β-Adrenergic stimulation of interleukin-1α and interleukin-6 expression in mouse brown adipocytes

Iodothyronine type II 5'-deiodinase (5'D-II) activities were studied in cultures of rat brown adipocytes. In the presence of serum, the adrenergically stimulated 5'D-II activities were very low. In the absence of serum, adenosine 3',5'-cyclic monophosphate (cAMP) analogues stimulated 5'D-II activity. Thyroxine (T4) inhibited these increases. Norepinephrine slightly increased 5'D-II activity in hypothyroid conditions, but 3,5,3'-triiodothyronine (T3) strongly potentiated the adrenergic stimulation of 5'D-II (20-fold). T3 amplification of the adrenergic stimulation was via beta-adrenergic receptors, specifically mimicked by beta3-agonists, but it was not observed using cAMP analogues. The stimulatory effect of T3 predominated over the inhibitory action of T4, increased with exposure to T3, and required de novo protein synthesis. The half-life of 5'D-II was 30 min, suggesting that stabilization of 5'D-II did not occur. The effect was only observed in differentiated adipocytes. Retinoic acid has similar although smaller effects than T3. In conclusion, the presence of T3 is required and strongly potentiates the noradrenergic stimulation of 5'D-II activity in rat brown adipocytes.

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

Biochemical Journal ◽

10.1042/bj2360757 ◽

1986 ◽

Vol 236 (3) ◽

pp. 757-764 ◽

Cited By ~ 22

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.

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

Endocrinology ◽

10.1210/en.2010-0533 ◽

2010 ◽

Vol 151 (10) ◽

pp. 5074-5083 ◽

Cited By ~ 51

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00433.2001 ◽

2002 ◽

Vol 282 (5) ◽

pp. E1119-E1127 ◽

Cited By ~ 19

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.

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

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01568 ◽

2005 ◽

Vol 34 (1) ◽

pp. 139-151 ◽

Cited By ~ 26

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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Methylation of estrogens, obesity and breast cancer

Problems of Endocrinology ◽

10.14341/probl9550 ◽

2018 ◽

Vol 64 (4) ◽

pp. 244-251

Author(s):

Natalia B. Chagay ◽

Ashot M. Mkrtumyan

Keyword(s):

Adipose Tissue ◽

Methylation Status ◽

The Body ◽

Hormone Sensitive Lipase ◽

Main Function ◽

Adrenergic Stimulation ◽

Brown Adipocytes ◽

Brown Adipose ◽

Hormone Sensitive ◽

Stimulation Of

Methylation of catechol estrogens is catalyzed by catechol-O-methyltransferase. Synthesis and activity of this enzyme is encoded by the COMT gene. Downregulation of COMT expression is responsible for the risk of developing estrogen-dependent tumors. Obesity is a factor determining the overall methylation status in the body. There are two main types of adipose tissue differing in their functional and metabolic characteristics, as well as the microscopic structure: white adipose tissue (WAT) and brown adipose tissue (BAT). Lipolysis of WAT is controlled by hormone-sensitive lipase, which depends is catecholamine dependent. BAT is a special type of adipose tissue whose main function is to produce heat. Activation of β3-adrenergic receptors by catecholamines, both at the central and peripheral levels, is the primary mechanism regulating thermogenesis in mature BAT. Obese patients develop adipose tissue hypoxia, as well as WAT and BAT dysfunction. Adrenergic stimulation of thermogenesis is unclaimed because of «whitening» of brown adipocytes, which manifests itself as degradation of mitochondria. Redirection of stimulation of hormone-sensitive lipase by catecholamines to WAT and the increased need to enhance COMT expression are the potential consequences of modifying the BAT metabolism. Estrogens are natural modulators of lipolysis (as they selectively affect activity of hormone-sensitive lipase) and regulators of BAT thermogenesis. Obesity is accompanied by elevated synthesis of estrone. However, in postmenopausal women it is characterized by a decrease in the total mass and activity of BAT. The role of BAT in the progression or inhibition of growth of the estrogen-dependent tumor tissue at premenopausal and postmenopausal age has not been studied yet and is of interest to researchers. The possible correlation between the activity of brown adipocytes and the COMT expression level is discussed in the context of the risk of developing benign breast dysplasia and cancer.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.5.e769 ◽

2000 ◽

Vol 278 (5) ◽

pp. E769-E777 ◽

Cited By ~ 27

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.

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α1 -Adrenergic stimulation of Cl− efflux in isolated brown adipocytes

FEBS Letters ◽

10.1016/0014-5793(90)80144-8 ◽

1990 ◽

Vol 262 (1) ◽

pp. 25-28 ◽

Cited By ~ 8

Author(s):

Leonardo Dasso ◽

Eamonn Connolly ◽

Jan Nedergaard

Keyword(s):

Adrenergic Stimulation ◽

Brown Adipocytes ◽

Stimulation Of

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Adrenergic Stimulation of Regional Plasminogen Activator Release in Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646315 ◽

1992 ◽

Vol 68 (05) ◽

pp. 545-549 ◽

Cited By ~ 5

Author(s):

W L Chandler ◽

S C Loo ◽

D Mornin

Keyword(s):

Lower Extremity ◽

Plasminogen Activator ◽

Beta Blocker ◽

Time Course ◽

Vascular System ◽

Adrenergic Stimulation ◽

Epinephrine Administration ◽

Adrenergic Antagonist ◽

Vascular Beds ◽

Stimulation Of

SummaryThe purpose of this study was to determine whether different regions of the rabbit vascular system show variations in the rate of plasminogen activator (PA) secretion. To start, we evaluated the time course, dose response and adrenergic specificity of PA release. Infusion of 1 µg/kg of epinephrine stimulated a 116 ± 60% (SD) increase in PA activity that peaked 30 to 60 s after epinephrine administration. Infusion of 1 µg/kg of norepinephrine, isoproterenol and phenylephrine had no effect on PA activity. Pretreatment with phentolamine, an alpha adrenergic antagonist, blocked the release of PA by epinephrine while pretreatment with the beta blocker propranolol had no effect. This suggests that PA release in the rabbit was mediated by some form of alpha receptor.Significant arterio-venous differences in basal PA activity were found across the pulmonary and splanchnic vascular beds but not the lower extremity/pelvic bed. After stimulation with epinephrine, PA activity increased 46% across the splanchnic bed while no change was seen across the lower extremity/pelvic bed. We conclude that several vascular beds contribute to circulating PA activity in the rabbit, and that these beds secrete PA at different rates under both basal and stimulated conditions.

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Activation of Hageman Factor by α-Adrenergic Stimulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654067 ◽

1970 ◽

Vol 23 (03) ◽

pp. 417-422 ◽

Cited By ~ 13

Author(s):

D. G McKay ◽

J.-G Latour ◽

Mary H. Parrish

Keyword(s):

Disseminated Intravascular Coagulation ◽

Adrenergic Receptor ◽

Adrenergic Stimulation ◽

Hageman Factor ◽

Intravascular Coagulation ◽

Receptor Sites ◽

High Doses ◽

Stimulation Of

SummaryThe infusion of epinephrine in high doses produces disseminated intravascular coagulation by activation of Hageman factor. The effect is blocked by phenoxybenz-amine and is therefore due to stimulation of α-adrenergic receptor sites.

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