Tissue-specific functional interaction between apolipoproteins A1 and E in cold-induced adipose organ mitochondrial energy metabolism

White (WAT) and brown (BAT) adipose tissue, the two main types of adipose organ, are responsible for lipid storage and non-shivering thermogenesis, respectively. Thermogenesis is a process mediated by mitochondrial uncoupling protein 1 (UCP1) which uncouples oxidative phosphorylation from ATP production, leading to the conversion of free fatty acids to heat. This process can be triggered by exposure to low ambient temperatures, caloric excess, and the immune system. Recently mitochondrial thermogenesis has also been associated with plasma lipoprotein transport system. Specifically, apolipoprotein (APO) E3 is shown to have a bimodal effect on WAT thermogenesis that is highly dependent on its site of expression. Similarly, APOE2 and APOE4 differentially affect BAT and WAT mitochondrial metabolic activity in processes highly modulated by APOA1. Furthermore, the absence of classical APOA1 containing HDL (APOA1-HDL), is associated with no measurable non-shivering thermogenesis in WAT of mice fed high fat diet. Based on these previous observations which indicate important regulatory roles for both APOA1 and APOE in adipose tissue mitochondrial metabolic activity, here we sought to investigate the potential roles of these apolipoproteins in BAT and WAT metabolic activation in mice, following stimulation by cold exposure (7 °C). Our data indicate that APOA1-HDL promotes metabolic activation of BAT only in the presence of very low levels (virtually undetectable) of APOE3-containing HDL (APOE3-HDL), which acts as an inhibitor in this process. In contrast, induction of WAT thermogenesis is subjected to a more complicated regulation which requires the combined presence of both APOA1-HDL and APOE3-HDL.     

Retrieval of precursors for white-type adipose conversion in brown adipose tissue.

A cellular compartment from brown adipose tissue (BAT) of newborn rats was isolated by Percoll-density-gradient centrifugation and was shown to proliferate and to undergo adipose conversion in vitro in primary culture. The features of the effector requirement for adipose conversion as well as the differentiated morphological and biochemical phenotype are almost identical with that of a compartment designated HCF, from white adipose tissue (WAT). A possible role for these precursors from BAT and WAT in the involution of BAT into WAT, on the one hand, and in the development of brown adipose cells among typical WAT deposits, on the other, is discussed.     

White adipose tissue contributes to UCP1-independent thermogenesis

Beta3-adrenergic receptors (AR) are nearly exclusively expressed in brown and white adipose tissues, and chronic activation of these receptors by selective agonists has profound anti-diabetes and anti-obesity effects. This study examined metabolic responses to acute and chronic beta3-AR activation in wild-type C57Bl/6 mice and congenic mice lacking functional uncoupling protein (UCP)1, the molecular effector of brown adipose tissue (BAT) thermogenesis. Acute activation of beta3-AR doubled metabolic rate in wild-type mice and sharply elevated body temperature and BAT blood flow, as determined by laser Doppler flowmetry. In contrast, beta3-AR activation did not increase BAT blood flow in mice lacking UCP1 (UCP1 KO). Nonetheless, beta3-AR activation significantly increased metabolic rate and body temperature in UCP1 KO mice, demonstrating the presence of UCP1-independent thermogenesis. Daily treatment with the beta3-AR agonist CL-316243 (CL) for 6 days increased basal and CL-induced thermogenesis compared with naive mice. This expansion of basal and CL-induced metabolic rate did not require UCP1 expression. Chronic CL treatment of UCP1 KO mice increased basal and CL-stimulated metabolic rate of epididymal white adipose tissue (EWAT) fourfold but did not alter BAT thermogenesis. After chronic CL treatment, CL-stimulated thermogenesis of EWAT equaled that of interscapular BAT per tissue mass. The elevation of EWAT metabolism was accompanied by mitochondrial biogenesis and the induction of genes involved in lipid oxidation. These observations indicate that chronic beta3-AR activation induces metabolic adaptation in WAT that contributes to beta3-AR-mediated thermogenesis. This adaptation involves lipid oxidation in situ and does not require UCP1 expression.     

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.     

