Lipolytic effects of beta1, beta2 and beta3-adrenergic agonists in isolated human fat cells from omental and retroperitoneal adipose tissues.
MP PortilloRocandio AmGarcia-Calonge MaElena Diaz VicunaElı́as CampoC Martinez-BlazquezJosé Errastidel Barrio As
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The presence of beta1- and beta2-adrenoceptors has been clearly established in human fat cells. There is some controversy about the presence and function of beta3-adrenoceptors. It is well established that there are marked regional variations in catecholamine-induced lipolysis. In this work the possibility that a beta3-adrenoceptor plays a significant role in the control of lipid mobilization is studied and also its importance in comparison to beta1- and beta2-adrenoceptors in isolated human fat cells, is evaluated, by measuring the in vitro lipolysis induced by dobutamine, salbutamol, metaproterenol, BRL 37344 and CGP 12177A. Human adipocytes from omental and retroperitoneal fat deposits exhibited an "atypical" beta-adrenergic response but, given the small lipolytic effect initiated by BRL 37344 and CGP 12177A, they are probably poorly equipped in functional beta3-adrenoceptors.Keywords:
B2 receptor
Fat pad
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The presence of beta1- and beta2-adrenoceptors has been clearly established in human fat cells. There is some controversy about the presence and function of beta3-adrenoceptors. It is well established that there are marked regional variations in catecholamine-induced lipolysis. In this work the possibility that a beta3-adrenoceptor plays a significant role in the control of lipid mobilization is studied and also its importance in comparison to beta1- and beta2-adrenoceptors in isolated human fat cells, is evaluated, by measuring the in vitro lipolysis induced by dobutamine, salbutamol, metaproterenol, BRL 37344 and CGP 12177A. Human adipocytes from omental and retroperitoneal fat deposits exhibited an "atypical" beta-adrenergic response but, given the small lipolytic effect initiated by BRL 37344 and CGP 12177A, they are probably poorly equipped in functional beta3-adrenoceptors.
B2 receptor
Fat pad
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The main intention of this study was to characterize the alpha-adrenoceptor responsible for the inhibition of lipolysis in dog fat cell and to define circumstances that may be associated to a modification of the alpha-mediated antilipolytic effect. Isolated fat cells from omental and subcutaneous adipose tissue from normal and obese dogs were used. Basal and theophylline stimulated lipolysis was studied in the presence of selected alpha-adrenergic agonists and antagonists. The antilipolytic effect of catecholamines is mediated by alpha 2-type adrenoceptors in dog fat cell. The alpha-adrenergic responsiveness is enhanced (or unmasked) in large fat cells of obese dogs and depends on the site from which the adipose tissue sample is taken. The alpha-response is stronger in subcutaneous than in omental adipocytes. In conclusion, the weakened lipolytic responsiveness to epinephrine of obese dog fat cells seems related to an increased alpha-adrenergic response rather than a decreased beta-lipolytic effect. Obesity is a circumstance characterized in the dog fat cell by a modification of the balance between alpha-2 and beta receptors.
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Alpha-2 adrenergic receptor
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Abstract. The regulation of lipolysis has been studied in subcutaneous adipose tissue removed under local anesthesia from hypothyroid patients. As control subjects were used hypothyroid subjects on replacement therapy. Noradrenaline induced no significant increase in lipolysis in tissue removed from hypothyroid patients, while the increase in glycerol release from adipose tissue of the control group was almost twofold. The addition of the alpha‐adrenergic blocking agent phentholamine to noradrenaline‐containing media produced a significant increase in the glycerol release from tissue of the hypothyroid patients as well as from the control subjects. Iso‐propylnoradrenaline, a nearly selective beta‐adrenergic agonist, theophylline or dibutyryl‐cyclic AMP stimulated lipolysis in tissue from both groups. These results indicate that the lipase system cannot be the rate‐limiting factor for the lipolytic response to noradrenaline in adipose tissue from hypothyroid patients. The decreased lipolytic response to noradrenaline in this tissue seems to be due to a more pronounced alpha‐adrenergic effect of noradrenaline counteracting the lipolytic effect mediated by the beta‐adrenergic receptor.
