UCP1 In Brown Adipose Tissue Research Articles

Exendin-4 Improves Diabetic Kidney Disease in C57BL/6 Mice Independent of Brown Adipose Tissue Activation.

Background The role of exendin-4 in brown adipose tissue (BAT) activation was not very clear. This study is to verify the role of BAT involved in renal benefits of exendin-4 in diabetes mellitus (DM). Methods In vivo, C57BL/6 mice were randomly divided into nondiabetic (control) and diabetic groups (DM). The diabetic mice were randomized into a control group (DM-Con), BAT-excision group (DM+Exc), exendin-4-treated group (DM+E4), and BAT-excision plus exendin-4-treated group (DM+Exc+E4). The weight, blood glucose and lipids, 24 h urine albumin and 8-OH-dG, and renal fibrosis were analyzed. In vitro, we investigated the role of exendin-4 in the differentiation process of 3T3-L1 and brown preadipocytes and its effect on the rat mesangial cells induced by oleate. Results The expressions of UCP-1, PGC-1α, ATGL, and CD36 in BAT of DM mice were all downregulated, which could be upregulated by exendin-4 treatment with significant effects on ATGL and CD36. BAT-excision exacerbated high blood glucose (BG) with no significant effect on the serum lipid level. Exendin-4 significantly lowered the level of serum triglycerides (TG) and low-density lipoprotein- (LDL-) c, 24 h urine albumin, and 8-OH-dG; improved renal fibrosis and lipid accumulation; and activated renal AMP-activated protein kinase (AMPK) in diabetic mice regardless of BAT excision. In vitro, there was no significant effect of exendin-4 on brown or white adipogenesis. However, exendin-4 could improve lipid accumulation and myofibroblast-like phenotype transition of mesangial cells induced by oleate via activating the AMPK pathway. Conclusions Exendin-4 could decrease the renal lipid deposit and improve diabetic nephropathy via activating the renal AMPK pathway independent of BAT activation.

Age-related sex differences in the expression of important disease-linked mitochondrial proteins in mice

The prevalence and progression of many illnesses, such as neurodegenerative and cardiovascular diseases, obesity, and cancer, vary between women and men, often in an age-dependent manner. A joint hallmark of these diseases is some type of mitochondrial dysfunction. While several mitochondrial proteins are known to be regulated by sex hormones, the levels of those proteins have not been systematically analyzed with regard to sex and age, and studies that consider sex and/or age differences in the protein expression are very rare. In this study, we compared the expression patterns of physiologically important mitochondrial proteins in female and male C57BL/6N mice of age cohorts frequently used in experiments. We found that sex-related differences in the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) occur in an age-dependent manner. The sex-specific expression of UCP1 and UCP3 in brown adipose tissue (BAT) was inversely correlated with differences in body weight. Expression of UCP4 in the brain, Complex I in the spleen, and Complex II in the brain and BAT was least affected by the sex of the mouse. We further demonstrated that there are serious limitations in using VDAC1 and actin as markers in western blot analyses, due to their sex- and age-specific fluctuations. Our results confirm that sex and age are important parameters and should be taken into account by researchers who examine the mechanistic aspects of diseases.HighlightsThe levels of UCP1 and UCP3 protein expression differ between females and males in an age-dependent manner.Pre-pubertal expression of almost all proteins tested in this study does not depend on the sex of the mouse.Expression of VDAC1 and actin, which are often used as loading control proteins in western blot analysis, is tissue-specifically influenced by sex and age.

New Antidiabetes Agent Targeting Both Mitochondrial Uncoupling and Pyruvate Catabolism: Two Birds With One Stone.

