Biomedical subjects

C Atgié

Publications and source records attributed to C Atgié.

16 recordsLinked to original sources

PubMed2006

Prolonged treatment with the beta3-adrenergic agonist CL 316243 induces adipose tissue remodeling in rat but not in guinea pig: 1) fat store depletion and desensitization of beta-adrenergic responses.

Beta3-adrenergic agonists have been considered as potent antiobesity and antidiabetic agents mainly on the basis of their beneficial actions discovered twenty years ago in obese and diabetic rodents. The aim of this work was to verify whether prolonged treatment with a beta3-adrenergic agonist known to stimulate lipid mobilisation, could promote desensitization of beta-adrenergic responses. Wistar rats and guinea pigs were treated during one week with CL 316243 (CL, 1 mg/kg/d) by implanted osmotic minipumps. In control animals, beta3-adrenergic agonists were lipolytic in rat but not in guinea pig adipocytes. CL-treatment did not alter body weight gain in both species, but reduced fat stores in rats. Lipolysis stimulation by forskolin was unmodified but responses to beta1-, beta2- and beta3-agonists were reduced in visceral or subcutaneous white adipose tissues of CL-treated rats. Similarly, the beta3-adrenergic-dependent impairment of insulin action on glucose transport and lipogenesis in rat adipocytes was diminished after CL-treatment. In rat adipocytes, [125I]ICYP binding and beta3-adrenoceptor mRNA levels were reduced after sustained CL administration. These findings show that CL 316243 exerts (beta3-adrenergic lipolytic and antilipogenic effects in rat adipocytes. These actions, which are likely involved in the fat depletion observed in rat, also lead to the desensitization of all beta-adrenergic responses. Therefore this desensitization, together with the lack of slimming action in guinea pig, seriously attenuates the usefulness of beta3-agonists as antiobesity agents, and may explain why such agonists have not been conducted to a widespread clinical use.

Adipocytes, White↗

PubMed2005

Effect of vitamin A content in cafeteria diet on the expression of nuclear receptors in rat subcutaneous adipose tissue.

The aim of this study was to determine the effects of cafeteria diet containing control or elevated level of vitamin A on the expression of nuclear receptors in adipose tissue. Male Wistar rats were submitted to 3 experimental diets during 8 weeks, a standard diet and two hyper-energetic, hyperlipidic "cafeteria" diets containing normal (Caf) or higher (Caf+) vitamin A level. During the experiment, body weights and energy intakes were measured. At the end of the experimental period, subcutaneous adipose tissue (Swat) and all the fat mass were removed and weighted. Nuclear receptors mRNA levels of RARalpha, RARgamma, RXRalpha, PPARgamma were measured in the Swat by a real-time semi-quantitative RT-PCR method. We observed that energy intake of Caf+ and Caf groups was significantly higher than that of the control group. Despite a higher increase of the energy intake in the Caf group compared to the Caf+ group, no significant difference was observed in the body weight gain of the Caf+ compared to the Caf group. The Caf+ and Caf diets led to a significant increase of adipose tissue in cafeteria groups as observed in the Swat depot. The mRNA levels of PPARgamma and RXRalpha were significantly increased in the Caf+ group as compared to control group, with a significant positive correlation between these two parameters. Expressions of RARalpha and RARgamma were not modified in experimental groups compared to controls. In conclusion, 8-week exposure to cafeteria diets with normal and higher levels of vitamin A led to an increase of adiposity in rats, associated, only in the group fed with the higher vitamin A level cafeteria diet, with an increase of PPARgamma and RXRalpha expressions in subcutaneous adipose tissue.

Adipose Tissue↗

PubMed2003

Effect of tyramine, a dietary amine, on glycerol and lactate release by isolated adipocytes from old rats.

Amine degradation by adipocyte amine oxidases leads to the production of metabolites that interact with lipid and glucose metabolisms and their hormonal regulations. To further investigate these interactions, we determined the effect of a dietary amine, tyramine (TYR), on glycerol and lactate releases, respectively taken as indices of lipolytic and glycolytic activities of isolated adipocytes. Old male Wistar rats were used to prepare adipocytes by collagenase dissociation of retroperitoneal fat pads. The two tested doses of tyramine (10 microM and 1 mM) had no effect on basal glycerol release. On the other hand, TYR, at the highest dose tested (1 mM), weakly but significantly increased basal lactate release, which was elevated in adipocytes from old rats. Norepinephrine (NE), highly stimulated adipocyte lipolysis with a submaximal effect at 1 microM which was slightly but significantly inhibited by TYR 1 mM. Insulin 1 nM (INS) also poorly inhibited the NE-stimulated lipolysis in adipocytes isolated from old rats. TYR was able to potentiate the poor antilipolytic efficiency of INS. Under similar conditions, a high dose of NE greatly reduced lactate production and TYR (1 mM) reversed this inhibition of lactate release. INS was also able to totally reverse the inhibitory effect of NE on lactate release, but there was no potentiation between insulin and tyramine effects. It can be concluded that high doses of TYR interact with norepinephrine and insulin, at least on the control of glycerol and lactate release, by counteracting catecholamine effects and by mimicking insulin actions.