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Abstract. The role of peripheral catecholamine sensitivity in lipid mobilization was investigated in 78 healthy non‐obese subjects by comparing beta‐adre‐nergic regulation of lipolysis in isolated adipocytes with circulating catecholamines and glycerol (lipolysis index). Small intra‐individual variations (5–7%) in adipocyte lipolytic beta‐adrenoceptor sensitivity (ED 50 ) for isoprenaline were found. However, large inter‐individual variations (almost 10 5 ‐fold) in isoprenaline ED 50 were observed in abdominal or gluteal adipocytes, which correlated (r = ‐0.52) negatively with the resting plasma noradrenaline levels. A correlation was also observed between circulating noradrenaline and adipocyte ED 50 for noradrenaline (r= ‐0.38). In subjects with high (ED 50 < 10 ‐1 mol 1 ‐1 ) as compared to low isoprenaline sensitivity (ED 50 > 10 ‐10 mol 1 ‐1 ) physical exercise induced a two times greater increase in plasma glycerol ( P < 0.01), in spite of a 50% less marked increase of plasma noradrenaline ( P < 0.01). Findings with beta‐adrenoceptor mRNA and with total beta‐adrenoceptor number or affinity for agonist did not show any strong correlation with the resting plasma noradrenaline level (r<0.25). In conclusion, inter‐individual variations in beta‐adrenoceptor sensitivity and its relation to circulating noradrenaline can be ascribed to specific modulations of either BAR‐subtypes or in the postreceptor activation of lipolysis. These variations in adipocyte beta‐adrenoceptor sensitivity may participate in the regulation of peripheral nervous activity and play a putative role in lipolysis during exercise when subjects with high beta‐adrenoceptor sensitivity increased their ability to mobilize lipids despite a reduced noradrenaline response.
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The relative anatomical distribution of adipose tissue in central (abdominal) vs. peripheral (extremity) depots is highly correlated with the risk of adiposity-related morbidities, such as hypertension, cardiovascular disease, and diabetes mellitus. In adults, comparisons of the functional status of plasma membrane adrenergic receptors indicate that abdominal adipocytes are more responsive to the lipolytic action of β1-adrenergic agonists, while gluteal adipocytes are more responsive to the antilipolytic action of α2-adrenergic agonists. To determine whether such regional differences in adipocyte adrenoreceptor status are present before puberty, we obtained needle biopsy samples of abdominal and gluteal sc adipose tissue in the postabsorptive state from 13 prepubertal children and 47 adults of varying body compositions (obese vs. lean). Lipolysis rates were measured in the basal state and in the presence of 10−7m norepinephrine (a mixed α- and β-adrenergic agonist) and 10−7m isoproterenol (a β-adrenergic agonist). In children, there were no significant regional differences in either the basal rate of lipolysis or the responses to adrenergic lipolytic and antilipolytic stimuli. In lean and obese adults, gluteal sc adipose tissue was strikingly more responsive to antilipolytic α-adrenergic stimulation (P < 0.0001) and less responsive to lipolytic β-adrenergic stimuli (P < 0.005) compared to abdominal tissue. Abdominal sc adipocytes from children had a significantly lower rate of basal lipolysis (P < 0.01) and were more responsive to α2-adrenergic (antilipolytic) stimuli (P < 0.05) than abdominal adipocytes in adults. These results suggest that peripubertal endocrine changes may mediate the striking regional differences in adrenoreceptor status of adult adipose tissue, and that a decrease in the preponderance of α2-receptors (antilipolytic) in abdominal adipose tissue may account in part for the relative loss of central vs. peripheral fat that occurs during puberty.
