Energy Metabolism In Brown Adipose Tissue Research Articles

Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis.

Brown adipose tissue (BAT) plays an important role in energy homeostasis by generating heat from chemical energy via uncoupled oxidative phosphorylation. Besides its high mitochondrial content and its exclusive expression of the uncoupling protein 1, another key feature of BAT is the high expression of myoglobin (MB), a heme-containing protein that typically binds oxygen, thereby facilitating the diffusion of the gas from cell membranes to mitochondria of muscle cells. In addition, MB also modulates nitric oxide (NO•) pools and can bind C16 and C18 fatty acids, which indicates a role in lipid metabolism. Recent studies in humans and mice implicated MB present in BAT in the regulation of lipid droplet morphology and fatty acid shuttling and composition, as well as mitochondrial oxidative metabolism. These functions suggest that MB plays an essential role in BAT energy metabolism and thermogenesis. In this review, we will discuss in detail the possible physiological roles played by MB in BAT thermogenesis along with the potential underlying molecular mechanisms and focus on the question of how BAT-MB expression is regulated and, in turn, how this globin regulates mitochondrial, lipid, and NO• metabolism. Finally, we present potential MB-mediated approaches to augment energy metabolism, which ultimately could help tackle different metabolic disorders.

208-LB: Plasma Lipidomics Reveals Sex-Specific Associations with? Brown Adipose Tissue in Asian Children

Brown adipose tissue (BAT) plays a crucial role in lipid metabolism. Activated BAT oxidizes fatty acids from triglycerides in lipid droplets during thermogenesis, increasing energy expenditure. The lipidomic profile of BAT has been primarily studied in animals but little in humans. We sought to identify the plasma lipidomic profile associated with BAT in a thermoneutral condition in 6-year-old children (n=134) in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. LC-MS/MS-based quantification of 480 lipids was performed on plasma samples; %BAT was quantified based on fat-signal-fractions of water-fat-MRI. Associations between plasma lipids and the child's %BAT were investigated using multivariate regression analysis adjusting for sex, ethnicity, and BMI. Sex stratification was applied to investigate the sex-specific lipid signatures of %BAT among the 68 boys and 66 girls. The inverse association between %BAT and BMI was stronger in boys (R2 =0.28) than in girls (R2 =0.07). More lipid signatures of %BAT were observed in boys compared to girls; of 63 unique lipid species significantly associated with %BAT, 12 were associated in both genders, 50 in boys and 11 in girls. In boys, lipid species representing triacylglycerol, cholesteryl ester, acylcarnitine, sphingomyelin, ceramide, hexosylceramides and lysophosphatidylcholine classes showed negative associations with %BAT, whereas several phosphatidylethanolamine lipids displayed positive association with %BAT. In girls, opposite trends in effect sizes (R=-0.44) were, however, observed; several lipids in acylcarnitine, diacylglycerol and sphingolipid classes presented positive association with %BAT, while phosphatidylethanolamine lipids showed negative associations with %BAT. These unique associations between plasma lipid species and BAT in a sex-specific manner provide insights into the different potential lipidomic pathways involved in BAT energy metabolism. Disclosure M. Tint: None. M. Fortier: None. K. Godfrey: Other Relationship; See box. M. Wenk: None. J. Eriksson: None. L. Chen: None. N. Kothandaraman: None. M. K. Leow: None. B. Kn: None. F. Yap: None. Y. Lee: None. E. H. Tham: None. Y. Chong: None. Funding Open Fund Large-Collaborative Grant (000504)

The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice.

During thermogenesis, adipose tissue (AT) becomes more active and enhances oxidative metabolism. The promotion of this process in white AT (WAT) is called "browning" and, together with the brown AT (BAT) activation, is considered as a promising approach to counteract obesity and metabolic diseases. Transient receptor potential cation channel, subfamily M, member 2 (TRPM2), is an ion channel that allows extracellular Ca2+ influx into the cytosol, and is gated by adenosine diphosphate ribose (ADPR), produced from NAD+ degradation. The aim of this study was to investigate the relevance of TRPM2 in the regulation of energy metabolism in BAT, WAT, and liver during thermogenesis. Wild type (WT) and Trpm2-/- mice were exposed to 6°C and BAT, WAT and liver were collected to evaluate mRNA, protein levels and ADPR content. Furthermore, O2 consumption, CO2 production and energy expenditure were measured in these mice upon thermogenic stimulation. Finally, the effect of the pharmacological inhibition of TRPM2 was assessed in primary adipocytes, evaluating the response upon stimulation with the β-adrenergic receptor agonist CL316,243. Trpm2-/- mice displayed lower expression of browning markers in AT and lower energy expenditure in response to thermogenic stimulus, compared to WT animals. Trpm2 gene overexpression was observed in WAT, BAT and liver upon cold exposure. In addition, ADPR levels and mono/poly-ADPR hydrolases expression were higher in mice exposed to cold, compared to control mice, likely mediating ADPR generation. Our data indicate TRPM2 as a fundamental player in BAT activation and WAT browning. TRPM2 agonists may represent new pharmacological strategies to fight obesity.