Obesity and type 2 diabetes are emerging as global epidemics and impose huge burdens on patient families as well as society. They are leading causal factors for cardiovascular disease, neurological disease, cancer, and kidney disease and negatively impact health span and life span. However, treatment options are limited, and there is an unmet need for developing effective and safe medications. In this issue of Diabetes , Jiang et al. (1) report a new treatment strategy and a new antidiabetes agent. Obesity arises from energy imbalance, and excessive energy is stored as triacylglycerol in fat (2). Mitochondria are an essential organelle responsible for cellular respiration and energy production. Mitochondria oxidize free fatty acids (FFAs) and glucose to produce ATP (referred to as oxidative phosphorylation). The inner mitochondrial membrane (IMM) contains an electron transport chain composed of the complexes I, II, III, IV, and V. Burning of FFAs and glucose produces high-energy electrons that are transported from complex I or II to complexes III and IV, where electron-carried energy is released to pump out protons, generating proton gradients across the IMM (Fig. 1). The IMM proton gradients drive ATP synthesis by complex V. The IMM also contains uncoupling proteins (UCPs) that mediate proton influx, thus suppressing ATP synthesis. UCPs release free energy as heat (thermogenesis) and are engaged in body temperature homeostasis. Brown adipose tissue UCP1 plays a pivotal role in the maintenance of body …

Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice

ObjectivesThe activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis. Materials/methodsIn this study, adipose tissue specific knockout (ASKO) mice were generated to evaluate APPL1's role in BAT thermogenesis in vivo, and possible signaling pathways were further explored in cultured brown adipocytes. ResultsAfter high fat diet challenge, APPL1 ASKO mice developed more severe obesity, glucose intolerance and insulin resistance compared with control mice. Metabolic cage study showed that APPL1 deficiency impaired energy expenditure and adaptive thermogenesis in ASKO mice. PET-CT analysis showed decreased standardized uptake value (SUV) in the inter-scapular region which indicated impaired BAT activity in ASKO mice. Further study showed deletion of APPL1 attenuated brown fat specific gene expression, such as UCP1 and PGC1α in both BAT and brown adipocytes. In cultured brown adipocytes, upon cAMP stimulation, APPL1 shuttled from cytosol to nuclei. Co-IP and ChIP study showed that APPL1 could directly interact with histone deacetylase 3 (HDAC3) to mediate chromatin remodeling and UCP1 gene expression. ConclusionsOur data demonstrated the essential role of APPL1 in regulating brown adipocytes thermogenesis via interaction with HDAC3, which may have potential therapeutic implications for treatment of obesity.

269-OR: miR-409-3p Regulates Angiogenesis Brown Fat Adiposity and Insulin Resistance

White and brown adipose tissues are highly vascularized organs, capable of plasticity based on metabolic demands and energy expenditure, which if maladaptive can lead to insulin resistance. Critical gaps remain in our understanding of how angiogenesis impacts adipose tissue dysfunction and overall metabolism. MicroRNAs (miRs) are implicated in the regulation of the angiogenic response to pathophysiological stimuli. Function of miRNAs regulating the angiogenic response in diet-induced insulin resistance remains poorly understood. Using a miRNA-Seq approach, we identified that miR-409-3p expression was significantly increased in endothelial cells (ECs) of brown adipose tissue (BAT) of diet-induced obese (DIO) mice and in human diabetic plasma samples compared to nondiabetic patients. Overexpression of miR-409-3p markedly inhibited EC growth and migration, whereas miR-409-3p inhibition had the opposite effects. miR-409-3p targets the 3’UTR of Zinc Finger E-box binding Homeobox 1 (ZEB1). Overexpression of miR-409-3p decreased ZEB1 expression in ECs and in human subcutaneous white adipose tissue (sWAT). SiRNA knock down of ZEB1 expression in ECs phenocopied the effects of miR-409-3p overexpression and significantly decreased cell proliferation and migration. In addition, 3T3-L1 cells co-cultured with supe harvested from ECs deficient in miR-409-3p had increased expression of brown fat markers (UCP1, Cidea, PGC1-α) by RT-qPCR and Western blot analyses. Systemic intravenous delivery of LNA-anti-miR-409-3p inhibitor to DIO mice significantly increased angiogenesis by CD31 staining, accompanied by higher UCP-1 in BAT and sWAT by RT-qPCR, Western blot and immunohistochemistry analyses, while improving glucose tolerance and overall metabolism. miR-409-3p plays a key regulatory role between impaired angiogenesis in diet-induced obesity and adipose tissue dysfunction, an effect that could be exploited for therapeutic intervention in obesity-induced insulin resistance. Disclosure D.R. Becker-Greene: None. H. Li: None. W. Wu: None. D. Ozdemir: None. I. Hollan: None. M.W. Feinberg: None. B. Icli: None. Funding American Diabetes Association (1-16-JDF-046 to B.I.)

