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.

Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes

2000 ◽  
Vol 278 (5) ◽  
pp. E769-E777 ◽  
Author(s):  
Arturo Hernández ◽  
Maria Jesús Obregón
Keyword(s):  
Uncoupling Protein ◽  
Primary Cultures ◽  
Mitochondrial Protein ◽  
Mrna Levels ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Adrenergic Agents ◽  
Brown Adipose ◽  
Mrna Transcripts ◽  
Stimulation Of

Uncoupling protein (UCP), the mitochondrial protein specific to brown adipose tissue, is activated transcriptionally in response to cold and adrenergic agents. We studied the role of triiodothyronine (T3) on the adrenergic stimulation of UCP mRNA expression by use of primary cultures of rat brown adipocytes. Basal UCP mRNA levels are undetectable. Norepinephrine (NE) increases UCP mRNA during differentiation, not during proliferation. In hypothyroid conditions, UCP mRNA response to NE is almost absent. The presence of T3 (0.2–20 nM) greatly increases the adrenergic response (30-fold). The sensitivity of UCP mRNA responses to NE is potentiated ∼100-fold by the presence of T3. The effect is proportional to the dose and time of preexposure to T3. The increases obtained with NE and T3 are prevented by actinomycin and cycloheximide. T3 greatly stabilizes UCP mRNA transcripts. The effects of thyroxine and retinoic acid are weaker than those of T3. In conclusion, in cultured rat brown adipocytes, T3 is required and both synergizes with NE to increase UCP mRNA and stabilizes its mRNA transcripts.

Beta-1 and Not Beta-3 Adrenergic Receptors May Be the Primary Regulator of Human Brown Adipocyte Metabolism

2019 ◽  
Vol 105 (4) ◽  
pp. e994-e1005 ◽  
Author(s):  
Mette Ji Riis-Vestergaard ◽  
Bjørn Richelsen ◽  
Jens Meldgaard Bruun ◽  
Wei Li ◽  
Jacob B Hansen ◽  
...  
Keyword(s):  
Adrenergic Receptors ◽  
Cell Model ◽  
Uncoupling Protein ◽  
Brown Adipocyte ◽  
Mrna Levels ◽  
Glycerol Release ◽  
Adrenergic Stimulation ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Treatment Of Obesity

Abstract Purpose Brown adipose tissue (BAT) activation in humans has gained interest as a potential target for treatment of obesity and insulin resistance. In rodents, BAT is primarily induced through beta-3 adrenergic receptor (ADRB3) stimulation, whereas the primary beta adrenergic receptors (ADRBs) involved in human BAT activation are debated. We evaluated the importance of different ADRB subtypes for uncoupling protein 1 (UCP1) induction in human brown adipocytes. Methods A human BAT cell model (TERT-hBA) was investigated for subtype-specific ADRB agonists and receptor knockdown on UCP1 mRNA levels and lipolysis (glycerol release). In addition, fresh human BAT biopsies and TERT-hBA were evaluated for expression of ADRB1, ADRB2, and ADRB3 using RT-qPCR. Results The predominant ADRB subtype in TERT-hBA adipocytes and BAT biopsies was ADRB1. In TERT-hBA, UCP1 mRNA expression was stimulated 11.0-fold by dibutyryl cAMP (dbcAMP), 8.0-fold to 8.4-fold by isoproterenol (ISO; a pan-ADRB agonist), and 6.1-fold to 12.7-fold by dobutamine (ADRB1 agonist), whereas neither procaterol (ADRB2 agonist), CL314.432, or Mirabegron (ADRB3 agonists) affected UCP1. Similarly, dbcAMP, ISO, and dobutamine stimulated glycerol release, whereas lipolysis was unaffected by ADRB2 and ADRB3 agonists. Selective knockdown of ADRB1 significantly attenuated ISO-induced UCP1 expression. Conclusion The adrenergic stimulation of UCP1 and lipolysis may mainly be mediated through ADRB1. Moreover, ADRB1 is the predominant ADRB in both TERT-hBA and human BAT biopsies. Thus, UCP1 expression in human BAT may, unlike in rodents, primarily be regulated by ADRB1. These findings may have implications for ADRB agonists as future therapeutic compounds for human BAT activation.

