Metallothionein is expressed in adipocytes of brown fat and is induced by catecholamines and zinc

2000 ◽  
Vol 278 (4) ◽  
pp. R1082-R1089 ◽  
Author(s):  
John H. Beattie ◽  
Anne M. Wood ◽  
Paul Trayhurn ◽  
Bharat Jasani ◽  
Adele Vincent ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Uncoupling Protein ◽  
Immunohistochemical Analysis ◽  
Energy Reserves ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Antioxidant Function ◽  
Ucp1 Expression ◽  
Rats And Mice

Metallothionein (MT) is thought to have an antioxidant function and is strongly expressed during activation of thermogenesis and increased oxidative stress in brown adipose tissue (BAT). Localization and regulation of MT expression in BAT was therefore investigated in rats and mice. Immunohistochemical analysis of BAT from rats exposed to 4°C for 24 h showed that MT and uncoupling protein 1 (UCP1) were coexpressed in differentiated adipocytes, and both cytoplasmic and nuclear localization of MT was observed. Cold induction of MT-1 expression in BAT was also observed in mice. Administration of norepinephrine to rats and isoproterenol to mice stimulated MT and UCP1 expression in BAT, implying a sympathetically mediated pathway for MT induction. In mice, zinc, and particularly dexamethasone, induced MT-2 expression in BAT and liver. Surprisingly, zinc also induced UCP1 in BAT, suggesting that elevated zinc may induce thermogenesis. We conclude that expression of MT in mature brown adipocytes upon β-adrenoceptor activation is consistent with a role in protecting against physiological oxidative stress or in facilitating the mobilization or utilization of energy reserves.

scholarly journals Rheb promotes brown fat thermogenesis by Notch-dependent activation of the PKA signaling pathway

2019 ◽  
Vol 11 (9) ◽  
pp. 781-790 ◽  
Author(s):  
Wen Meng ◽  
Xiuci Liang ◽  
Ting Xiao ◽  
Jing Wang ◽  
Jie Wen ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Regulatory Subunit ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Beige Fat

Abstract Increasing brown and beige fat thermogenesis have an anti-obesity effect and thus great metabolic benefits. However, the molecular mechanisms regulating brown and beige fat thermogenesis remain to be further elucidated. We recently found that fat-specific knockout of Rheb promoted beige fat thermogenesis. In the current study, we show that Rheb has distinct effects on thermogenic gene expression in brown and beige fat. Fat-specific knockout of Rheb decreased protein kinase A (PKA) activity and thermogenic gene expression in brown adipose tissue of high-fat diet-fed mice. On the other hand, overexpression of Rheb activated PKA and increased uncoupling protein 1 expression in brown adipocytes. Mechanistically, Rheb overexpression in brown adipocytes increased Notch expression, leading to disassociation of the regulatory subunit from the catalytic subunit of PKA and subsequent PKA activation. Our study demonstrates that Rheb, by selectively modulating thermogenic gene expression in brown and beige adipose tissues, plays an important role in regulating energy homeostasis.

scholarly journals Synergism between cAMP and PPARγSignalling in the Initiation of UCP1 Gene Expression in HIB1B Brown Adipocytes

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
H. Y. Chen ◽  
Q. Liu ◽  
A. M. Salter ◽  
M. A. Lomax
Keyword(s):  
Tandem Repeats ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Specific Gene ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Promoter Construct ◽  
Ucp1 Expression ◽  
Signalling Systems ◽  
Antagonist Gw9662

