alpha2-adrenoceptoren
...aber dafür sind gerade die ausgeprägtesten "birnen" am wenigsten herzinfarktgefährdet
. das mit den adrenoceptoren und der lipolytischen aktivität ist derzeit noch nicht so ganz klar und wird v.a. am nagetiermodell untersucht. die problematik der 1:1-übertragung auf den menschen kennst du. aber es ist zweifellos ein interessantes forschungsgebiet, das aufzeigt, dass die lipolyse keine so g'mahte wiesn ist, wie man meinen mag. klinische relevanz besteht v.a. für die viszerale adipositas und damit für das metabolische syndrom - womit wir wieder beim thema wären :winke:. es spielt halt alles zusammen...
zum letzten paper: celiprolol (handelsname "selectol") macht als cardioselektiver betablocker mit ISA (intrinsischer sympathikomimetischer aktivität) wenig sinn und ist eigentlich obsolet. man steigt ja beim autofahren auch nicht gleichzeitig auf die bremse und auf's gas :winke:
und es wird wohl niemand auf die idee kommen, celiprolol als "fatburner" einzusetzen
aber das paper is eh schon "uralt" :winke:
gruß, kurt
J Clin Endocrinol Metab 2000 Jul;85(7):2446-54
Subcutaneous adipose tissue metabolism at menopause: importance of body fatness and regional fat distribution.
Mauriege P, Imbeault P, Prud'Homme D, Tremblay A, Nadeau A, Despres JP. CHUQ Medical Research Center, Department of Social and Preventive Medicine, Laval University, Quebec, Canada.
diabolo@internetclub.fr
The aim of this study was to examine the contribution of menopause per se on sc adipose tissue (AT) metabolism in 16 women classified on the basis of their menopausal status: 8 postmenopausal (mean +/- SD age, 57 +/- 6 yr) vs. 8 premenopausal individuals (37 +/- 5 yr). These 2 groups were matched for sc abdominal adipose cell size (within 0.02 microg lipid/cell) and visceral AT accumulation (within 15 cm2), measured by computed tomography. Fasting plasma glucose and insulin levels as well as their responses to an oral glucose load were similar regardless of the women's hormonal status. Subcutaneous abdominal and femoral AT lipoprotein lipase activities as well as fat cell lipolysis were determined in both groups. Epinephrine induced antilipolysis at low concentrations and lipolysis at higher doses in both adipose sites and groups. The maximal lipolytic response to epinephrine or to isoproterenol (beta-adrenergic agonist) as well as the maximal antilipolytic effect of either the catecholamine or UK-14304 (alpha2-adrenergic agonist) assessed in sc adipocytes were similar in pre- and postmenopausal women. In addition, neither the beta- nor the alpha2-adrenoceptor sensitivity of sc adipose cells differed according to subjects' age. Finally, maximal lipolysis promoted by postadrenoceptor agents and AT-lipoprotein lipase activity did not vary among adipose regions or between groups. Taken together, these results suggest that menopause per se does not influence sc AT metabolism once the variation related to adipose cell size and total body fatness is taken into account.
Publication Types: Clinical Trial PMID: 10902792 [PubMed - indexed for MEDLINE]
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Pflugers Arch 2001 Jun;442(3):396-403
Sexual dimorphism in the adrenergic control of rat brown adipose tissue response to overfeeding.
Rodriguez E, Monjo M, Rodriguez-Cuenca S, Pujol E, Amengual B, Roca P, Palou A. Departament de Biologia Molecular, Nutrico i Biotecnologia, Universitat de les Illes Balears, Palma de Mallorca, Spain.
Gender-related differences in the brown adipose tissue (BAT) response to overfeeding rats on a cafeteria diet were studied by assessing the balance between the expression of beta-adrenoceptors (beta1-, beta2-, beta3-AR) and alpha2A-AR and their relation to the expression of uncoupling proteins (UCP1, UCP2, UCP3). Cafeteria diet feeding for 15 days, which involved a similar degree of hyperphagia in both sexes, led to a greater body weight excess in females than in males and a lower activation of thermogenesis. Gender-related differences were found for different adrenoceptor expression and protein levels, which might explain, in part, sex differences in the thermogenic parameters. The lower expression of alpha2A-AR in females than in males could be responsible for the higher expression of UCP1 and thermogenic capacity under non-hyperphagic conditions. However, in a situation of high adrenergic stimulation--as occurs with overfeeding--as there is a preferential recruitment of the beta3-AR by noradrenaline compared with other adrenergic receptors, the higher levels of beta3-AR in males rats than in females could be responsible for the greater thermogenic capacity and the lesser weight gain in males. Thus, the alpha2/beta3 balance in BAT could be a key in the thermogenic control.