scholarly journals Stimulation of phosphoinositide metabolism in hamster brown adipocytes exposed to α1-adrenergic agents and its inhibition with phorbol esters

1986 ◽  
Vol 236 (3) ◽  
pp. 757-764 ◽  
Author(s):  
R J Schimmel ◽  
D Dzierzanowski ◽  
M E Elliott ◽  
T W Honeyman
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Time Course ◽  
Early Event ◽  
Phosphoinositide Metabolism ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Adrenergic Agents ◽  
Kinase C ◽  
Stimulation Of

The present experiments were undertaken to investigate the role of the phosphoinositides phosphatidylinositol 4-phosphate (PtdIns-4-P) and phosphatidylinositol 4,5-biphosphate (PtdIns-4,5-P2) in the alpha 1-adrenergic stimulation of respiration in isolated hamster brown adipocytes. Exposure of isolated brown adipocytes to the alpha-adrenergic-receptor agonist phenylephrine provoked a breakdown of 30-50% of the PtdIns-4-P and PtdIns-4,5-P2 after prelabelling of the cells with [32P]Pi. Coincident with the breakdown of phosphoinositides was an accumulation of labelled phosphatidic acid, which continued for the duration of the cell incubation. The time course of phosphoinositide breakdown was defined more precisely by pulse-chase experiments. Under these conditions, phenylephrine caused radioactivity in phosphatidylinositol, PtdIns-4-P and PtdIns-4,5-P2 to fall by more than 50% within 30 s and to remain at the depressed value for the duration of the incubation (10 min). This phospholipid response to alpha-adrenergic stimulation was blocked by exposure of the cells to phorbol 12-myristate 13-acetate (PMA); likewise phenylephrine stimulation of respiration was prevented by PMA. beta-Adrenergic stimulation of respiration and inhibition of respiration by 2-chloroadenosine and insulin were, however, unaffected by treatment with PMA. On the assumption that PMA is acting in these cells as an activator of protein kinase C, these results suggest the selective interruption of alpha-adrenergic actions in brown adipocytes by activated protein kinase C. These findings suggest that breakdown of phosphoinositides is an early event in alpha-adrenergic stimulation of brown adipocytes which may be important for the subsequent stimulation of respiration. The results from the pulse-chase studies also suggest, however, that phenylephrine-stimulated breakdown of inositol phospholipids is a short-lived event which does not appear to persist for the entire period of exposure to the alpha 1-adrenergic ligand.

scholarly journals Inducible brown adipocytes in subcutaneous inguinal white fat: the role of continuous sympathetic stimulation

2014 ◽  
Vol 307 (9) ◽  
pp. E793-E799 ◽  
Author(s):  
G. Andres Contreras ◽  
Yun-Hee Lee ◽  
Emilio P. Mottillo ◽  
James G. Granneman
Keyword(s):  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Sympathetic Innervation ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Main Site ◽  
Adipose Tissue Depots ◽  
Brown Adipose ◽  
White Fat

Brown adipocytes (BA) generate heat in response to sympathetic activation and are the main site of nonshivering thermogenesis in mammals. Although most BA are located in classic brown adipose tissue depots, BA are also abundant in the inguinal white adipose tissue (iWAT) before weaning. The number of BA is correlated with the density of sympathetic innervation in iWAT; however, the role of continuous sympathetic tone in the establishment and maintenance of BA in WAT has not been investigated. BA marker expression in iWAT was abundant in weaning mice but was greatly reduced by 8 wk of age. Nonetheless, BA phenotype could be rapidly reinstated by acute β3-adrenergic stimulation with CL-316,243 (CL). Genetic tagging of adipocytes with adiponectin-CreERT2 demonstrated that CL reinstates uncoupling protein 1 (UCP1) expression in adipocytes that were present before weaning. Chronic surgical denervation dramatically reduced the ability of CL to induce the expression of UCP1 and other BA markers in the tissue as a whole, and this loss of responsiveness was prevented by concurrent treatment with CL. These results indicate that ongoing sympathetic activity is critical to preserve the ability of iWAT fat cells to express a BA phenotype upon adrenergic stimulation.

scholarly journals Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

2020 ◽  
Vol 21 (8) ◽  
pp. 3020 ◽  
Author(s):  
Winifred W. Yau ◽  
Paul M. Yen
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Body Temperature ◽  
Uncoupling Protein ◽  
Adrenergic Stimulation ◽  
Adipose Tissues ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Ucp1 Expression ◽  
Independent Effects

Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues.

