Response Of Brown Adipose Tissue Research Articles

Modulation of aquaporin gene expression by n-3 long-chain PUFA lipid structures in white and brown adipose tissue from hamsters.

EPA (20 : 5n-3) and DHA (22 : 6n-3) fatty acids have weight-reducing properties with physiological activity depending on their molecular structure - that is, as TAG or ethyl esters (EE). Aquaporins (AQP) are membrane protein channels recognised as important players in fat metabolism, but their differential expression in white adipose tissue (WAT) and brown adipose tissue (BAT), as well as their modulation by dietary n-3 long-chain PUFA (LCPUFA) such as EPA and DHA, has never been investigated. In this study, the transcriptional profiles of AQP3, AQP5, AQP7 and selected lipid markers of WAT (subcutaneous and visceral) and BAT (interscapular) from hamsters fed diets containing n-3 LCPUFA in different lipid structures such as fish oil (FO, rich in EPA and DHA in the TAG form) and FO-EE (rich in EPA and DHA in the EE form) were used and compared with linseed oil (LSO) as the reference group. A clear effect of fat depot was observed for AQP3 and leptin (LEP), with the lowest values of mRNA found in BAT relative to WAT. The opposite occurred for PPARα. AQP7 was affected by diet, with FO-fed hamsters having higher mRNA levels compared with LSO-fed hamsters. The relative gene expression of AQP5, adiponectin (ADIPO), GLUT4 and PPARγ was influenced by both fat tissue and diet. Taken together, our results revealed a differential expression profile of AQP and some markers of lipid metabolism in both WAT and BAT in response to feeding n-3 LCPUFA in two different structural formats: TAG v. EE.

Nicotinamide riboside induces a thermogenic response in lean mice

AimsNicotinamide Riboside (NR) is a NAD+ booster with wide physiological repercussion including the improvement on glucose and lipid homeostasis, increasing the life expectancy in mammals. However, the effects of NR on metabolism are only partially known. Here, we evaluated the effects of NR on the thermogenic response, highlighting the brown adipose tissue (BAT) in lean mice. Main methodsMale C57BL/67 mice were supplement with NR (400 mg/Kg/day) during 5 weeks. The Comprehensive Lab Animal Monitoring System (CLAMS) and thermographic images were used to evaluated the physiological effects of NR treatment. The BAT were extracted and analyzed by Western Blotting and qPCR. Also, bioinformatics analyses were performed to establish the connection between the NAD+ synthesis pathway in BAT and thermogenic response in several isogenic strains of BXD mice. Key findingsTranscriptomic analysis revealed that genes involved in NAD+ synthesis (Nampt and Nmnat1) in the BAT were negatively correlated with body weight and fat mass. The heat map showed a strong positive correlation between Nampt and Ucp1 mRNA in BAT and body temperature in several strains of BXD lean mice. The experimental approaches demonstrated that oral NR supplementation reduced the abdominal visceral fat depots, with discrete impact on oxygen consumption in C57BL/6J mice. Interestingly, NR significantly increased the body temperature, and this phenomenon was accompanied by high levels of UCP1 protein content and Pgc1α mRNA in BAT. SignificanceThis study demonstrated the oral NR supplementation was sufficient to induce the thermogenic response in lean mice changing the BAT metabolism.

Chronic Exercise Improves Mitochondrial Function and Insulin Sensitivity in Brown Adipose Tissue.