PMID: 11484771 [PubMed - indexed for MEDLINE]
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Horm Metab Res 2000 Nov-Dec;32(11-12):443-52
Millennium fat-cell lipolysis reveals unsuspected novel tracks.
Langin D, Lucas S, Lafontan M. INSERM unit 317, Institut Louis Bugnard, H pital Rangueil, Universite Paul Sabatier, Toulouse, France.
langin@rangueil.inserm.fr
Adipose tissue lipolysis, i.e., the catabolic process leading to the breakdown of triglycerides into fatty acids and glycerol, is often considered as a simple and well-understood metabolic pathway. However, progress on the hormonal regulation and molecular mechanism of fat-cell lipolysis is opening new avenues and points to a number of unanswered questions. Recent studies on the lipolytic beta- and antilipolytic alpha2-adrenergic control of lipolysis has allowed a better understanding of the relative contribution of the two types of receptors and provide strong evidence for the in vivo implication of alpha2-adrenoceptors in the physiological control of subcutaneous adipose-tissue lipolysis. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. The molecular details of the lipolytic reaction are not fully understood. Translocation of hormone-sensitive lipase, the rate-limiting enzyme of lipolysis, to the lipid droplet seems to be an important step during lipolytic activation. Reorganization of the lipid droplet coating by perilipins may also facilitate the access of the enzyme. Unexpectedly, hormone-sensitive lipase-deficient mice are not obese and show residual adipose-tissue lipolysis, which suggests the existence of another triglyceride lipase. Whether the expression of this uncharacterized neutral lipase is compensatory for the lack of hormone-sensitive lipase is an important question yet to be resolved. In humans, alterations of hormone-sensitive lipase expression are associated with changes in lipolysis in various physiological and pathological states. Genetic studies show that beta2-adrenoceptor and hormone-sensitive lipase genes may participate in the polygenic background of obesity.
Publication Types: Review Review, Tutorial PMID: 11246809 [PubMed - indexed for MEDLINE]
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J Clin Endocrinol Metab 2000 Jul;85(7):2455-62
Adipose tissue metabolism in young and middle-aged men after control for total body fatness.
Imbeault P, Prud'Homme D, Tremblay A, Despres JP, Mauriege P. Department of Social and Preventive Medicine, Laval University, Quebec, Canada.
The aim of this study was to compare the sc adipose tissue metabolism of young (29 +/- 4 yr) vs. middle-aged men (57 +/- 5 yr), once the concomitant variation in total adiposity was taken into account. For this purpose, sc abdominal and femoral adipose tissue lipoprotein lipase activities, as well as fat cell lipolytic responses, were investigated in 2 groups of 16 men, differing in age but displaying similar adipose tissue mass (within 2 kg) and sc abdominal adipose tissue area, measured by computed tomography (within 15 cm2). No difference was observed in adipose tissue lipoprotein lipase activity of young vs. middle-aged subjects, regardless of the adipose region considered. Epinephrine induced antilipolysis at low concentrations (10(-9) to 10(-7) mol/L) and a net lipolytic response at higher doses (10(-6) to 10(-5) mol/L), regardless of the subjects' age and the anatomic location of fat. In addition, the selective alpha2-adrenergic agonist, UK-14304, promoted a similar antilipolytic response in sc abdominal and femoral adipose cells from both groups. However, maximal lipolysis induced by isoproterenol (beta-adrenergic agonist) or by postadrenoceptor agents such as dibutyryl-cAMP, forskolin, and theophylline were lower in both adipose regions of middle-aged (as compared with young) men. No difference in the beta- or the alpha2-adrenoceptor sensitivity of sc adipose cells was observed between groups. These results indicate that there is, with age, a selective decrease in the lipolytic capacity to beta-adrenergic agonist, which seems to be caused by postadrenoceptor impairments. Because subjects in the 2 age-groups displayed similar body fatness, these alterations are independent from the age-expected increase in total adiposity.