Triiodothyronine is required for the stimulation of type II 5′-deiodinase mRNA in rat brown adipocytes

2002 ◽  
Vol 282 (5) ◽  
pp. E1119-E1127 ◽  
Author(s):  
Raquel Martinez-deMena ◽  
Arturo Hernández ◽  
Maria-Jesús Obregón
Keyword(s):  
Prolonged Exposure ◽  
Short Exposure ◽  
Type Ii ◽  
Adrenergic Stimulation ◽  
Iodothyronine Deiodinase ◽  
Brown Adipocytes ◽  
Absolute Requirement ◽  
Brown Adipose ◽  
Mrna Half Life ◽  
Stimulation Of

Type II 5′-iodothyronine deiodinase (D2), produces triiodothyronine (T3) and is stimulated by cold exposure via norepinephrine (NE) release in brown adipose tissue. Cultured rat brown adipocytes require T3for the adrenergic stimulation of D2 activity. D2 mRNA expression in cultured brown adipocytes is undetectable with the use of basal conditions or NE without T3. Full D2 expression is achieved using NE + T3, especially after prolonged T3 exposure. β3-Adrenergic agonists mimic the NE action, whereas cAMP analogs do not. Prolonged exposure to T3 alone increases D2 mRNA. High T3 doses (500 nM) inhibit the adrenergic stimulation of D2 activity while increasing D2 mRNA. The effects obtained with NE + T3 or T3 alone are suppressed by actinomycin, but not by cycloheximide, which leads to accumulation of short D2 mRNA transcripts. Prolonged or short exposure to T3 did not change D2 mRNA half-life, but T3 seemed to elongate it. In conclusion, T3 is an absolute requirement for the adrenergic stimulation of D2 mRNA in brown adipocytes. T3upregulates D2 mRNA, an effect that might involve stimulation of factors required for transcription or for stabilization of D2 mRNA.

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 Selective loss of the uncoupling protein from light versus heavy mitochondria of brown adipocytes after a decrease in noradrenergic stimulation in vivo and in vitro

1995 ◽  
Vol 311 (1) ◽  
pp. 327-331 ◽  
Author(s):  
M L Bonet ◽  
F Serra ◽  
J C Matamala ◽  
F J García-Palmer ◽  
A Palou
Keyword(s):  
Uncoupling Protein ◽  
Adrenergic Stimulation ◽  
Fat Cell ◽  
Brown Adipocytes ◽  
Selective Loss ◽  
Mitochondrial Fractions ◽  
Brown Adipose ◽  
Undifferentiated Cells

The relative stability against a decrease in adrenergic stimulation of the uncoupling protein (UCP) incorporated into different mitochondrial fractions was investigated in brown-fat-cell cultures. Cultures were initiated with undifferentiated cells from young mice and were acutely stimulated with noradrenaline at confluence (day 7). Cells were harvested just after the finish of the 24 h stimulation treatment or 24 h later, and three mitochondrial fractions were isolated by differential centrifugation: the M1 fraction (1000 g), the M3 fraction (3000 g) and the M15 fraction (15,000 g). The results obtained in vitro indicate that removal of adrenergic stimulation determines a selective loss of UCP from the lightest mitochondrial fractions (M3 and M15). Similar results were obtained in a situation in vivo (24 h starvation in mice) which is known to lead to a decreased noradrenaline input to brown adipose tissue, with decreased UCP levels. Thus brown adipocytes possess different mitochondrial subpopulations, which exhibit characteristic changes in their UCP turnover in response to thermogenic signals.