The aim of the present work was to study the consequences of chronic exercise training on factors involved in the regulation of mitochondrial remodeling and biogenesis, as well as the ability to produce energy and improve insulin sensitivity and glucose uptake in rat brown adipose tissue (BAT). Male Wistar rats were divided into two groups: (1) control group (C; n = 10) and (2) exercise-trained rats (ET; n = 10) for 8 weeks on a motor treadmill (five times per week for 50 min). Exercise training reduced body weight, plasma insulin, and oxidized LDL concentrations. Protein expression of ATP-independent metalloprotease (OMA1), short optic atrophy 1 (S-OPA1), and dynamin-related protein 1 (DRP1) in BAT increased in trained rats, and long optic atrophy 1 (L-OPA1) and mitofusin 1 (MFN1) expression decreased. BAT expression of nuclear respiratory factor type 1 (NRF1) and mitochondrial transcription factor A (TFAM), the main factors involved in mitochondrial biogenesis, was higher in trained rats compared to controls. Exercise training increased protein expression of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and AMP-activated protein kinase (pAMPK/AMPK ratio) in BAT. In addition, training increased carnitine palmitoyltransferase II (CPT II), mitochondrial F1 ATP synthase α-chain, mitochondrial malate dehydrogenase 2 (mMDH) and uncoupling protein (UCP) 1,2,3 expression in BAT. Moreover, exercise increased insulin receptor (IR) ratio (IRA/IRB ratio), IRA-insulin-like growth factor 1 receptor (IGF-1R) hybrids and p42/44 activation, and decreased IGF-1R expression and IR substrate 1 (p-IRS-1) (S307) indicating higher insulin sensitivity and favoring glucose uptake in BAT in response to chronic exercise training. In summary, the present study indicates that chronic exercise is able to improve the energetic profile of BAT in terms of increased mitochondrial function and insulin sensitivity.

CXCL14, a Brown Adipokine that Mediates Brown-Fat-to-Macrophage Communication in Thermogenic Adaptation

The beneficial effects of brown adipose tissue (BAT) are attributed to its capacity to oxidize metabolites and produce heat, but recent data suggest that secretory properties of BAT may also be involved. Here, we identify the chemokine CXCL14 (C-X-C motif chemokine ligand-14) as a novel regulatory factor secreted by BAT in response to thermogenic activation. We found that the CXCL14 released by brown adipocytes recruited alternatively activated (M2) macrophages. Cxcl14-null mice exposed to cold showed impaired BAT activity and low recruitment of macrophages, mainly of the M2 phenotype, into BAT. CXCL14 promoted the browning of white fat and ameliorated glucose/insulin homeostasis inhigh-fat-diet-induced obese mice. Impairment oftype 2 cytokine signaling, as seen in Stat6-null mice, blunts the action of CXCL14, promoting adipose tissue browning. We propose that active BAT is a source of CXCL14, which concertedly promotes adaptive thermogenesis via M2 macrophage recruitment, BAT activation, and the browning of white fat.

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

Recent advances in the detection of brown adipose tissue in adult humans: a review.

The activation of brown adipose tissue (BAT) is associated with reductions in circulating lipids and glucose in rodents and contributes to energy expenditure in humans indicating the potential therapeutic importance of targetting this tissue for the treatment of a variety of metabolic disorders. In order to evaluate the therapeutic potential of human BAT, a variety of methodologies for assessing the volume and metabolic activity of BAT are utilized. Cold exposure is often utilized to increase BAT activity but inconsistencies in the characteristics of the exposure protocols make it challenging to compare findings. The metabolic activity of BAT in response to cold exposure has most commonly been measured by static positron emission tomography of 18F-fluorodeoxyglucose in combination with computed tomography (18F-FDG PET-CT) imaging, but recent studies suggest that under some conditions this may not always reflect BAT thermogenic activity. Therefore, recent studies have used alternative positron emission tomography and computed tomography (PET-CT) imaging strategies and radiotracers that may offer important insights. In addition to PET-CT, there are numerous emerging techniques that may have utility for assessing BAT metabolic activity including magnetic resonance imaging (MRI), skin temperature measurements, near-infrared spectroscopy (NIRS) and contrast ultrasound (CU). In this review, we discuss and critically evaluate the various methodologies used to measure BAT metabolic activity in humans and provide a contemporary assessment of protocols which may be useful in interpreting research findings and guiding the development of future studies.

