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

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UCP1 Induction during Recruitment of Brown Adipocytes in White Adipose Tissue Is Dependent on Cyclooxygenase Activity

Background

The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis.

Methodology/Principal Findings

Here we report that cyclooxygenase (COX) activity and prostaglandin E₂ (PGE₂) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed β-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE₂ receptor antagonists implicated EP₄ as a main PGE₂ receptor, and injection of the stable PGE₂ analog (EP_3/4 agonist) 16,16 dm PGE₂ induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality.

Conclusions/Significance

Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development.     

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.     

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.     

Early B Cell Factor 1 Regulates Adipocyte Morphology and Lipolysis in White Adipose Tissue

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Anatomical Grading for Metabolic Activity of Brown Adipose Tissue

Background

Recent advances in obesity research suggest that BAT activity, or absence thereof, may be an important factor in the growing epidemic of obesity and its manifold complications. It is thus important to assess larger populations for BAT-activating and deactivating factors. ¹⁸FDG-PET/CT is the standard method to detect and quantify metabolic BAT activity, however, the manual measurement is not suitable for large studies due to its time-consuming nature and poor reproducibility across different software and devices.

Methodology/Main Findings

In a retrospective study, 1060 consecutive scans of 1031 patients receiving a diagnostic ¹⁸FDG-PET/CT were examined for the presence of active BAT. Patients were classified according to a 3-tier system (supraclavicular, mediastinal, infradiaphragmatic) depending on the anatomical location of their active BAT depots, with the most caudal location being the decisive factor. The metabolic parameters (maximum activity, total volume and total glycolysis) were measured on a standard PET/CT workstation. Mean age of the population was 60±14.6y. 41.61% of patients were female. Metabolically active BAT was found in 53 patients (5.1%). Female, younger and leaner patients tended to have more active BAT, higher metabolic activity and more caudally active BAT. In total, 15 patients showed only supraclavicular, 27 additional mediastinal, and 11 infradiaphragmal activity. Interestingly, the activation of BAT always followed a cranio-caudal gradient. This anatomical pattern correlated with age and BMI as well as with all metabolic parameters, including maximum and total glycolysis (p<0.001).

Conclusion

Based on our data we propose a simple method to grade or quantify the degree of BAT amount/activity in patients based on the most caudally activated depot. As new modalities for BAT visualization may arise in the future, this system would allow direct comparability with other modalities, in contrary to the PET-metrics, which are restricted to ¹⁸FDG-PET/CT.     

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.     

A Role for Brown Adipose Tissue in Diet-Induced Thermogenesis

Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity.     

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.     

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.     

Uncoupling Protein 1 Decreases Superoxide Production in Brown Adipose Tissue Mitochondria

In thermogenic brown adipose tissue, uncoupling protein 1 (UCP1) catalyzes the dissipation of mitochondrial proton motive force as heat. In a cellular environment of high oxidative capacity such as brown adipose tissue (BAT), mitochondrial uncoupling could also reduce deleterious reactive oxygen species, but the specific involvement of UCP1 in this process is disputed. By comparing brown adipose tissue mitochondria of wild type mice and UCP1-ablated litter mates, we show that UCP1 potently reduces mitochondrial superoxide production after cold acclimation and during fatty acid oxidation. We address the sites of superoxide production and suggest diminished probability of “reverse electron transport” facilitated by uncoupled respiration as the underlying mechanism of reactive oxygen species suppression in BAT. Furthermore, ablation of UCP1 represses the cold-stimulated increase of substrate oxidation normally seen in active BAT, resulting in lower superoxide production, presumably avoiding deleterious oxidative damage. We conclude that UCP1 allows high oxidative capacity without promoting oxidative damage by simultaneously lowering superoxide production.     

Adiposity-Related Cancer and Functional Imaging of Brown Adipose Tissue

Objective: Brown adipose tissue (BAT) is involved in energy dissipation and cytokine production and is potentially beneficial for the human body. The aim of the paper is to review the literature on adiposity-related cancer and functional imaging of BAT.Methods: We performed a review on adiposity-related cancer and functional imaging of BAT. We extensively researched papers for information on BAT molecular biology, as well as functional imaging modalities.Results: Adipose tissue is linked to the development of many cancers. Multiple drugs including fenofibrate, spironolactone, and other substances, as well as experimental agents like β-3 receptor agonists, caffeine, green tea extract, medium chain triglycerides (MCTs), and adenosine are known to stimulate and activate BAT. However, cold and nonshivering thermogenesis are the main activators of BAT. BAT has been detected on both magnetic resonance imaging (MRI) and 18F-fluorodexoxyglucose positron emission tomography (18F-FDG-PET)-based imaging in multiple studies. Different methods of cold stimulation and static and dynamic protocols have been used to detect and image BAT. Factors like sex, fasting or fed state, surface skin temperature, and/or body mass index (BMI) may influence PET-based BAT detection. BAT has also been detected using MRI, ^99mTechnetium(Tc)-sestamibi, and 123I- metaiodobenzylguanidine single-photon emission computed tomography/computed tomography (MIBG SPECT/CT).Conclusions: Stimulation of BAT offers promise in the management of obesity-related conditions. Tracers like &lsqb;¹⁵O]-H₂O, &lsqb;¹¹C] acetate, and 18F-fluoro-6-thia-heptadecanoic acid (18F-FTHA) that measure BAT blood flow, oxygen utilization, and nonessential fatty acid (NEFA) uptake, respectively, have been studied in humans. Future studies should focus on BAT tissue generation by altering the genetic pathways of adiposity-linked genes.Abbreviations: BAT = brown adipose tissue BMI = body mass index CT = computed tomography 18F-FDG = 18F-fluorodexoxyglucose 18F-FTHA = 18F-fluoro-6- thia-heptadecanoic acid GLUT = glucose transporter MIBG = metaiodobenzylguanidine MRI = magnetic resonance imaging PET = positron emission tomography PPAR = peroxisome proliferator-activated receptor SPECT = single-photon emission computed tomography SUV = standard uptake value Tc = technetium UCP-1 = uncoupling protein 1 WAT = white adipose tissue     

Mitochondria Isolated from Rat Brown Adipose Tissue and Liver

Mitochondrial fractions, relatively free from contamination by other cytoplasmic structures, have been isolated by differential centrifugation from homogenates of brown adipose tissue from starved rats. It was possible in such fractions to distinguish two types of mitochondria in this tissue. Type I mitochondria, when morphologically intact, are limited by a bilaminar membrane and show regular parallel cristae. In isolated fractions, a proportion of these mitochondria are swollen, vacuolation occurring within the cristae between their limiting membranes. Type II mitochondria are distinguished from the more numerous type I bodies by the opaque appearance of their matrix. They are limited by a membrane which is in part single, and in part double. They show a few, but crisply outlined internal membranes. Vacuolation of this type of mitochondrion has not been observed. Vacuolation comparable to that in brown fat mitochondria was also observed between the two laminae of the enclosing membrane and within the cristae of liver mitochondria.     

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.