Effect of Quercetin on Non-shivering Thermogenesis and Intestinal Microbial Populations (P06-037-19)

ObjectivesActivation of non-shivering thermogenesis in adipose tissues and alteration in intestinal microbiome have been linked with improved obese condition. With emerging evidences of dietary compounds to prevent obesity, the objective of this study was to examine whether quercetin activates non-shivering thermogenesis in adipose tissues and influences intestinal microbiome, which eventually improves obese condition. MethodsFour-week-old C57BL/6 male mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) with or without 1% quercetin (Q) for 16 weeks. On the completion of the feeding study, brown adipose tissue (BAT), white adipose tissue (WAT), and cecum were collected. Total RNA was extracted from BAT and WAT, and then cDNA was synthesized. The expression of genes that are involved in the regulation of non-shivering thermogenesis such as uncoupling protein 1 (ucp1), cell death-inducing DFFA-like effector A (cidea), peroxisome proliferator-activated receptor gamma (pparγ), pparγ-coactivator 1 alpha (pgc1α), fibroblast growth factor 21 (fgf21), positive regulatory domain containing 16 (prdm16), and T-box protein 1 (tbx1) were determined by a real-time PCR. The expression of the proteins such as UCP1 and AMP-activated protein kinase (AMPK) was assessed by western blot analysis. Microbial populations in cecum were analyzed via the Illumnia MiSeq sequencing platform and QIIME (Quantitative Insights Into Microbial Ecology) Software. ResultsMice fed HFDQ showed reduced body weight and retroperitoneal (R) WAT weight compared to mice fed HFD. Quercetin supplementation increased the expression of ucp1, prdm16, pgc1α, cidea, and tbx1 genes in BAT and RWAT of mice fed HFD. The expression of UCP1 protein and phosphorylation of AMPK were increased. However, browning effect was not observed in other WATs. Mice fed LFDQ and HFDQ exhibited higher relative abundance of Bacteroidetes than mice fed LFD and HFD whereas the relative abundance of Firmicutes was decreased. ConclusionsQuercetin may be a potential dietary compound that increases energy metabolism by activating BAT and attracting beige adipocytes in RWAT. In addition, quercetin-induced energy metabolism may have a correlation with changes of microbial populations in intestine. Funding SourcesThe work was supported by USDA.

312-OR: Functional Decline in Brown Adipose Progenitors during BAT Remodeling

In humans, there is a striking decrease in the prevalence and activity of brown adipose tissue (BAT) with age and obesity; however, the cellular and molecular mechanisms of BAT remodeling are almost completely unknown. Rodent models have been widely used to study BAT but they possess constitutively active BAT throughout life even at thermoneutrality; therefore, complementary animal models that possess characteristics of human BAT remodeling are needed. Here, we found that BAT progressively whitened in rabbits in a similar manner as in humans. As rabbits mature, preadipocytes in BAT displayed reduced capacity to be differentiated into brown adipocytes, when transplanted into immune-deficient mice. RNA-sequencing of brown preadipocytes identified that, during BAT remodeling, genes enriched for muscle contraction and mitochondrial function were down-regulated, while genes involved in lipid and amino acid metabolism were up-regulated. Single-cell RNA sequencing discovered a unique population of stromal vascular fraction cells specifically expressing genes regulating muscle and mitochondrial function. Knocking down these genes in rabbit brown preadipocytes blunted their ability to become mature brown adipocytes. We also identified follistatin like 1 (FSTL1) as a novel “batokine” that is specifically expressed by brown preadipocytes but not mature brown adipocytes. FSTL1 gradually reduced its expression when BAT whitens in rabbits, but was stably expressed in mouse BAT during life. Deleting FSTL1 specifically in the Myf5 lineage in mice reduced BAT size, UCP1 expression, and body temperature in newborns, suggesting the constitutive expression of FSTL1 prevents BAT whitening in mice. Taken together, we identify potential molecular mechanisms underlying functional decline in the browning ability of preadipocytes that contribute to BAT remodeling in rabbits and possibly humans. Disclosure Z. Huang: None. Z. Zhang: None. H. Ruan: None. Funding American Diabetes Association (1-18-IBS-167 to H-B.R.)

Regulation of UCP1 and Mitochondrial Metabolism in Brown Adipose Tissue by Reversible Succinylation.