A map of the PGC-1\u03b1- and NT-PGC-1\u03b1-regulated transcriptional network in brown adipose tissue

Transcriptional coactivator PGC-1α and its splice variant NT-PGC-1α play crucial roles in regulating cold-induced thermogenesis in brown adipose tissue (BAT). PGC-1α and NT-PGC-1α are highly induced by cold in BAT and subsequently bind to and coactivate many transcription factors to regulate expression of genes involved in mitochondrial biogenesis, fatty acid oxidation, respiration and thermogenesis. To identify the complete repertoire of PGC-1α and NT-PGC-1α target genes in BAT, we analyzed genome-wide DNA-binding and gene expression profiles. We find that PGC-1α-/NT-PGC-1α binding broadly associates with cold-mediated transcriptional activation. In addition to their known target genes in mitochondrial biogenesis and oxidative metabolism, PGC-1α and NT-PGC-1α additionally target a broad spectrum of genes involved in diverse biological pathways including ubiquitin-dependent protein catabolism, ribonucleoprotein complex biosynthesis, phospholipid biosynthesis, angiogenesis, glycogen metabolism, phosphorylation, and autophagy. Our findings expand the number of genes and biological pathways that may be regulated by PGC-1α and NT-PGC-1α and provide further insight into the transcriptional regulatory network in which PGC-1α and NT-PGC-1α coordinate a comprehensive transcriptional response in BAT in response to cold.

β-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity.

Brown adipose tissue (BAT) thermogenic functions are primarily mediated by uncoupling protein (UCP)-1. Ucp1 gene expression is highly induced by cold temperature, via sympathetic nervous system and β-adrenergic receptors (βARs). Ucp1 is also repressed by the clock gene Rev-erbα, contributing to its circadian rhythmicity. In this study, we investigated mice lacking βARs (β-less mice) to test the relationship between βAR signaling and the BAT molecular clock. We found that in addition to controlling the induction of Ucp1 and other key BAT genes at near freezing temperatures, βARs are essential for the basal expression of BAT Ucp1 at room temperature. Remarkably, although basal Ucp1 expression is low throughout day and night in β-less mice, the circadian rhythmicity of Ucp1 and clock genes in BAT is maintained. Thus, the requirement of βAR signaling for BAT activity is independent of the circadian rhythmicity of Ucp1 expression and circadian oscillation of the molecular clock genes. On the other hand, we found that βARs are essential for the normal circadian rhythms of locomotor activity. Our results demonstrate that in addition to controlling the BAT response to extreme cold, βAR signaling is necessary to maintain basal Ucp1 tone and to couple BAT circadian rhythmicity to the central clock.-Razzoli, M., Emmett, M. J., Lazar, M. A., Bartolomucci, A. β-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity.

Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats: implications for obesity control.

Melatonin limits obesity in rodents without affecting food intake and activity, suggesting a thermogenic effect. Previously we demonstrated that melatonin browns subcutaneous fat in Zücker diabetic fatty (ZDF) rats. Other works pointed to melatonin as a signal that increases brown adipose tissue (BAT) mass and function in rodents. However, direct proof of thermogenic properties (uncoupled mitochondria) of the newly recruited BAT in response to melatonin is still lacking. Therefore, in this work, we investigated if melatonin recruits thermogenic BAT in ZDF rats. Zücker lean (ZL) and ZDF animals were subdivided into two groups, control (C) and treated with oral melatonin (M) for 6weeks. Mitochondrial mass, activity of citrate synthase (CS), and respiratory chain complexes I and IV were lower in C-ZDF than in C-ZL animals (P<.001). Melatonin treatment increased BAT weight in ZDF rats (P<.001). Also, it rose mitochondrial mass (P<.01) and activities of CS and complexes I and IV (P<.001) in both, ZDF and ZL rats. Uncoupling protein 1 (UCP1) mRNA and protein were 50% lower in BAT from obese rats. Also, guanosine diphosphate (GDP) binding was lower in ZDF than in lean rats (P<.01). Melatonin treatment of obese rats restored the expression of UCP1 and GDP binding to levels of lean rats and sensitized the thermogenic response to cold exposure. These data demonstrated that melatonin recruits thermogenic BAT in ZDF rats. This may contribute to melatonin's control of body weight and its metabolic benefits.