Effects of α-(prazosin and yohimbine) and β-receptors activity on cAMP generation and UCP1 gene expression in brown adipocytes

2018 ◽  
Vol 29 (5) ◽  
pp. 545-552 ◽  
Author(s):  
Hirendra M. Biswas
Keyword(s):  
Mrna Expression ◽  
Uncoupling Protein ◽  
Inhibitory Effect ◽  
Brown Adipocytes ◽  
Culture Cells ◽  
Camp Generation ◽  
Brown Adipose ◽  
Β Adrenergic Receptors ◽  
The Relationship ◽  
Stimulation Of

AbstractBackgroundBrown adipose tissue (BAT) contains both α- and β-adrenergic receptors. In the literature, the activity of α-adrenoreceptors is less documented, and their functions still remain puzzling. The present investigation has been undertaken to understand α-adrenoreceptors’ activity and their relation between uncoupling protein 1 (UCP1) mRNA expression and cyclic AMP (cAMP) generation in BAT.MethodsBAT precursor cells from young mice were grown in culture. Cells were exposed to norepinephrine (NE) and other agents. RNA was isolated after harvesting the cells, and northern blot was performed. Filters were exposed to film after hybridization with nick-translated complementary DNA probes, and results were evaluated by scanning. Amersham assay kit was used for cAMP measurement.ResultsTreatment of prazosin and yohimbine separately with 1 μM of NE shows stimulation ofUCP1mRNA expression 106% and 154%, respectively, whereas with that of both drugs shows only 76%. cAMP generation occurs 282% with prazosin, 100% with yohimbine, and 382% with both drugs with 1 μM of NE, whereas it is 310%, 40%, and 358%, respectively, with 10 μM of NE.ConclusionsStimulation of thermogenesis after treatment of prazosin and NE may be due to the inhibition of phosphodiesterase enzyme and with yohimbine and NE indicates the possibility of inhibition of the inhibitory effect of α2- and stimulation of α1-receptors. Increase of cAMP concentration with yohimbine and both drugs with NE are not correlated toUCP1mRNA expression. This indicates that the relationship between cAMP elevation and stimulation of thermogenesis is not simple. This study clearly shows the interaction between β- and α-adrenoreceptor activities.

scholarly journals Insulin increases the adrenergic stimulation of 5′ deiodinase activity and mRNA expression in rat brown adipocytes; role of MAPK and PI3K

2005 ◽  
Vol 34 (1) ◽  
pp. 139-151 ◽  
Author(s):  
Raquel Martinez-deMena ◽  
Maria-Jesus Obregón
Keyword(s):  
Mrna Expression ◽  
Primary Cultures ◽  
Mapk Signaling ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Mapk Activity ◽  
Absolute Requirement ◽  
Brown Adipose ◽  
Stimulation Of

Type II 5′ deiodinase (D2) activity produces triiodothyronine (T3) from thyroxine (T4) and is induced by cold and norepinephrine (NE) in brown adipose tissue. T3 is required for and amplifies the adrenergic stimulation of D2 activity and mRNA in cultured brown adipocytes. D2 is upregulated by insulin and decrease in fasting. We now study the regulation by insulin of the adrenergically induced D2 activity and mRNA in primary cultures of rat brown adipocytes. Insulin alone does not increase D2 activity or mRNA. Insulin-depleted cells show a reduction in the adrenergically induced D2 activity, which is proportional to the length of insulin depletion and is restored after insulin addition. IGFs mimic this effect at higher doses. ERK 1/2 MAPK activity (p44/p42), stimulated by insulin, serum and NE, is an absolute requirement for the adrenergic stimulation of D2 activity and mRNA. PI3K is stimulated by insulin and serum, and NE increases the effect of insulin. The action of insulin on D2 is not due to changes in D2 half-life or in the proteasome-mediated degradation of D2, but it seems to modulate the transcriptional induction mediated by NE. D2 mRNA expression, induced by NE plus T3, is reduced when insulin is withdrawn at early differentiation stages. Insulin or IGF-I promotes increases in D2 mRNA. Insulin is required for the induction of D2 mRNA by T3. In conclusion, MAPK signaling is required for the adrenergic stimulation of D2 activity and mRNA, and insulin stimulates D2 activity via MAPK and PI3K and enhances the adrenergic pathways.

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