Brown adipose tissue (BAT) is rich in mitochondria and plays important roles in energy expenditure, thermogenesis, and glucose homeostasis. We find that levels of mitochondrial protein succinylation and malonylation are high in BAT and subject to physiological and genetic regulation. BAT-specific deletion of Sirt5, a mitochondrial desuccinylase and demalonylase, results in dramatic increases in globalprotein succinylation and malonylation. Mass spectrometry-based quantification of succinylation reveals that Sirt5 regulates the key thermogenic protein in BAT, UCP1. Mutation of the two succinylated lysines in UCP1 to acyl-mimetic glutamine and glutamic acid significantly decreases its stability and activity. The reduced function of UCP1 and other proteins in Sirt5KO BAT results in impaired mitochondria respiration, defective mitophagy, and metabolic inflexibility. Thus, succinylation of UCP1 and other mitochondrial proteins plays an important role in BAT and in regulation of energy homeostasis.

Regulation of Brown Adipose Tissue Function by HuR

Stimulating the metabolic function of brown adipose tissue (BAT) and/or inducing the beiging of white adipocytes (WAT) to BAT‐like cells represent potential therapeutic strategies for increasing energy expenditure and reducing obesity. HuR (ELAVL1) is an RNA binding protein that mediates gene expression through stabilization of mRNA targets and is highly expressed in both WAT and BAT. We identified an inverse correlation between HuR expression and obesity in humans via the METabolic Syndrome In Men study of Finnish men. Thus, we hypothesized that HuR expression in adipocytes plays a critical role in maintaining metabolic homeostasis.Our results show that, compared to control littermates, adipocyte‐specific HuR‐null (adipo‐HuR−/−) mice display a lean phenotype with decreased fat mass and increased energy expenditure, independent of diet. Interestingly, adipo‐HuR−/− mice also show a disruption of BAT structure and function, with increased lipid droplet size, decreased BAT density, and an inability to thermoregulate when subjected to cold. Examination of skeletal muscle suggests that the lean phenotype in adipo‐HuR−/− mice is due to compensatory shivering to thermoregulate in the absence of functional BAT, a result consistent with UCP1−/− mice. Surprisingly, we found no difference in basal expression of UCP1 in BAT from control and adipo‐HuR−/− mice. However, HuR is activated downstream of β3 adrenergic stimulation and appears to play a role in cold/β3 induced UCP1 expression. Additionally, adipo−HuR−/− mice show a decrease in mitochondrial density in both BAT and subcutaneous (sc) WAT, as well as a decrease in brown/beige adipocyte marker genes (PRDM16, Elovl3) in scWAT.In conclusion, our results demonstrate that HuR plays a central role in the structure and function of BAT. Work is ongoing to identify the transcriptome wide changes in HuR‐dependent gene expression as well as the potential role of HuR in beiging of WAT.Support or Funding InformationThis work was partially funded by a University of Cincinnati Heart, Lung, and Vascular Institute Pilot Grant (MT, APO).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Functional decline in brown adipose progenitors during BAT remodeling

In humans, there is a striking decrease in the prevalence and activity of brown adipose tissue (BAT) with age and obesity; however, the cellular and molecular mechanisms of BAT remodeling are almost completely unknown. Rodent models have been widely used to study BAT but they possess constitutively active BAT throughout life even at thermoneutrality; therefore, complementary animal models that possess characteristics of human BAT remodeling are needed. Here, we found that BAT progressively whitened in rabbits in a similar manner as in humans. As rabbits mature, preadipocytes in BAT displayed reduced capacity to be differentiated into brown adipocytes, when transplanted into immune‐deficient mice. RNA‐sequencing of brown preadipocytes identified that, during BAT remodeling, genes enriched for muscle contraction and mitochondrial function were down‐regulated, while genes involved in lipid and amino acid metabolism were up‐regulated. Knocking down genes regulating muscle and mitochondrial function in rabbit brown preadipocytes blunted their ability to become mature brown adipocytes in vitro and in vivo. We also identified follistatin like 1 (FSTL1) as a novel “batokine” that is specifically expressed by brown preadipocytes but not mature brown adipocytes. FSTL1 gradually reduced its expression when BAT whitens in rabbits, but was stably expressed in mouse BAT during life. Deleting FSTL1 specifically in the Myf5 lineage in mice reduced BAT size, UCP1 expression, and body temperature in newborns, suggesting the constitutive expression of FSTL1 prevents BAT whitening in mice. Taken together, we identify potential molecular mechanisms underlying functional decline in the browning ability of preadipocytes that contribute to BAT remodeling in rabbits and possibly humans.Support or Funding InformationAmerican Diabetes Association (18‐IBS‐167)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PO-044 Effects of one-time high intensity intermittent training on the expression of UCP1 mRNA in adipose tissue of obese rats