Publication Types: Clinical Trial PMID: 10902793 [PubMed - indexed for MEDLINE]
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J Lipid Res 1999 Sep;40(9):1559-71
Regional and gender variations in adipose tissue lipolysis in response to weight loss.
Mauriege P, Imbeault P, Langin D, Lacaille M, Almeras N, Tremblay A, Despres JP. Lipid Research Center, Laval University, Ste-Foy, Quebec, Canada G1K 7P4.
Catecholamine-induced lipolysis was investigated in 32 obese subjects (14 men and 18 premenopausal women), aged 36-50 years, whose body mass index ranged from 30 to 42 kg/m(2). Isolated subcutaneous (subc) abdominal and femoral adipocytes were studied before and after a 15-week weight reducing program, during which mean body weight loss averaged 9 vs. 10 kg in women and men, respectively (P < 0.0001). Participants were re-examined when they were weight-stable. Fat cell weight decreased by about 15;-20% in both depots (P values ranging from 0.01 to 0.05). Epinephrine (mixed alpha2-/beta-adrenoceptor (AR) agonist) induced antilipolysis at low concentrations and a net lipolytic response at higher doses, irrespective of subjects' fatness and anatomic location of fat. Basal lipolysis, maximal lipolytic responses to isoprenaline (beta-AR agonist), dobutamine and procaterol (beta1- and beta2-AR agonists, respectively) as well as maximal antilipolytic effects of epinephrine or UK-14304 (alpha2-AR agonist) were similar before and after weight reduction. However, both beta- and beta2-AR lipolytic sensitivities and the beta-AR density were increased in both genders after weight reduction, this effect being more marked in subc abdominal than in femoral adipocytes (P values ranging from 0.001 to 0.05). The alpha2-AR antilipolytic sensitivity was reduced in adipose cells from both regions in women, but only in subc abdominal adipocytes in men (P < 0.05), although the alpha2-AR density remained unchanged after weight reduction. In conclusion, a moderate weight loss leads to a higher adipose cell lipolytic efficiency which is associated with changes at receptor levels (mainly an increased beta2- and a decreased alpha2-AR sensitivities), in both genders.
PMID: 10484603 [PubMed - indexed for MEDLINE]
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J Clin Endocrinol Metab 1999 Feb;84(2):736-42
Is visceral adiposity a significant correlate of subcutaneous adipose cell lipolysis in men?
Mauriege P, Brochu M, Prud'homme D, Tremblay A, Nadeau A, Lemieux S, Despres JP. Lipid Research Center, Laval University Medical Research Center, Laval University, Ste-Foy, Quebec, Canada.
The aim of the present study was to examine whether site differences in s.c. adipose tissue (AT) lipolysis may be considered a contributing factor to the altered metabolic risk profile of visceral compared to peripheral obese men once the concomitant variation in adipose cell size is taken into account. For this purpose, sc abdominal and femoral fat cell lipolytic responses were investigated in two groups of men (body mass index, 28 +/- 2 kg/m2), aged 36 +/- 3 yr, who were matched for both s.c. abdominal AT area (256 +/- 64 cm2) and s.c. abdominal adipose cell weight (0.55 +/- 0.08 microg lipid/cell) but were characterized by either a high (162 +/- 29 cm2; n = 18) or a low (101 +/- 21 cm2; n = 18) visceral AT deposition. The maximal lipolytic response to epinephrine or to isoproterenol (beta-adrenergic agonist) as well as the maximal antilipolytic effect of either epinephrine or clonidine (alpha2-adrenergic agonist) assessed in s.c. adipocytes were similar among men with low vs. high levels of visceral AT. However, the beta-adrenoceptor sensitivity was increased in s.c. abdominal adipose cells of individuals with a high visceral AT accumulation compared to those with a low intraabdominal fat deposition. Positive relationships were also found between the lipolytic sensitivity of s.c. abdominal adipocytes and plasma insulin concentrations measured in the fasting state and after an oral glucose load. These results suggest that variation in the degree of visceral adiposity in men does not seem to be associated with differences in regional adipose cell maximal lipolytic capacity once fat cell size is taken into account. However, the greater beta-adrenoceptor lipolytic sensitivity of s.c. abdominal adipocytes could be considered a significant correlate of the increased insulinemia observed among men characterized by high levels of visceral AT.