Adipocytes↗

PubMed1999

Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells.

Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3-isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and 4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a beta1-selective antagonist]. Octopamine had other properties in common with beta3-AR agonists: stimulation of oxygen consumption in rat brown fat cells and very low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less affinity than noradrenaline while it exhibited an affinity around 200-fold lower than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data suggest that, among the biogenic amines metabolically related to catecholamines, octopamine can be considered as the most selective for beta3-ARs.

Adipose Tissue↗

PubMed1998

Lipolytic and antilipolytic responses of the Siberian hamster (Phodopus sungorus sungorus) white adipocytes after weight loss induced by short photoperiod exposure.

Short day photoperiod promotes thermogenesis and extensive weight loss in Siberian hamsters (Phodopus sungorus sungorus). To determine whether a change in hormone-sensitive lipolysis occurs after short-photoperiod exposure, some lipolytic responses were measured on white adipocytes isolated from animals exposed in warm conditions to short or Long daylight photoperiod. The body mass of male Siberian hamsters exposed during 11 weeks to short days (SD; light: dark, 6:18 hr) reached only 50% of those kept in long days (LD; 16: 8 hr). In SD-hamsters, adipose depot mass also represented approximately 50% of the LD group. A lower DNA content was observed in intra-abdominal fat pads of SD-hamsters. Lipolytic responses to noradrenaline, adrenaline, isoproterenol and ACTH were unchanged. However, sensitivity to the beta-3 adrenergic agonist, BRL 37344, was moderately increased. The major component of the adrenergic control of lipolysis was mediated by beta-3 adrenoceptors in both LD- and SD-Siberian hamsters. The limited antilipolytic effect of alpha-2 adrenergic agonists, PYY or insulin was rather surprising in Siberian hamsters since these inhibitory systems are efficient in hibernants and other photoperiod-sensitive rodents. Our results show that, after short photoperiod exposure, white adipose tissue mass and DNA content are reduced, especially in the epididymal fat pad, with only minor changes in the adipocyte sensitivity to lipolytic hormones.

Adipocytes↗

PubMed1998

Effects of chronic treatment with noradrenaline or a specific beta3-adrenergic agonist, CL 316 243, on energy expenditure and epididymal adipocyte lipolytic activity in rat.

1. The effects of 7 days exposure to a specific beta3-adrenergic agonist, CL 316 243 (1 mg/kg x 24 hr), or to the physiological hormone, noradrenaline (5 mg/kg x 24 hr), were tested on energy expenditure and on in vitro lipolysis in male Sprague-Dawley rats. 2. At the second day of treatment, the total energy expenditure and the resting metabolic rate were increased by 20 and 30%, respectively, in the CL-treated group. Under the same conditions, a dose five times higher of NA increased the resting metabolic rate by 11% without any significant change in the total daily energy expenditure. 3. The CL-treated group showed a lower weight gain, correlated with a significant reduction in retroperitoneal adipose tissue weight. Both treatments resulted in a marked desensitization (increased EC50 values) of the NA stimulated lipolysis of epididymal adipocytes. The effects of both treatments on maximal lipolysis were opposite. Indeed, chronic NA-treatment decreased the responsiveness of lipolysis while chronic treatment with CL increased the maximal stimulation of lipolysis to NA. Furthermore, dose-response curve for CL on lipolysis showed a marked functional desensitization of beta3-adrenergic response. 4. Our results demonstrate the high selectivity of beta3-adrenergic agonists to stimulate whole body energy expenditure and lipid mobilization in rodents. The present results point out for the first time an adrenergic desensitization of the lipolytic response after chronic administration of a beta3-agonist.

Adipocytes↗

PubMed1997

Characterization of a melatonin binding site in Siberian hamster brown adipose tissue.

Melatonin has been shown, in various rodent species, to mediate photoperiodic effects on body weight and, consequently, fat mass. Pharmacological investigations indicated that the brown adipose tissue of Siberian hamsters possesses a melatonin binding site with a dissociation constant of 570+/-300 pM and a density of 3.2+/-1.8 fmol/mg protein. This binding site can also be detected on mature brown adipocyte membranes. The rank order of potency of a variety of drugs to displace 2-[125I]iodomelatonin from binding sites on Siberian hamster brown adipose tissue was as follows: 2-iodomelatonin > melatonin = prazosin > GR135531 (5-methoxycarbonylamino-N-acetyltryptamine) > N-acetylserotonin > 6-chloromelatonin > S20304 (N-(2-(1-naphthyl)ethyl)cyclobutanecarboxamide) >> methoxamine, phenylephrine, serotonin. Mel(1a) mRNA was not detected by RT-PCR (reverse transcription-polymerase chain reaction) in brown adipose tissue. Melatonin had no effect on either basal or stimulated lipolysis. Moreover, melatonin did not modify intracellular cAMP accumulation or inositol phosphate content. Together, these results suggest that the melatonin binding site characterized in brown adipose tissue is clearly different from the Mel(1) cloned subtype and has some features different from those of the Mel2 subtype.