Objective To observe the effect of one-time high-intensity intermittent training (HIIT) on the white fat browning in obese rats.
 Methods 12 obese male rats at the age of 19-week were randomly divided into control group (OC group, n=6) and HIIT group (n=6). OC group doesn’t do exercise, and HIIT group finish the once high-intensity intermittent training ( ①Warm up: 70%VO2max, 7min; ②High intensity exercise: 90%VO2max, 3min+ 50%VO2max, 3min, 6 times; ③Convalescence: 70%VO2max, 7min.). The maximal oxygen uptake (VO2max) of HIIT group was tested before training, and the exercise intensity was determined according to the average VO2max. The subcutaneous and testicle white adipose tissue (WAT) and brown adipose tissue (BAT) of the scapula were taken immediately after exercise. The expression of UCP1 mRNA in the WAT and BAT using the fluorescent quantitative PCR.
 Results Compared with the OC group, the expression of BAT UCP1 mRNA , in the HIIT group was increased, but there was no significant difference (1.40±0.50 vs 1.03±0.27, P>0.05). In both OC and HIIT group, the expression of UCP1 mRNA of the subcutaneous and testicle WAT were too low to test. The results showed that one-time HIIT exercise had no effect on the expression of UCP1 mRNA in WAT.
 Conclusions The effects of One-time HIIT on the expression of UCP1 mRNA in adipose tissue of obese rats are still not definite.

Pepper and cinnamon improve cold induced cognitive impairment via increasing non-shivering thermogenesis; a study

Despite an understanding that a major effect of cold exposure is a fall in core body temperature which is responsible for the observed decrements in the performance, it is surprising that thermogenic supplements are seldom evaluated to verify if they can aid in improving the performance during cold exposure. Following evidence from our previous study indicating the ability of pepper and cinnamon to improve cold endurance, we investigated further here if the improved endurance had advantages in real time where they could positively affect cognitive performance (assessed by Novel object test) when exposed to cold in albino wistar rats. In order to delineate if the observed improvement if any, was due to their cognitive enhancing ability or thermogenic potential, distinctive room temperature (RT) and cold temperature (CT) groups were used. Cold exposure impaired cognitive performance which improved following treatment with both the spices. We noted an increased rate of cold adaptive thermogenesis in CT treated group as evidenced by an elevated norepinephrine, free fatty acid levels in blood, increased expression of UCP1 in brown adipose tissue, the net effect being a decreased fall in the core body temperature. Absence of any notable effect in these parameters in the RT treated group ascertained that at least in the current experimental set up the observed improvement in performance in CT treated group is due to the thermogenic potential of the spices alone. In conclusion, our results demonstrate that the cognitive impairment caused by exposure to cold can be effectively countered by agents with thermogenic potential.

Inhibition of Adipose Tissue Angiogenesis Prevents Rebound Weight Regain after Calorie Restriction Independent of Hypothalamic Melanocortin System in Obese Mice Fed a High-Fat Diet