PMID: 10022446 [PubMed - indexed for MEDLINE]
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Am J Physiol 1998 Dec;275(6 Pt 1):E951-6
Endurance training changes in lipolytic responsiveness of obese adipose tissue.
De Glisezinski I, Crampes F, Harant I, Berlan M, Hejnova J, Langin D, Riviere D, Stich V. Laboratoire des Adaptations de l'Organisme a l'Exercice Musculaire, Hopital Purpan, 31059 Toulouse Cedex, France.
The aim of this study was to investigate the effect of aerobic exercise training on the lipolytic response of adipose tissue in obese subjects. Thirteen men (body mass index = 36.9 +/- 1.3 kg/m2) were submitted to aerobic physical training on a cycloergometer (30-45 min, 4 days a wk) for 3 mo. Adipocyte sensitivity to the action of catecholamines and insulin was studied in vitro before and after training. Training induced a decrease in the percentage of fat mass (P < 0.05) without changing the body weight. Basal lipolysis and hormone-sensitive lipase activity were significantly decreased after training (P < 0.05). The lipolytic effects of epinephrine, isoprenaline (beta-adrenoceptor agonist), and dobutamine (beta1-adrenoceptor agonist) were significantly increased (P < 0.05) but not those of procaterol (beta2-adrenoceptor agonist). The antilipolytic effects of alpha2-adrenoceptor and insulin were significantly decreased (P < 0.05). Lipolysis stimulation by agents acting at the postreceptor level was unchanged after training. In conclusion, aerobic physical training in obese male subjects modifies adipose tissue lipolysis through an enhancement of beta-adrenergic response and a concomitant blunting of adipocyte antilipolytic activity.
PMID: 9843736 [PubMed - indexed for MEDLINE]
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Metabolism 1998 Apr;47(4):467-73
Regional differences in adrenoceptor binding and fat cell lipolysis in obese, postmenopausal women.
Berman DM, Nicklas BJ, Rogus EM, Dennis KE, Goldberg AP. Department of Medicine, University of Maryland School of Medicine; the Geriatric Research, Education and Clinical Center, Baltimore Veterans Affair Medical Center, 21201, USA.
In women there is an increase in visceral obesity, subcutaneous abdominal adipocyte lipolysis, and risk of cardiovascular disease (CVD) associated with weight gain after menopause. The mechanisms underlying this increase in adrenoreceptor (AR)-agonist catecholamine-stimulated lipolysis and abdominal obesity in postmenopausal women were studied in intact adipocytes isolated from the abdominal and gluteal subcutaneous fat depots in 19 obese (48% +/- 1% body fat, mean +/- SE) women with a mean +/- SE age of 58 +/- 1 years. The fat cell size and adipose tissue lipoprotein lipase (ATLPL) activity were similar in both sites. The maximal lipolytic responsiveness and sensitivity to isoproterenol were higher (P < .05) in abdominal compared with gluteal adipocytes, but maximal lipolytic response to a post-AR agent was similar. Abdominal adipocytes had a higher beta-AR ([3H]-CGP-12177) and alpha2-AR ([3H]-yohimbine) affinity than gluteal cells (P < .05), lower alpha2-AR density (P < .05), but similar beta-AR density as gluteal cells. Both abdominal and gluteal cell size correlated with alpha2-AR density (P < .01), but not with beta-AR density. Thus, a higher beta-AR affinity and lower alpha2-AR relative to beta-AR density may explain the higher in vitro catecholamine-mediated lipolysis in abdominal compared with gluteal adipocytes in obese, postmenopausal women. Publication Types: Clinical Trial PMID: 9550547 [PubMed - indexed for MEDLINE]
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Eur J Pharmacol 1997 Jun 11;328(2-3):207-15
Anti-obesity effect of MPV-1743 A III, a novel imidazoline derivative, in genetic obesity.