Expression of the brown adipocyte-specific gene, uncoupling protein 1 (UCP1), is increased by both PPARγstimulation and cAMP activation through their ability to stimulate the expression of the PPAR coactivator PGC1α. In HIB1B brown preadipocytes, combination of the PPARγagonist, rosiglitazone, and the cAMP stimulator forskolin synergistically increased UCP1 mRNA expression, but PGC1αexpression was only increased additively by the two drugs. The PPARγantagonist, GW9662, and the PKA inhibitor, H89, both inhibited UCP1 expression stimulated by rosiglitazone and forskolin but PGC1αexpression was not altered to the same extent. Reporter studies demonstrated that combined rosiglitazone and forskolin synergistically activated transcription from a full length 3.1 kbp UCP1 luciferase promoter construct, but the response was only additive and much reduced when a minimal 260 bp proximal UCP1 promoter was examined. Rosiglitazone and forskolin in combination were able to synergistically stimulate promoters comprising of tandem repeats of either PPREs or CREs. We conclude that rosiglitazone and forskolin act together to synergistically activate the UCP1 promoter directly rather than by increasing PGC1αexpression and by a mechanism involving cross-talk between the signalling systems regulating the CRE and PPRE on the promoters.

Uncoupling protein 1 expression and high-fat diets

2011 ◽  
Vol 300 (1) ◽  
pp. R1-R8 ◽  
Author(s):  
Tobias Fromme ◽  
Martin Klingenspor
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Caloric Intake ◽  
High Fat ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Thermoregulatory Function

Uncoupling protein 1 (Ucp1) is the key component of β-adrenergically controlled nonshivering thermogenesis in brown adipocytes. This process combusts stored and nutrient energy as heat. Cold exposure not only activates Ucp1-mediated thermogenesis to maintain normothermia but also results in adaptive thermogenesis, i.e., the recruitment of thermogenic capacity in brown adipose tissue. As a hallmark of adaptive thermogenesis, Ucp1 synthesis is increased proportionally to temperature and duration of exposure. Beyond this classical thermoregulatory function, it has been suggested that Ucp1-mediated thermogenesis can also be employed for metabolic thermogenesis to prevent the development of obesity. Accordingly, in times of excess caloric intake, one may expect a positive regulation of Ucp1. The general impression from an overview of the present literature is, indeed, an increased brown adipose tissue Ucp1 mRNA and protein content after feeding a high-fat diet (HFD) to mice and rats. The reported increases are very variable in magnitude, and the effect size seems to be independent of dietary fat content and duration of the feeding trial. In white adipose tissue depots Ucp1 mRNA is generally downregulated by HFD, indicating a decline in the number of interspersed brown adipocytes.

scholarly journals The T3 Receptor β1 Isoform Regulates UCP1 and D2 Deiodinase in Rat Brown Adipocytes

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 5074-5083 ◽  
Author(s):  
Raquel Martinez de Mena ◽  
Thomas S. Scanlan ◽  
Maria-Jesus Obregon
Keyword(s):  
Uncoupling Protein ◽  
Weight Maintenance ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Adrenergic Agents ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
High Doses ◽  
Stimulation Of

Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T3. In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T3 required for UCP1 expression. T3 actions are mediated by thyroid hormone nuclear T3 receptors (TR), TRα and TRβ. Studies in mice suggest that TRβ is required for UCP1 induction, whereas TRα regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T3vs. specific TRβ1 and TRα1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nm). GC-1 at low doses (0.2–10 nm) was less potent than T3, increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T3, GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The α1- and α2-adrenergic D2 responses increased using high T3 doses. In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TRβ1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TRβ1.

scholarly journals The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1

2020 ◽  
Vol 295 (17) ◽  
pp. 5588-5601
Author(s):  
Sho Sugawara ◽  
Yusuke Kanamaru ◽  
Shiori Sekine ◽  
Lila Maekawa ◽  
Akinori Takahashi ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Energy Consumption ◽  
Energy Expenditure ◽  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Uncoupling Protein ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
A Genome ◽  
Brown Adipose

Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (PISD), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression.

scholarly journals Thyrotropin Receptors in Brown Adipose Tissue: Thyrotropin Stimulates Type II Iodothyronine Deiodinase and Uncoupling Protein-1 in Brown Adipocytes*

Endocrinology ◽  
2001 ◽  
Vol 142 (3) ◽  
pp. 1195-1201 ◽  
Author(s):  
Masami Murakami ◽  
Yuji Kamiya ◽  
Tadashi Morimura ◽  
Osamu Araki ◽  
Makoto Imamura ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Type Ii ◽  
Uncoupling Protein 1 ◽  
Iodothyronine Deiodinase ◽  
Brown Adipocytes ◽  
Brown Adipose