Prevention of rebound weight gain after dieting is essential to treat obesity. However, its attempts have been unsuccessful and the underlying mechanism remains unclear. In this study, we sought to investigate the role of adipose tissue (AT) vasculature in rebound weight gain after calorie restriction in obese mice fed a high-fat diet (HFD). Obese mice were randomly assigned to 4 groups including mice fed HFD ad libitum (CON), mice under 40% calorie restriction for 5 weeks (CR), 3 days of HFD ad libitum after CR (CRAL), or CRAL treated with TNP-470, an angiogenesis inhibitor (TNP). We compared parameters of energy balance, AT morphometry and remodeling, and hypothalamic neuropeptides gene expression among the groups. Rebound weight gain and food intake were significantly lower and the level of brown AT UCP-1 gene expression was higher in TNP group than CRAL group. Fat mass was significantly lower in TNP group than CRAL group and it was similar to CR group while lean mass was not different between TNP and CRAL groups. Notably, the CD31-positive area was not different in AT between CON, CR, and CRAL groups, indicating that AT vasculature was maintained independently of nutritional status. However, that tended to be lower in AT of TNP group compared to other groups, implicating that inhibition of AT vasculature might be crucial to suppress rebound weight gain after calorie restriction. Consistently, circulating leptin levels were significantly lower in TNP group than CRAL group. However, the pattern of hypothalamic neuropeptides gene expression was different from the changes in food intake among the groups, suggesting an existence of novel regulatory signals independent of melanocortin system. Taken together, these results suggested a critical role of AT vasculature in regulating rebound weight gain and hyperphagia after calorie restriction independent of hypothalamic melanocortin system. Disclosure H. Lee: None. M. Song: None. N. Ha: None. B. Jin: None. S. Choi: None. D. Kim: None.

Postprandial Oxidative Metabolism of Human Brown Fat Indicates Thermogenesis

Human studies suggest that a meal elevates glucose uptake in brown adipose tissue (BAT). However, inpostprandial state the thermogenic activity and the metabolism of non-esterified fatty acids (NEFAs) in BAT remain unclear. Using indirect calorimetry combined with positron emission tomography and computed tomography (PET/CT), we showed that whole-body and BAT thermogenesis (oxygen consumption) increases after the ingestion of a mixed carbohydrate-rich meal, to the same extent as in cold stress. Postprandial NEFA uptake into BAT is minimal, possibly due to elevated plasma insulin inhibiting lipolysis. However, the variation in postprandial NEFA uptake is linked to BAT thermogenesis. Weidentified several genes participating in lipid metabolism to be expressed at higher levels in BATcompared with white fat in postprandial state, and to be positively correlated with BAT UCP1 expression. These findings suggest that substrates preferred by BAT in postprandial state are glucose or LPL-released NEFAs due to insulin stimulation.

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.

Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch

In acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals have another mechanism to cope with long-term cold stress by inducing the browning of the subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic-dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation-independent acute Ucp1 induction in BAT and demethylation-dependent chronic Ucp1 expression in beige scWAT provides complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namely, β-adrenergic receptor and peroxisome proliferator-activated receptor-γ (PPARγ) activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis. S265 phosphorylation of JMJD1A, and the following demethylation of H3K9me2 might prove to be a novel molecular target for the treatment of metabolic disorders, via promoting beige adipogenesis.

Neonatal tobacco smoke reduces thermogenesis capacity in brown adipose tissue in adult rats.

Maternal smoking is a risk factor for progeny obesity. We have previously shown, in a rat model of neonatal tobacco smoke exposure, a mild increase in food intake and a considerable increase in visceral adiposity in the adult offspring. Males also had secondary hyperthyroidism, while females had only higher T4. Since brown adipose tissue (BAT) hypofunction is related to obesity, here we tested the hypothesis that higher levels of thyroid hormones are not functional in BAT, suggesting a lower metabolic rate. We evaluated autonomic nerve activity in BAT and its function in adult rats that were exposed to tobacco smoke during lactation. At birth, litters were adjusted to 3 male and 3 female pups/litter. From postnatal day (PND) 3 to 21, Wistar lactating rats and their pups were divided into SE group, smoke-exposed in a cigarette smoking machine (4 times/day) and C group, exposed to filtered air. Offspring were sacrificed at PND180. Adult SE rats of both genders had lower interscapular BAT autonomic nervous system activity, with higher BAT mass but no change in morphology. BAT UCP1 and CPT1a protein levels were decreased in the SE groups of both genders. Male SE rats had lower β3-AR, TRα1, and TRβ1 expression while females showed lower PGC1α expression. BAT Dio2 mRNA and hypothalamic POMC and MC4R levels were similar between groups. Hypothalamic pAMPK level was higher in SE males and lower in SE females. Thus, neonatal cigarette smoke exposure induces lower BAT thermogenic capacity, which can be obesogenic at adulthood.

Expression of genes involved in carbohydrate-lipid metabolism in muscle and fat tissues in the initial stage of adult-age obesity in fed and fasted mice.