PMON182 PACAP Receptor Expression in Sympathetic Ganglia of the Autonomic Nervous System

Abstract In obesity, energy intake exceeds energy expenditure and concomitantly increases risk of chronic diseases, including metabolic diseases such as diabetes. Therapeutics to correct dysregulations in energy balance are needed and one notable neuropeptide being studied is pituitary adenylate cyclase-activating polypeptide (PACAP), an overarching regulator of the stress response1,2. In the context of metabolism, PACAP has been shown to regulate adaptive thermogenesis, an energy burning process regulated by the sympathetic nervous system (SNS) in response to cold stress and overfeeding. While research suggests PACAP acts centrally at the level of the hypothalamus to regulate energy balance3-5, PACAP is also known to be expressed in the SNS. In preganglionic neurons innervating the adrenal medulla6, PACAP is co-localized with acetylcholine and regulates catecholamine synthesis and release. Recent neuronal tracing studies have shown that postganglionic fibres of the stellate ganglia innervate intrascapular brown adipose tissue (BAT), the main thermogenic tissue in mammals7. However, PACAP's role within the sympathetic nerves innervating and regulating energy metabolism in adipose tissues is not known. As such, our group is interested in characterizing PACAP and PACAP receptor expression in sympathetic nerves innervating and regulating energy metabolism in BAT (via the stellate ganglia) in response to metabolic stressors, such as cold stress. We hypothesize that PACAP is released from preganglionic nerves which binds PACAP receptors (PAC1, VPAC1, VPAC2) expressed in postganglionic nerves of the stellate ganglia. Here we report, for the first time, PAC1 and VPAC1 expression in the stellate ganglia with sex-specific differential gene expression based on housing temperature. Analysis of PAC1 splice variant expression identified at least two variants in tissues of the SNS (adrenal gland, superior cervical ganglia and the stellate ganglia). These results will support future functional studies characterizing PACAP regulation of catecholamine production in peripheral ganglia which will contribute to assessing G-protein coupled receptors (GPCRs) as potential therapeutic targets for obesity and metabolic disease.

Aging attenuates diurnal lipid uptake by brown adipose tissue.

Brown adipose tissue (BAT) contributes to cardiometabolic health by taking up glucose and lipids for oxidation, a process that displays a strong diurnal rhythm. While aging has been shown to reduce thermogenic characteristics of BAT, it is as yet unknown whether this reduction is specific to the time of day. Therefore, we assessed whole-body and BAT energy metabolism in young and middle-aged male and female C57BL/6J mice and studied the consequences for lipid metabolism in humanized APOE*3-Leiden.CETP mice (also on a C57BL/6J background). We demonstrate that in middle-aged versus young mice body temperature is lower in both male and female mice, while uptake of triglyceride (TG)-derived fatty acids (FAs) by BAT, reflecting metabolic activity, is attenuated at its peak at the onset of the dark (wakeful) phase in female mice. This coincided with delayed plasma clearance of TG-rich lipoproteins and TG-depleted lipoprotein core remnants, and elevated plasma TGs at the same time point. Furthermore, middle-aged female mice showed increased adiposity, accompanied by lipid accumulation, increased expression of genes involved in lipogenesis, and reduced expression of genes involved in fat oxidation and the intracellular clock machinery in BAT. Peak abundance of lipoprotein lipase (LPL), a crucial regulator of FA uptake, was attenuated in BAT. Our findings suggest that LPL is a potential therapeutic target for restoring diurnal metabolic BAT activity, and that efficiency of strategies targeting BAT may be improved by including time of day as an important factor.

Adipocyte Utx Deficiency Promotes High-Fat Diet-Induced Metabolic Dysfunction in Mice.