Exercise-induced effects on UCP1 expression in classical brown adipose tissue: a systematic review

2017 ◽  
Vol 31 (2) ◽  
Author(s):  
Andreas D. Flouris ◽  
Petros C. Dinas ◽  
Angelica Valente ◽  
Cláudia Marlise Balbinotti Andrade ◽  
Nair Honda Kawashita ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Regular Exercise ◽  
Uncoupling Protein 1 ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Exercise Induced ◽  
The Impact

AbstractUnderstanding the impact of regular exercise training on uncoupling protein 1 (UCP1) activity in classical brown adipose tissue (

Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration

2014 ◽  
Vol 306 (10) ◽  
pp. C918-C930 ◽  
Author(s):  
Jiyoung Bae ◽  
Carolyn J. Ricciardi ◽  
Debora Esposito ◽  
Slavko Komarnytsky ◽  
Pan Hu ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Mitochondrial Respiration ◽  
Uncoupling Protein ◽  
Mapk Signaling ◽  
Pattern Recognition Receptors ◽  
Brown Adipocyte ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Brown Adipose

Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-κB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP-coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention.

scholarly journals 3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes

Biology ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 95
Author(s):  
Manuela Gencarelli ◽  
Annunziatina Laurino ◽  
Elisa Landucci ◽  
Daniela Buonvicino ◽  
Costanza Mazzantini ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Uncoupling Protein ◽  
M Cells ◽  
Uncoupling Protein 1 ◽  
Cell Content ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
20 Nm

We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance.

scholarly journals Interscapular brown adipose tissue recruitment is hindered by a temperature environment of 33°C: Uncoupling protein-1 underexpression is not associated with obesity development in rats

2018 ◽  
Vol 70 (3) ◽  
pp. 567-579
Author(s):  
Gordana Juric-Lekic ◽  
Ljiljana Bedrica ◽  
Dragutin Loncar
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mrna Expression ◽  
Uncoupling Protein ◽  
Precursor Cells ◽  
Nonshivering Thermogenesis ◽  
Uncoupling Protein 1 ◽  
Brown Adipocytes ◽  
Gold Particles ◽  
Brown Adipose

Brown adipose tissue (BAT) generates heat due to unique thermogenic UC-mitochondria, an event known as nonshivering thermogenesis. Cold, adrenergic agents, hormones, etc., activate nonshivering thermogenesis, resulting in lipid mobilization, an increase in the mitochondria and mitochondrial cristae, and increased uncoupling protein-1 (UCP1) expression and its incorporation into mitochondrial cristae. BAT precursor cells mature and contribute to BAT growth in a process known as BAT recruitment. For the first time, we herein report the effect of a thermoneutral environment of 33?C on interscapular BAT (IBAT) in rats delivered and raised at 33?C. The control animals were housed at 20?C. Thermoneutral IBAT was atrophic (73 mg vs. 191 mg) but with more adipocyte precursor cells; euthermia (37.6?C) was maintained without nonshivering thermogenesis. Although IBAT was inactive, the thermoneutral animals did not develop obesity, and on the contrary, the thermoneutral environment of 33?C hindered the rats? growth, weight (65 gm vs. 139 gm), volume (67 gm vs.136 gm) and length (12 cm vs. 16 cm). The thermoneutral brown adipocytes were smaller (7234 ?m3 vs. 9198 ?m3) with more lipids (4919 ?m3 vs. 4507 ?m3) and a smaller mitochondrial cristae area (52504 ?m2 vs. 61288 ?m2/adipocyte). Lipoprotein lipase mRNA expression was 11% (vs. 58% in control) and UCP1 mRNA expression was 34% (vs. 93% control). UCP1 immunoelectron microscopic study detected 160 UCP1-gold particles (vs. 700 in control) per UC-mitochondrion; thermoneutral brown adipocytes had 9-fold fewer UCP1-gold particles (0.34x106 vs. 2.99x106 UCP1-gold particles), and thermoneutral UC-mitochondria developed specific intramitochondrial tubular inclusions.

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