Lipoprotein lipase in adipose tissues of rats running during cold exposure

This study evaluated the individual and combined effects of exercise training and intermittent cold exposure of similar energy cost on serum lipids and lipoprotein lipase (LPL) activity on epididymal white (WAT) and interscapular brown (BAT) adipose tissues of the rat. The animals were subjected daily to 2 h of treadmill running at 24 degrees C or for the same period of time at -5 degrees C, with or without exercise, for 28 days. Exercise training lowered serum triglycerides (P less than 0.01), whereas serum cholesterol was reduced by cold exposure (P less than 0.05). Cholesterol lowering occurred in the lipoproteins of lower densities. WAT weight was diminished by both treatments. Exercise training had an overall lowering effect on WAT total LPL activity (P less than 0.05), whereas cold exposure did not affect enzyme activity significantly. Exercise and intermittent cold interacted on BAT weight. Cold increased total BAT LPL activity (P less than 0.03), whereas simultaneous exercise in the cold greatly diminished this effect. Serum insulin levels were not affected by either treatment. Thus, in WAT, intermittent exposure to cold did not have any lasting effect on LPL activity, whereas exercise training decreased the latter. In contrast, exercise did not influence LPL in BAT of rats not exposed to cold but prevented the stimulation of enzyme activity induced by repeated cold exposure. These results support the notion that the regulation of LPL is tissue specific.     

Effects of cold acclimation on the activity of lipoprotein lipase in adipose tissues of genetically obese Zucker rats

The activity of lipoprotein lipase (LPL) was studied in interscapilar brown adipose tissue (BAT), epididymal white adipose tissue (WAT) and in the heart of lean and obese adult Zucker rats maintained at 22 degrees C or adapted to cold (10 degrees C). In WAT the specific activity per gram of tissue was lower in obese than in lean rats but the total activity within the tissue was three-fold higher. Cold acclimation did not modify total activity in either lean or obese rats. In BAT, but not in the heart, both specific and total activities were lower in obese than in lean animals. They were enhanced in both tissues following cold acclimation. Six-hour fasting led to a decrease in specific activity in WAT of lean rats but had no effect in obese animals; an increase was observed in BAT and heart of both genotypes. Insulin administration has no effect on activities in WAT in either 22 or 10 degrees C adapted obese rats. Norepinephrine administration stimulates LPL activity in BAT and heart of all groups. It is concluded that the lack of development of obesity previously observed in obese rats following cold acclimation is not due to a decreased capacity of lipid uptake by WAT. It might in part be due to an increased lipid oxidation in BAT.     

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.     

Brown adipose tissue activity controls triglyceride clearance

Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.     

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...     

From heterogeneity to plasticity in adipose tissues: site-specific differences

In mammals, two types of adipose tissues are present, brown (BAT) and white (WAT). WAT itself can be divided into subcutaneous and internal fat deposits. All these tissues have been shown to present a great tissue plasticity, and recent data emphasized on the multiple differentiation potentials obtained from subcutaneous WAT. However, no study has compared the heterogeneity of stroma-vascular fraction (SVF) cells and their differentiation potentials according to the localization of the fat pad. This study clearly demonstrates that WAT and BAT present different antigenic features and differentiation potentials. WAT by contrast to BAT contains a large population of hematopoietic cells composed essentially of macrophages and hematopoietic progenitor cells. In WAT, the non-hematopoietic population is mainly composed of mesenchymal stem cell (MSC)-like but contains also a significant proportion of immature cells, whereas in BAT, the stromal cells do not present the same phenotype. Internal and subcutaneous WAT present some discrete differences in the phenotype of their cell populations. WAT derived SVF cells give rise to osteoblasts, endothelial cells, adipocytes, hematopoietic cells, and cardiomyoblasts only from inguinal cells. By contrast, BAT derived SVF cells display a reduced plasticity. Adipose tissues thus appear as complex tissues composed of different cell subsets according to the location of fat pads. Inguinal WAT appears as the most plastic adipose tissue and represents a potential and suitable source of stem cell, considering its easy sampling as a major advantage for cell therapy.     

Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype

While fatty acids (FAs) released by white adipose tissue (WAT) provide energy for other organs, lipolysis is also critical in brown adipose tissue (BAT), generating FAs for oxidation and UCP-1 activation for thermogenesis. Here we show that adipose-specific ablation of desnutrin/ATGL in mice converts BAT to a WAT-like tissue. These mice exhibit severely impaired thermogenesis with increased expression of WAT-enriched genes but decreased BAT genes, including UCP-1 with lower PPARα binding to its promoter, revealing the requirement of desnutrin-catalyzed lipolysis for maintaining a BAT phenotype. We also show that desnutrin is phosphorylated by AMPK at S406, increasing TAG hydrolase activity, and provide evidence for increased lipolysis by AMPK phosphorylation of desnutrin in adipocytes and in?vivo. Despite adiposity and impaired BAT function, desnutrin-ASKO mice have improved hepatic insulin sensitivity with lower DAG levels. Overall, desnutrin is phosphorylated/activated by AMPK to increase lipolysis and brings FA oxidation and UCP-1 induction for thermogenesis.     