C57Bl mice exhibit impaired glucose metabolism by the late adult age under standard living conditions. The aim of this study was to evaluate white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle expression of genes involved in carbohydrate‐lipid metabolism at postpubertal stages preceding the late adult age in C57Bl mice. Muscle mRNA levels of uncoupling protein 3 (Ucp3) and carnitine palmitoyltransferase 1 (Cpt1) (indicators of FFA oxidation), WAT mRNA levels of hormone‐sensitive lipase (Lipe) and lipoprotein lipase (Lpl) (indicators of lipolysis and lipogenesis), muscle and WAT mRNA levels of the type 4 glucose transporter Slc2a4 (indicators of insulin‐dependent glucose uptake), and BAT mRNA levels of uncoupling protein 1 (Ucp1) (indicator of thermogenesis) were measured in fed and 16 h‐fasted mice in three age groups: 10‐week‐old (young), 15‐week‐old (early adult), and 30‐week‐old (late adult). Weight gain from young to early adult age was not accompanied by changes in WAT and BAT indexes and biochemical blood parameters. Weight gain from early to late adult age was accompanied by increased WAT and BAT indexes and decreased glucose tolerance. Muscle Ucp3 and Cpt1 mRNA levels and WAT Lipe and Slc2a4 mRNA levels increased from young to early adult age and then sharply decreased by the late adult age. Moreover, BAT Ucp1 mRNA level decreased in the late adult age. Fasting failed to increase muscle Cpt1 mRNA levels in late adult mice. These transcriptional changes could contribute to impaired glucose metabolism and the onset of obesity in late adult mice during normal development.

Brown adipose tissue activation in a rat model of Parkinson's disease.

Loss of body weight and fat mass is one of the nonmotor symptoms of Parkinson's disease (PD). Weight loss is due primarily to reduced energy intake and increased energy expenditure. Whereas inadequate energy intake in PD patients is caused mainly by appetite loss and impaired gastrointestinal absorption, the underlying mechanisms for increased energy expenditure remain largely unknown. Brown adipose tissue (BAT), a key thermogenic tissue in humans and other mammals, plays an important role in thermoregulation and energy metabolism; however, it has not been tested whether BAT is involved in the negative energy balance in PD. Here, using the 6-hydroxydopamine (6-OHDA) rat model of PD, we found that the activity of sympathetic nerve (SN), the expression of Ucp1 in BAT, and thermogenesis were increased in PD rats. BAT sympathetic denervation blocked sympathetic activity and decreased UCP1 expression in BAT and attenuated the loss of body weight in PD rats. Interestingly, sympathetic denervation of BAT was associated with decreased sympathetic tone and lipolysis in retroperitoneal and epididymal white adipose tissue. Our data suggeste that BAT-mediated thermogenesis may contribute to weight loss in PD.

Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction.

Brown adipose tissue thermogenesis at the cost of energy is not only important for the development of obesity, but also possesses great promise in anti-obesity treatment. Uncoupling protein 1 (UCP1) expression has been reported to be under control of the intracellular deacetylase SIRT1. Here, we investigated the effect and mechanism of inflammation and sirtuin-1 (SIRT1) activation on the induction of thermogenic genes in immortalized brown adipocytes incubated with LPS or IL1β and mice with elevated inflammatory tone. In vitro stimulation of brown adipocytes with dibutyryl cyclic adenosine monophosthate (dbcAMP) reduced the expression of deleted in breast cancer-1 (Dbc1) (SIRT1 inhibitor) and increased the Ucp1 expression. Silencing of SIRT1 attenuated dbcAMP induction of Ucp1. In contrast, IL1β increased the expression of Dbc1 and greatly reduced the induction of Ucp1. Similarly, in vivo studies revealed decreased expression of Ucp1 in brown adipose tissue (BAT) in mice chronically infused with LPS. Resveratrol, a known SIRT1 activator, partly rescued the Ucp1 downregulation by inflammation in both the cell cultures and mice. Here, we describe how the expression of Ucp1 in BAT is controlled via SIRT1 and is reduced under inflammation and can be rescued by SIRT1 activation by resveratrol. We suggest the reduced UCP1 expression under inflammation is mediated by the increased expression of DBC1, which inhibits SIRT1 activity.