Savontaus E, Raasmaja A, Rouru J, Koulu M, Pesonen U, Virtanen R, Savola JM, Huupponen R. Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland.
erisan@utu.fi
MPV-1743 A III ((+/-)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole) is a novel imidazoline derivative. In this study, it was shown to bind with high affinity to alpha2-adrenoceptor subtypes alpha2A (IC50) = 0.66 +/- 0.06 nM), alpha2B (IC50) = 3.8 +/- 0.53 nM), alpha2C (IC50) = 3.1 +/- 0.61 nM) in the recombinant S115 cells and to alpha2D (IC50 = 0.94 +/- 0.10 nM) in the rat submandibular gland. MPV-1743 A III also showed remarkably high affinity to alpha1-adrenoceptors (IC50 = 150 +/- 12 nM) in the rat cerebral cortex and to imidazoline I2b-binding sites (IC50) = 150 +/- 5.0 nM) in the rat liver. The functional alpha2-adrenoceptor antagonistic effect of MPV-1743 A III was demonstrated by studying the ability of orally administered MPV-1743 A III to reverse and prevent the alpha2-adrenoceptor agonist detomidine-induced mydriasis in rat. The anti-obesity effect of MPV-1743 A III was investigated in genetically obese (fa/fa) Zucker rats in two different phases of obesity. Chronic treatment with MPV-1743 A III (0.3 3 mg/kg per day p.o. for 3 weeks) dose dependently decreased weight gain in early-phase obesity. In fully established obesity, GDP binding to mitochondria and expression of uncoupling protein mRNA were increased in brown adipose tissue by MPV-1743 A III indicating an activation of non-shivering thermogenesis. The present study shows that MPV- 1743 A III has a modest anti-obesity effect in the genetic rodent model of obesity. The relative importance of alpha2- and alpha1-adrenoceptors and imidazoline I2b-binding sites in mediating the effects of MPV-1743 A III needs further evaluation.
PMID: 9218703 [PubMed - indexed for MEDLINE]
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Arch Int Pharmacodyn Ther 1984 Nov;272(1):40-55
Effects of celiprolol (REV 5320), a new cardioselective beta-adrenoceptor antagonist, on in vitro adenylate cyclase, alpha- and beta-adrenergic receptor binding and lipolysis.
Van Inwegen RG, Khandwala A, Weinryb I, Pruss TP, Neiss E, Sutherland CA.
Celiprolol has been previously shown in vivo to be an effective beta-adrenergic antagonist with cardio-selectivity and weak intrinsic sympathomimetic activity but no membrane stabilizing or "quinidine-like" effects. With in vitro systems reported here, the following was observed. Against the stimulation of adenylate cyclase from dog ventricular muscle by isoproterenol, celiprolol had a Ki of 2.6 X 10(-7) M which was about 1/20 the potency of propranolol. At 100 microM, celiprolol did not affect histamine or dopamine concentration-response curves for the stimulation of adenylate cyclase from guinea-pig cerebral cortex. By itself, up to 1 mM, celiprolol did not affect basal adenylate cyclase activity from either preparation. With in vitro radioligand binding assays to directly measure beta-adrenergic receptor interactions, celiprolol had Ki values of 1.4 X 10(-7) to 8.3 X 10(-6) M. A 35-fold beta selectivity was noted with membranes from rat heart vs. rat reticulocytes, which supports previously reported in vivo data on cardioselectivity. No difference in affinity to beta-receptors was noted with frog vs. turkey erythrocyte membranes which supports the contention that these two non-mammalian systems are not predictive of beta1/beta2 specificity with mammalian systems. Celiprolol also showed some selective alpha2-adrenoceptor antagonism against (3H)-yohimbine binding vs. (3H)-prazosin binding to membranes from rat cerebral cortex. With rat adipocytes, up to 300 microM celiprolol did not stimulate basal lipolysis in the presence or absence of 10 microM 1-methyl-3-isobutyl-xanthine. Celiprolol inhibited isoproterenol-induced lipolysis with a potency about 2 times greater than practolol. Unlike propranolol, celiprolol at very high concentrations did not show non-specific inhibition of lipolysis induced with cyclic nucleotides. These and other published data would suggest the following: in vitro beta adrenergic receptor antagonist activity can be demonstrated for celiprolol, cardioselectivity is due to a combination of many factors including stereochemistry of the molecule and in vivo distribution and metabolism, celiprolol does not possess "non-specific" membrane activity, the "intrinsic-sympathomimetic activity" of celiprolol is selectively observed in some but not all in vitro test models, celiprolol has about a 10-fold selectivity for alpha 2-vs. alpha 1-receptors which is relatively unique to beta-antagonists and needs further investigations as to the potential physiological significance.
PMID: 6151380 [PubMed - indexed for MEDLINE]