Estrogen-Related Receptors Mediate the Adaptive Response of Brown Adipose Tissue to Adrenergic Stimulation

SummaryAdrenergic stimulation of brown adipose tissue (BAT) induces acute and long-term responses. The acute adrenergic response activates thermogenesis by uncoupling oxidative phosphorylation and enabling increased substrate oxidation. Long-term, adrenergic signaling remodels BAT, inducing adaptive transcriptional changes that expand thermogenic capacity. Here, we show that the estrogen-related receptors alpha and gamma (ERRα, ERRγ) are collectively critical effectors of adrenergically stimulated transcriptional reprogramming of BAT. Mice lacking adipose ERRs (ERRαγAd−/−) have reduced oxidative and thermogenic capacity and rapidly become hypothermic when exposed to cold. ERRαγAd−/− mice treated long term with a β3-adrenergic agonist fail to expand oxidative or thermogenic capacity and do not increase energy expenditure in response to norepinephrine (NE). Furthermore, ERRαγAd−/− mice fed a high-fat diet do not lose weight or show improved glucose tolerance when dosed with β3-adrenergic agonists. The molecular basis of these defects is the finding that ERRs mediate the bulk of the transcriptional response to adrenergic stimulation.

ERRγ Preserves Brown Fat Innate Thermogenic Activity

Brown adipose tissue (BAT) adaptively transfers energy from glucose and fat into heat by inducing a gene network that uncouples mitochondrial electron transport. However, the innate transcription factors that enable the rapid adaptive response of BAT are unclear. Here, we identify estrogen-related receptor gamma (ERRγ) as a critical factor for maintaining BAT identity. ERRγ is selectively expressed in BATversus WAT, in which, in the absence of PGC1α, it drives a signature transcriptional network of thermogenic and oxidative genes in the basal (i.e., thermoneutral) state. Mice lacking ERRγ in adipose tissue (ERRγKO mice) display marked downregulation of BAT-selective genes that leads to a pronounced whitening of BAT. Consistent with the transcriptional changes, the thermogenic capacity of ERRγKO mice is severely blunted, such that they fail to survive an acute cold challenge. These findings reveal a role for ERRγ as a critical thermoneutral maintenance factor required to prime BAT for thermogenesis.

PPARγ agonist rosiglitazone switches fuel preference to lipids in promoting thermogenesis under cold exposure in C57BL/6 mice

Brown and beige adipose tissues play key roles in adaptive thermogenesis, which is essential for homoiotherms to maintain core temperature under cold exposure. PPARγ is a transcriptional regulator critical for brown adipose tissue (BAT) recruitment and white adipose tissue (WAT) browning. Here we evaluated the impact of PPARγ activation on thermogenic activity in C57BL/6 mice under thermo-neutral and 4 °C cold environment, and revealed the regulating mechanism and metabolic basis. Rosiglitazone slowed body temperature loss in cold environment in C57BL/6 mice, suppressed cold-induced decreases in blood glucose, reversed cold-promoted 18F-FDG uptake, and increased lipid consumption in BAT. Serum/adipose tissue metabolomic and transcriptomic analyses revealed that cold exposure and rosiglitazone affect metabolism in different way, especially in terms of free fatty acid/lipid metabolism. While all tested treatments stimulated stored-substance mobilization in epididymal WAT, in heat-generating adipose tissues (BAT and subcutaneous WAT), rosiglitazone-only treatment promoted the storage of substances such as lipids for subsequent thermogenic activation; conversely, cold exposure favoured glucose consumption and mobilization/transport of extracellular lipids. When combined with cold exposure, rosiglitazone treatment preferentially triggered BAT lipid consumption, mobilized and transported lipids from epididymal to subcutaneous WAT, and reduced glucose usage. Thus, rosiglitazone might promote thermogenesis under cold exposure by switching fuel preference. SignificanceIn current study, for the first time, PPARγ agonism by rosiglitazone was proved to promote thermogenesis under near-freezing conditions and enhance the heat generating response against cold-induced hypothermia in mice by switching the fuel preference from carbohydrates to lipids. The lipid substrates stored in BAT in response to PPARγ activation are spared for eventual thermogenic activation. These findings thus underline the remarkable actions of PPARγ in the control of energy metabolism in adipose tissues, especially the BAT.