Restricted food intake limits brown adipose tissue hypertrophy in cold exposure

Two factors that may determine brown adipose tissue (BAT) hypertrophy during conditions of increased metabolic heat production are increased food intake and increased sympathetic nervous system (SNS) activity. Since these two proceed pari passu during cold exposure, their independent contributions to BAT hypertrophy are unknown. To examine the role of each, we limited the food intake of a group of cold exposed rats by pair feeding them to warm exposed control rats and then compared the pair fed rats to ad lib fed cold exposed animals. Restricted food intake limited absolute BAT hypertrophy (0.226 +/- 0.01 g. vs 0.488 +/- 0.02 g, pair fed vs ad lib, P less than 0.01), BAT as per cent body weight (0.189 +/- 0.12 vs 0.252 +/- 0.012, P less than 0.01) and BAT protein content (34.4 +/- 3.8 vs 48.9 +/- 2.6 mg, P less than 0.01) despite evidence of quantitatively similar activation of the SNS in BAT in both groups. We conclude that increased food intake contributes to BAT hypertrophy in cold exposure independent of sympathetic activity.     

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.     

Up-regulation of genes related to the ubiquitin-proteasome system in the brown adipose tissue of 24-h-fasted rats

The functional balance between brown adipose tissue (BAT) and white adipose tissue (WAT) is important for metabolic homeostasis. We compared the effects of fasting on the gene expression profiles in BAT, WAT and liver by using a DNA microarray analysis. Tissues were obtained from rats that had been fed or fasted for 24 h. Taking the false discovery rate into account, we extracted the top 1,000 genes that had been differentially expressed between the fed and fasted rats. In all three tissues, a Gene Ontology analysis revealed that the lipid and protein biosynthesis-related genes had been markedly down-regulated. The whole-body fuel shift from glucose to triacylglycerol and the induction of autophagy were also observed. There was marked up-regulation of genes in the 'protein ubiquitination' category particularly in BAT of the fasted rats, suggesting that the ubiquitin-proteasome system was involved in saving energy as an adaptation to food shortage.     

Glycerokinase activity in human brown adipose tissue

Brown adipose tissue (BAT) is known to be responsible for heat production in newborn and adult hibernating mammals. In rats and mice, BAT has been demonstrated to possess a much higher glycerokinase activity than white adipose tissue (WAT). It has been speculated that this high activity may cause the futile cycle of triglyceride breakdown and resynthesis to be activated, thus contributing to heat production. However, at present very little information is available regarding the location, function, and quantitative importance of BAT in adult human subjects. Our objective in this study was to locate BAT in human subjects and to characterize it biochemically, especially with respect to the enzyme glycerokinase. We have looked for histologically identifiable BAT in 32 human subjects and found it in 12 subjects. Most of the BAT samples were obtained from perirenal adipose depots in children undergoing surgery. Some of the samples were almost totally comprised of BAT cells, whereas others were a mixture of BAT cells and WAT cells. The glycerokinase activity per gram of tissue was higher in BAT than in WAT in all the subjects where the above comparison was made. The activity per mg protein or per microgram DNA was higher in most BAT samples. In one pure BAT specimen, the basal lipolytic rate and the lipoprotein lipase activity were measured and they were both higher in BAT than in the WAT obtained from the same patient. These results show that human brown adipose tissue possesses an enzymatic profile very similar to that of rodent brown adipose tissue.     

A polyphenolic extract from green tea leaves activates fat browning in high-fat-diet-induced obese mice

Fat browning has emerged as an attractive target for the treatment of obesity and related metabolic disorders. Its activation leads to increased energy expenditure and reduced adiposity, thus contributing to a better energy homeostasis. Green tea extracts (GTEs) were shown to attenuate obesity and low-grade inflammation and to induce the lipolytic pathway in the white adipose tissue (WAT) of mice fed a high-fat diet. The aim of the present study was to determine whether the antiobesity effect of an extract from green tea leaves was associated with the activation of browning in the WAT and/or the inhibition of whitening in the brown adipose tissue (BAT) in HF-diet induced obese mice. Mice were fed a control diet or an HF diet supplemented with or without 0.5% polyphenolic GTE for 8 weeks. GTE supplementation significantly reduced HF-induced adiposity (WAT and BAT) and HF-induced inflammation in WAT. Histological analysis revealed that GTE reduced the adipocyte size in the WAT and the lipid droplet size in the BAT. Markers of browning were induced in the WAT upon GTE treatment, whereas markers of HF-induced whitening were reduced in the BAT. These results suggest that browning activation in the WAT and whitening reduction in the BAT by the GTE could participate to the improvement of metabolic and inflammatory disorders mediated by GTE upon HF diet. Our study emphasizes the importance of using GTE as a nutritional tool to activate browning and to decrease fat storage in all adipose tissues, which attenuate obesity.