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Activation of adenylyl cyclase by β-adrenergic receptors (βARs) plays a major role in adipose tissue homeostasis. The increase in cAMP promotes lipolysis in white adipose tissue, activates both thermogenesis and lipolysis in brown adipose tissue (BAT), and induces BAT hypertrophy. Previous studies indicated that among the three βAR subtypes present in adipose tissue, β3AR could be a potential target for antiobesity treatments in humans. We studied immortalized human brown adipocytes (PAZ6 adipocytes) as a model ofβ -adrenergic response in human BAT. PAZ6 adipocytes and freshly isolated mature human brown adipocytes display the same proportions ofβ AR subtypes, with β3AR being the most abundant (∼80% of the total). However, β3AR was poorly coupled to the adenylyl cyclase pathway in PAZ6 cells, contributing to only 10% of the isoproterenol-induced accumulation of cAMP, whereas 20% and 70% of the signal depended on β1- andβ 2-subtypes, respectively. Upon isoproterenol stimulation, β1- and β2AR down-regulated with a half-life of about 3 h and the β3AR with a half-life of 30–40 h. Long term stimulation with both saturating (micromolar) and nonsaturating (nanomolar) concentrations ofβ -adrenergic agonists caused a complete desensitization of theβ -adrenergic response at the adenylyl cyclase level and loss of stimulated protein kinase A activity and CREB phosphorylation. These results suggest that cAMP-dependent processes will be desensitized upon permanent treatment with β3AR agonists. Further studies should establish whether the β3AR is coupled to other signaling pathways in human brown adipocytes and whether these may contribute to BAT hypertrophy and/or thermogenesis.
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The influence of fasting on the dual adrenergic control of adipose tissue lipolysis was investigated in hamsters because in this species the adipocytes exhibit both beta-stimulatory and alpha 2-inhibitory adrenergic responses. In adipocytes from fed animals, the number of alpha 2-receptors (identified with [3H]clonidine and [3H]RX 821002) was greater than that of beta-receptors. As in humans, the alpha 2-adrenoceptor number was greater in adipocyte membranes from subcutaneous (inguinal and popliteal) than from internal (perirenal and epididymal) adipose tissues. Despite this difference in alpha 2-adrenoceptor number, the antilipolytic responses to the alpha 2-agonists clonidine and UK 14304 were similar in the two tissues. Food deprivation for a period of 1-6 days induced a net depletion of both adipose tissues. In 6-day starved animals the number of adipocyte alpha 2-adrenoceptors and the maximal antilipolytic effect of UK 14304 were less than 50% of those in fed controls. In contrast, the antilipolytic responses to phenylisopropyladenosine or prostaglandin E1 remained unchanged. Starvation induced a decrease in alpha 2-adrenoceptor number and an increase in beta-adrenergic sensitivity that were greater in adipocytes from subcutaneous than from internal fad pads. The data suggest that the adipocyte beta- and alpha 2-adrenoceptors are independently regulated during starvation. In the adipocyte, the alpha 2-antilipolytic responses and the alpha 2-adrenoceptor levels are dependent on the extent of the adipose mass; they are particularly reduced in emaciated hamsters.
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Abstract The interaction between thyroid hormones and catecholamines has been studied in vitro in subcutaneous adipose tissue specimens from 18 hypothyroid patients and 13 healthy controls. The lipolytic effect of nor‐adrenaline was found to be totally quenched in tissue specimens from hypothyroid subjects, but was restored by the addition of an α‐adrenergic antagonist, phentolamine. Furthermore, stimulation of the α‐adrenergic receptor by noradrenaline in the presence of the β‐adrenergic antagonist, propranolol, significantly decreased basal as well as theophylline‐induced lipolysis in adipose tissue from both groups of subjects. The dibutyryl cyclic AMP induced lipolysis was, however, unaffected by such α‐adrenergic stimulation. These data suggest that the α‐adrenergic response leads to a decrease in the level and/or production of cyclic AMP in the adipocyte, the most probable mechanism being inhibition of the formation of the nucleotide rather than enhancement of its destruction. The mechanism by which α‐adrenergic stimulation decreases lipolysis was found to be identical in adipose tissue from normal and hypothyroid subjects. The difference in response to noradrenaline between the two groups reflects quantitative rather than qualitative changes that the hypothyroid state induces in the balance between the α‐ and β‐adrenergic receptors.