While the main function of white adipose tissue (WAT) is to store surplus of energy as triacylglycerol, that of brown adipose tissue (BAT) is to burn energy as heat. Epigenetic mechanisms participate prominently in both WAT and BAT energy metabolism. We previously reported that the histone demethylase ubiquitously transcribed tetratricopeptide (Utx) is a positive regulator of brown adipocyte thermogenesis. Here, we aimed to investigate whether Utx also regulates WAT metabolism in vivo. We generated a mouse model with Utx deficiency in adipocytes (AUTXKO). AUTXKO animals fed a chow diet had higher body weight, more fat mass and impaired glucose tolerance. AUTXKO mice also exhibited cold intolerance with an impaired brown fat thermogenic program. When challenged with high-fat diet (HFD), AUTXKO mice displayed adipose dysfunction featured by suppressed lipogenic pathways, exacerbated inflammation and fibrosis with less fat storage in adipose tissues and more lipid storage in the liver; as a result, AUTXKO mice showed a disturbance in whole body glucose homeostasis and hepatic steatosis. Our data demonstrate that Utx deficiency in adipocytes limits adipose tissue expansion under HFD challenge and induces metabolic dysfunction via adipose tissue remodeling. We conclude that adipocyte Utx is a key regulator of systemic metabolic homeostasis.

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways.

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism.Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro.Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis.Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.

CD38 downregulation modulates NAD+ and NADP(H) levels in thermogenic adipose tissues

Different strategies to boost NAD+ levels are considered promising means to promote healthy aging and ameliorate dysfunctional metabolism. CD38 is a NAD+-dependent enzyme involved in the regulation of different cell functions. In the context of systemic energy metabolism, it has been demonstrated that brown adipocytes, the parenchymal cells of brown adipose tissue (BAT) as well as beige adipocytes that emerge in white adipose tissue (WAT) depots in response to catabolic conditions, are important to maintain metabolic homeostasis. In this study we aim to understand the functional relevance of CD38 for NAD+ and energy metabolism in BAT and WAT, also using a CD38−/− mouse model.During cold exposure, an increase in NAD+ levels occurred in BAT of wild type mice, together with a marked downregulation of CD38, as detected at the mRNA and protein level. CD38 downregulation was observed also in WAT of cold-exposed mice, where it was accompanied by a strong increase in NADP(H) levels. Accordingly, NAD kinase and glucose-6-phosphate dehydrogenase activities were enhanced in WAT (but not in BAT). Increased NAD+ levels were observed in BAT/WAT from CD38−/− compared with wild type mice, in line with CD38 being a major NAD+-consumer in AT. CD38−/− mice kept at 6 °C had higher levels of Ucp1 and Pgc-1α in BAT and WAT, and increased levels of phosphorylated hormone-sensitive lipase in BAT, compared with wild type mice.These results demonstrate that CD38, by modulating cellular NAD(P)+ levels, is involved in the regulation of thermogenic responses in cold-activated BAT and WAT.

Brown Adipose Tissue Energy Metabolism in Humans.

The demonstration of metabolically active brown adipose tissue (BAT) in humans primarily using positron emission tomography coupled to computed tomography (PET/CT) with the glucose tracer 18-fluorodeoxyglucose (18FDG) has renewed the interest of the scientific and medical community in the possible role of BAT as a target for the prevention and treatment of obesity and type 2 diabetes (T2D). Here, we offer a comprehensive review of BAT energy metabolism in humans. Considerable advances in methods to measure BAT energy metabolism, including nonesterified fatty acids (NEFA), chylomicron-triglycerides (TG), oxygen, Krebs cycle rate, and intracellular TG have led to very good quantification of energy substrate metabolism per volume of active BAT in vivo. These studies have also shown that intracellular TG are likely the primary energy source of BAT upon activation by cold. Current estimates of BAT's contribution to energy expenditure range at the lower end of what would be potentially clinically relevant if chronically sustained. Yet, 18FDG PET/CT remains the gold-standard defining method to quantify total BAT volume of activity, used to calculate BAT's total energy expenditure. Unfortunately, BAT glucose metabolism better reflects BAT's insulin sensitivity and blood flow. It is now clear that most glucose taken up by BAT does not fuel mitochondrial oxidative metabolism and that BAT glucose uptake can therefore be disconnected from thermogenesis. Furthermore, BAT thermogenesis is efficiently recruited upon repeated cold exposure, doubling to tripling its total oxidative capacity, with reciprocal reduction of muscle thermogenesis. Recent data suggest that total BAT volume may be much larger than the typically observed 50–150 ml with 18FDG PET/CT. Therefore, the current estimates of total BAT thermogenesis, largely relying on total BAT volume using 18FDG PET/CT, may underestimate the true contribution of BAT to total energy expenditure. Quantification of the contribution of BAT to energy expenditure begs for the development of more integrated whole body in vivo methods.