Epac2a-knockout mice are resistant to dexamethasone-induced skeletal muscle atrophy and short-term cold stress.

Exchange protein directly activated by cAMP (Epac) 2a-knockout (KO) mice exhibit accelerated diet-induced obesity and are resistant to leptin-mediated adipostatic signaling from the hypothalamus to adipose tissue, with sustained food intake. However, the impact of Epac2a deficiency on hypothalamic regulation of sympathetic nervous activity (SNA) has not been elucidated. This study was performed to elucidate the response of Epac2a-KO mice to dexamethasone-induced muscle atrophy and acute cold stress. Compared to age-matched wild-type mice, Epac2a-KO mice showed higher energy expenditures and expression of myogenin and uncoupling protein-1 in skeletal muscle (SM) and brown adipose tissue (BAT), respectively. Epac2a-KO mice exhibited greater endurance to dexamethasone and cold stress. In wild-type mice, exogenous leptin mimicked the responses observed in Epac2a-KO mice. This suggests that leptin-mediated hypothalamic signaling toward SNA appears to be intact in these mice. Hence, the potentiated responses of SM and BAT may be due to their high plasma leptin levels.

Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing

ObjectiveTo determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation. MethodsMice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A−/−), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue. ResultsChronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2A−/− mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2A−/− adipose tissue albeit to a lesser extent in Cpt2A−/− mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2A−/− mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2A−/− BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2A−/− mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss. ConclusionMitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.

MRI characterization of brown adipose tissue under thermal challenges in normal weight, overweight, and obese young men.

To implement quantitative Dixon magnetic resonance imaging (MRI) methods for brown adipose tissue (BAT) characterization at inactive and cold-activated states in normal weight, overweight, and obese subjects. The hypotheses are that MRI characteristics of BAT would differentiate between nonobese and obese subjects, and activation of BAT in response to thermal challenges that are detected by MRI would be correlated with BAT activity measured by positron emission tomography / computed tomography (PET/CT). Fifteen male subjects (20.7 ± 1.5 years old) including six normal weight, five overweight, and four obese subjects participated in the study. A multiecho Dixon MRI sequence was performed on a 1.5T scanner. MRI was acquired under thermoneutral, nonshivering thermogenesis, and subsequent warm-up conditions. Fat fraction (FF), R2*, and the number of double bonds (ndb) were measured by solving an optimization problem that fits in- and out-of-phase MR signal intensities to the fat-water interference models. Imaging acquisition and postprocessing were performed by two MRI physicists. In each subject, Dixon MRI measurements of FF, R2*, and ndb were calculated for each voxel within all BAT regions of interest (ROIs) under each thermal condition. Mean FF, R2*, and ndb were compared between nonobese (ie, normal-weight/overweight) and obese subjects using the two-sample t-test. Receiver operating characteristic (ROC) analyses were performed to differentiate nonobese vs. obese subjects. BAT MRI measurement changes in response to thermal condition changes were compared with hypermetabolic BAT volume/activity measured by PET/CT using the Pearson's correlation. In addition, BAT MRI measurements were compared with body adiposity using the Pearson's correlation. P < 0.05 was considered statistically significant. Obese subjects showed higher FF and lower R2* than nonobese subjects under all three thermal conditions (P < 0.01). ROC analyses demonstrated that FF and R2* were excellent predictors for the differentiation of nonobese from obese subjects (100% specificity and 100% sensitivity). FF changes under thermal challenges were correlated with hypermetabolic BAT volume (r = -0.55, P = 0.04 during activation, and r = 0.72, P = 0.003 during deactivation), and with BAT activity (r = 0.69, P = 0.006 during deactivation), as measured by PET/CT. FF and R2* under all three thermal conditions were highly correlated with body adiposity (P ≤ 0.002). MRI characteristics of BAT differentiated between nonobese and obese subjects in both inactivated and activated states. BAT activation detected by Dixon MRI in response to thermal challenges were correlated with glucose uptake of metabolically active BAT. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:936-947.