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Circulating leptin, the product of the ob gene, is known to be closely correlated with adipose tissue mass, but it is also subject to short-term regulation by a variety of hormones including catecholamines. The aim of this study was to investigate the contribution of the three beta-adrenergic receptors to leptin secretion from cultured human adipocytes.The model of in vitro differentiated human subcutaneous adipocytes was used in this study. The presence of the beta-adrenoceptor subtypes was studied by RT-PCR. The functional role of the receptor subtypes was determined by stimulation of lipolysis by selective beta-adrenergic agonists and by measuring glycerol release. Leptin secretion into the medium of cultured human adipocytes from young normal-weight females was measured by radioimmunoassay.In a first set of experiments, the expression of the three beta-adrenergic receptor subtypes in cultured human adipocytes was demonstrated. To test their functional activity, the effect of the beta-adrenoceptor agonists isoproterenol (non-selective agonist), dobutamine (beta(1)-selective), fenoterol (beta(2)-selective) and the beta(3)-selective agonists BRL 37344 and CGP 12177 was studied. All agonists exhibited a dose- and time-dependent stimulation of glycerol release into the medium in a rather uniform manner. Isoproterenol rapidly reduced leptin secretion from cultured subcutaneous adipocytes in a dose-dependent fashion. Incubation with 10(-6)mol/l isoproterenol for 24h resulted in a reduction of the leptin concentration by 48% (P < 0.01). A similar, but less pronounced suppressing effect was seen for dobutamine and fenoterol, whereas both BRL 37344 and CGP 12177 were not effective. These data provide evidence that catecholamines are able to suppress leptin release from differentiated human adipocytes, supporting the concept that leptin secretion is acutely regulated by surrounding hormones. This inhibition is obviously mediated via beta(1)- and beta(2)-adrenergic receptors.
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Regional variations in adipocyte lipolysis between subcutaneous and visceral fat may be important for obesity complications.In the present study, we compared adrenergic regulation of lipolysis in omental and subcutaneous adipocytes from obese (n = 15) and non-obese (n = 14) male subjects.Waist-to-hip ratio, blood pressure, plasma insulin, and plasma triglycerides were increased in obesity.No regional differences in adrenoceptor lipolytic function were observed in non-obese subjects with the exception of a slight increase in noradrenaline sensitivity in omental adipocytes ( P < 0.05), because of increased P1-adrenoceptor sensitivity ( P < 0.05).In the obese subjects, the rate of noradrenaline-induced glycerol release was 2-fold higher ( P < 0.005) and the noradrenaline sensitivity was 3-fold higher ( P < 0.05) in omental versus subcutaneous adipocytes.These findings were mainly due to a 50-fold increase in omental Ps-adrenoceptor sensitivity ( P < 0.002) and to a smaller 6fold increase in omental P,-adrenoceptor sensitivity ( P < 0.02), accompanied by increased P3as well as P,-adrenoceptor lipolytic rates at approximately 50% receptor subtype occupancy by the agonist ( P < 0.05).W In conclusion, minor regional differences in adipocyte lipolytic response to catecholamines are present in non-obese males.In contrast, catecholamine-induced lipolysis is markedly increased in omental as compared to subcutaneous adipocytes in obese males, mainly due to an increase in P3-adrenoceptor function of visceral fat cells, in combination with a smaller increase in P,-adrenoceptor function.-Hoffstedt,
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