解偶联蛋白-1(UCP1)的研究进展及其应用前景

UCP1是唯一在褐色脂肪组织(BAT)中表达的解偶联蛋白质。有别于解偶联蛋白家族其他成员的功能，UCP1的主要功能是参与BAT的产热调节和能量代谢来维持机体的能量代谢平衡。陆续有研究阐明调控UCP1参与BAT产热调节和能量代谢的分子机制，逐渐揭示了UCP1在BAT能量代谢过程中涉及的信号通路与转录调控。这不仅让我们更好地理解UCP1在BAT能量代谢调控中的重要作用，而且为基于褐色脂肪组织的肥胖治疗提供了理论依据。本文阐述了近年来研究发现的UCP1在BAT能量代谢过程中发挥重要作用的信号通路与转录调控，并讨论了多种基于针对褐色脂肪组织的肥胖治疗手段的有效性与可行性。 UCP1 is the only one expression of uncoupling protein in the brown adipose tissue (BAT). Different from the uncoupling protein family other member functions, UCP1’s main function is to participate thermogenic regulation and energy metabolism in BAT to maintain the body’s energy metabolic balance. In succession studies clarify regulation UCP1 participate heat production regulation and energy metabolism molecular mechanism in BAT, gradually reveals the UCP1 inBAT energy metabolic process involved in the signal path and transcription regulation. This not only let us better understand UCP1 inBAT energy metabolism control of the important role, but based on brown adipose tissue obesity treatment provides a theoretical basis. This paper describes the research in recent years UCP1 found in BAT energy metabolism process play an important role in the signal path and transcription regulation, and discussed based on various for brown adipose tissue obesity treatment of the effectiveness and feasibility.

Comparison of gene expression profiles between white and brown adipose tissues of rat by microarray analysis

To characterize the energy metabolism in brown adipose tissue (BAT), the differences in gene expression profiles between BAT and white adipose tissue (WAT) were analyzed using a high-density cDNA microarray. RNAs isolated from two adipose tissues were hybridized to an Agilent rat cDNA Microarray that contained about 14,500 cDNA probe sets. The expression levels of 499 cDNA/ESTs were found to be at least 5-fold higher or lower in BAT than in WAT. Consistent with our previous findings, high expression levels of genes encoding uncoupling protein 1, muscle-type carnitine palmitoyltransferase and some other proteins involved in energy metabolism in BAT were found. Most of the genes encoding mitochondrial proteins, such as subunits of ATP synthase, cytochrome c oxidase, and NADH dehydrogenase, were highly expressed, reflecting possible differences in the cellular content of mitochondria between BAT and WAT. However, the expression levels of several genes encoding mitochondrial protein, such as liver mitochondrial aldehyde dehydrogenase and dicarboxylate carrier, were remarkably lower in BAT. These results may give important clues to understand the unique energy metabolism in BAT.

Specific elevation of transcript levels of particular protein subtypes induced in brown adipose tissue by cold exposure

To understand the difference in metabolic flow in rat brown adipose tissue (BAT) from that in white adipose tissue (WAT) at the molecular level, we examined the steady-state transcript levels of 39 proteins in both adipose tissues with and without cold exposure by Northern blot analysis. In addition to the transcript levels of uncoupling protein isoforms, those of proteins involved in the transport and catabolism of fatty acids and glucose in BAT were elevated by cold exposure, suggesting the stimulation of utilization of fatty acids and glucose as fuels in BAT. As to these changes, the muscle-type subtypes were remarkable; and therefore, they were suggested to be responsible for the cold exposure-induced acceleration of energy expenditure in BAT. Furthermore, of the isoforms of β-adrenergic receptor (β-AR) and CCAAT enhancer binding protein (C/EBP), transcript levels of β 1-AR and C/EBPβ in BAT were increased by the cold exposure. Possible roles of these proteins in energy metabolism in BAT were discussed.