of dietary energy surfeit and deficit. Our aim was to study these mechanisms during diet-induced obesity and weight loss. Over 36 weeks rats were fed lard- or tallow-based diets (63% energy as fat), or a control diet (12% energy as fat). During periods of restriction rats were fed 50% of the energy intake of controls in the form of a control diet. Several components of thermogenic response increased in rats eating high fat diets and decreased following dietary restriction. BAT activation occurred, particularly with a lard-based diet, as indicated by increased GDP binding and uncoupling protein (UCP) content. Na,K pump activity in thymocytes increased with the feeding of both high fat diets at some time points. Plasma T₃ level increased in rats eating the lard-based diet and decreased with dietary restriction regardless of previous diet. Resting metabolic rate (RMR) of the animals was unchanged despite increases in these thermogenic components and was decreased in all groups following dietary restriction. Our results indicate a lack of any major role for activated BAT thermogenesis in mitigating the extent of the obesity induced by the high fat diets. The reasons for the differences in response to the two different sources of saturated fat, lard, and tallow, are not clear.     

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.     

Microbiota Depletion Impairs Thermogenesis of Brown Adipose Tissue and Browning of White Adipose Tissue

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Brown Adipose Tissue Activation Is Inversely Related to Central Obesity and Metabolic Parameters in Adult Human

Background

Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in affecting obesity. However, the supporting evidence on the relationship between BAT and central obesity and metabolic profile in large population based studies is sparse.

Methodology/Principal Findings

We studied 4011 (2688 males and 1323 females) tumor-free Chinese adults aged 18-89 for BAT activities, visceral/subcutaneous fat areas (VFA/SFA), waist circumferences (WC) and metabolic parameters. We found that the prevalence of BAT was around 2.7% in our study participants, with a significant sexual difference (5.5% in the females vs. 1.3% in the males; p<0.0001). BAT detection was increased in low temperature and declined in elderly subjects. The BAT positive subjects had lower BMI (P<0.0001), less SFA (P<0.01), VFA (P<0.0001), WC (P<0.0001), lower fasting glucose and triglyceride levels (both P<0.01) and increased HDL cholesterol concentrations (P<0.0001), compared with the BAT negative subjects. Robust logistic regression revealed that after adjustment for covariates (including age, sex, BMI, VFA, SFA and WC), age and BMI in the males (0.92 [95%CI, 0.88-0.96] and 0.84 [95% CI, 0.75-0.96], both P ≤0.008) while age and VFA in the females (0.87 [95%CI, 0.83-0.91] and 0.98 [95%CI, 0.97-0.99], respectively, P<0.05) were independently associated with detectable BAT.

Conclusions/Significance

Our data suggest that decreased amount of active BAT might be associated with accumulation of visceral fat content and unfavorable metabolic outcomes.     

免疫细胞在棕色脂肪产热及白色脂肪棕色化过程中的功能研究进展

肥胖已经成为威胁人类健康的全球性问题,棕色脂肪(Brown adipose tissue,BAT)及米色脂肪因其能够通过产热作用增加能量消耗这一特性,已成为一种备受关注的潜在肥胖治疗方法。近年来的研究发现M2型巨噬细胞(Alternatively activated macrophages,M2 type)能够促进BAT产热和白色脂肪(White adipose tissue,WAT)的棕色化(即米色脂肪的形成过程),但随后的一些研究却得到了相反的结论。到目前为止,M2型巨噬细胞是否参与促进WAT的棕色化过程仍是一个备受争议的话题。主要对M2型巨噬细胞、II型固有淋巴细胞(Type 2 Innate Lymphoid Cells,ILC2s)和嗜酸性粒细胞(Eosinophils)对BAT产热和WAT的棕色化的促进作用,以及M2型巨噬细胞不参与/抑制WAT棕色化这两个方面的研究状况做一综述。     

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.     

Brown Adipose Tissue Thermogenesis During Aging and Senescence

We have found that cold- and norepinephrine-induced brown adipose tissue (BAT) nonshiveringthermogenesis (NST) is significantly lower in old male Fischer 344 rats and is associatedwith the decreased ability of these animals to maintain homeothermy. This decline in BATthermogenesis is not as great in females. Although the mechanism(s) underlying this genderdifference in the age-related decrease in brown fat NST are not completely elucidated, theydo not appear to reflect decreased sympathetic neural activity of BAT in the older males vs.females. Rather, our investigations, strongly suggest that the blunted cold-induced heatproduction of BAT reflects less functional BAT. The fact that the older animals have less functionalBAT than do their younger counterparts may predispose them to the accumulation of excessbody fat. Our studies have also found that near the end of the natural life of these rats, theyenter a state of senescence that can be identified by spontaneous rapid body weight loss,resulting from decreased food intake. In this state, the rats are considerably more susceptibleto cold than are comparably aged presenescent (body weight stable) rats of the samechronological age. The greater hypothermia exhibited by the senescent vs. presenescent rats during coldexposure is associated with a significant reduction in the amount of functional brown fat andin the amount of heat each brown fat cell can generate. It is the intent of this review to discussthe findings of these investigations.     

肥胖与脂肪组织巨噬细胞的研究进展

肥胖被认为是一种慢性促炎症疾病。近年来巨噬细胞在肥胖的发生过程中起的重要作用越来越被研究者们所重视。研究发现脂肪组织巨噬细胞(ATMs)的极化和招募在肥胖的发生过程中扮演着重要角色:在肥胖的脂肪组织中,巨噬细胞M1/M2的比例出现失衡即M1促炎巨噬细胞比例上调M2抑炎巨噬细胞比例下调导致脂肪组织慢性炎症;脂肪组织的局部炎症发生时周边组织巨噬细胞招募至脂肪组织也能够促进肥胖的发展进程。本文就肥胖的发生与脂肪组织巨噬细胞的极化和招募的关系作一综述。     

Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity

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