The role of the brown adipose tissue in \u03b23-adrenergic receptor activation-induced sleep, metabolic and feeding responses

Brown adipose tissue (BAT) is regulated by the sympathetic nervous system via β3-adrenergic receptors (β3-AR). Here we tested the hypothesis that pharmacological stimulation of β3-ARs leads to increased sleep in mice and if this change is BAT dependent. In wild-type (WT) animals, administration of CL-316,243, a selective β3-AR agonist, induced significant increases in non-rapid-eye movement sleep (NREMS) lasting for 4–10 h. Simultaneously, electroencephalographic slow-wave activity (SWA) was significantly decreased and body temperature was increased with a delay of 5–6 h. In uncoupling protein 1 (UCP-1) knockout mice, the middle and highest doses of the β3-AR agonist increased sleep and suppressed SWA, however, these effects were significantly attenuated and shorter-lasting as compared to WT animals. To determine if somnogenic signals arising from BAT in response to β3-AR stimulation are mediated by the sensory afferents of BAT, we tested the effects of CL-316,243 in mice with the chemical deafferentation of the intra-scapular BAT pads. Sleep responses to CL-316,243 were attenuated by ~50% in intra-BAT capsaicin-treated mice. Present findings indicate that the activation of BAT via β3-AR leads to increased sleep in mice and that this effect is dependent on the presence of UCP-1 protein and sleep responses require the intact sensory innervation of BAT.

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue.

Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.

11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice

Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can amplify circulating GC concentrations. Therefore, 11β-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11β-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11β-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 μg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11β-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11β-HSD1 KO mice to model lifetime GC exposure. BAT 11β-HSD1 expression and activity were elevated in response to GC excess and with aging. 11β-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11β-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11β-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.

Lipidomic Adaptations in White and Brown Adipose Tissue in Response to Exercise Demonstrate Molecular Species-Specific Remodeling

Exercise improves whole-body metabolic health through adaptations to various tissues, including adipose tissue, but the effects of exercise training on the lipidome of white adipose tissue (WAT) and brown adipose tissue (BAT) are unknown. Here, we utilize MS/MSALL shotgun lipidomics to determine the molecular signatures of exercise-induced adaptations to subcutaneous WAT (scWAT) and BAT. Three weeks of exercise training decrease specific molecular species of phosphatidic acid (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylserines (PS) in scWAT and increase specific molecular species of PC and PE in BAT. Exercise also decreases most triacylglycerols (TAGs) in scWAT and BAT. In summary, exercise-induced changes to the scWAT and BAT lipidome are highly specific to certain molecular lipid species, indicating that changes in tissue lipid content reflect selective remodeling in scWAT and BAT of both phospholipids and glycerol lipids in response to exercise training, thus providing a comprehensive resource for future studies of lipid metabolism pathways.

Multimodal Imaging for the Detection of Brown Adipose Tissue Activation in Women: A Pilot Study Using NIRS and Infrared Thermography.

Purpose A clear link between obesity and brown adipose tissue (BAT) dysfunction has been recently demonstrated. The purpose of this pilot study is to determine if near-infrared spectroscopy (NIRS) 2D imaging together with infrared thermography (IRT) is capable of identifying thermal and vascular response in the supraclavicular (SCV) areas after the ingestion of an oral glucose load as a thermogenic stimulation. Method We studied two groups of women (obese versus lean) for discerning their different responses. NIRS and IRT images were acquired on the neck in the left SCV region during a 3 h oral glucose tolerance test (OGTT) and immediately after a cold stimulation. Results We detected a significant thermal response of BAT in SCV fossa in both groups. Both during OGTT and after cold stimulation, skin temperature was persistently higher in lean versus obese. This response was not coupled with changes in oxygen saturation of subcutaneous tissue in that area. Discussion and Conclusion The results show that NIRS/IRT may be a novel, noninvasive, radiation-free, easy to use, and low-cost method for monitoring, during the standard clinical practice, the diet and pharmacological intervention which aims to stimulate BAT as a potential therapeutic target against obesity and diabetes.