Adipose Tissue, Brown↗

PubMed1997

Regional variation in adipose tissue insulin action and GLUT4 glucose transporter expression in severely obese premenopausal women.

Insulin action and GLUT4 expression were examined in adipose tissue of severely obese premenopausal women undergoing gastrointestinal surgery. Fat samples were taken from three different anatomical regions: the subcutaneous abdominal site, the round ligament (deep abdominal properitoneal fat), and the greater omentum (deep abdominal intraperitoneal fat). The stimulatory effect of insulin on glucose transport and the ability of the hormone to inhibit lipolysis were determined in adipocytes isolated from these three adipose depots. Insulin stimulated glucose transport 2-3 times over basal rates in all adipocytes. However, round ligament adipose cells showed a significantly greater responsiveness to insulin when compared to subcutaneous and omental adipocytes. Round ligament fat cells also displayed the greatest sensitivity and maximal antilipolytic response to insulin. We also investigated whether regional differences in fat cell insulin-stimulated glucose transport were linked to a differential expression of the GLUT4 glucose transporter. GLUT4 protein content in total membranes was 5 and 2.2 times greater in round ligament adipose tissue than in subcutaneous and omental fat depots, respectively. Moreover, GLUT4 mRNA levels were 2.1 and 3 times higher in round ligament than in subcutaneous or omental adipose tissues, respectively. Adipose tissue GLUT4 protein content was strongly and negatively associated (r = -0.79 to -0.89, p < 0.01) with the waist-to-hip ratio but not with total adiposity. In conclusion, these results demonstrate the existence of site differences in adipose tissue insulin action in morbidly obese women. The greater insulin effect on glucose transport in round ligament adipocytes was associated with a higher expression of GLUT4 when compared to subcutaneous abdominal and omental fat cells. Moreover, despite the regional variation in GLUT4 expression, an increased proportion of abdominal fat was found to be associated with lower levels of GLUT4 in all adipose regions investigated.

Adipocytes↗

PubMed1997

Role of beta1- and beta3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes.

To evaluate the physiological functions of beta1-, beta2-, and beta3-adrenoceptors (ARs) in brown adipose tissue, the lipolytic and respiratory effects of various adrenergic agonists and antagonists were studied in rat brown adipocytes. The beta-agonists stimulated both lipolysis and respiration (8-10 times above basal levels), with the following order of potency (concentration eliciting 50% of maximum response): CL-316243 (beta3) > BRL-37344 (beta3) > isoproterenol (mainly beta1/beta2) > norepinephrine (NE; mainly beta1/beta2) > epinephrine (mainly beta1/beta2) >> dobutamine (beta1) >> procaterol (beta2). Schild plot coefficients of competitive inhibition experiments using ICI-89406 (beta1 antagonist) revealed that more than one type of receptor mediates NE action. It is concluded from our results that 1) NE, at low plasma levels (1-25 nM), stimulates lipolysis and respiration mainly through beta1-ARs, 2) NE, at higher levels, stimulates lipolysis and respiration via both beta1- and beta3-ARs, 3) beta2-ARs play only a minor role, and 4) beta3-ARs may represent the physiological receptors for the high NE concentrations in the synaptic cleft, where the high-affinity beta1-ARs are presumably desensitized. It is also suggested that lipolysis represents the flux-generating step regulating mitochondrial respiration.

Adipocytes↗

PubMed1996

Beta 3-adrenoceptor in guinea pig brown and white adipocytes: low expression and lack of function.

In the guinea pig, cold acclimation induced a conversion of unilocular to multilocular adipocytes in interscapular (IS) and retroperitoneal (RP) fat depots but not in the epididymal (EP) fat pad. The conversion was associated with an increase in mitochondriogenesis and the appearance of the uncoupling protein. The maximal lipolytic responses to norepinephrine and dibutyryl adenosine 3',5'-cyclic monophosphate were decreased in IS cells, unchanged in RP cells, and increased in EP cells, suggesting a site-specific regulation of lipolysis at the postreceptor level. beta 3-Adrenergic agonists were not lipolytic regardless of the depot and the thermal environment of the animal. These agents did not inhibit glucose transport and lipogenesis, as was previously reported for rodents. Cloning and sequencing of the guinea pig beta 3-adrenoceptor gene revealed a slightly higher amino acid sequence similarity with the human than with the rodent beta 3-adrenoceptors. beta 3-Adrenoceptor transcripts were present at a very low level in guinea pig adipocytes, and mRNA levels did not increase to a significant extent after cold acclimation. The guinea pig thus differs from rodents by an absence of beta 3-adrenergic effects and by low beta 3-adrenoceptor expression in brown and white adipose tissues.

Acclimatization↗

PubMed1996

Effects of both a melatonin agonist and antagonist on seasonal changes in body mass and energy intake in the garden dormouse.

BACKGROUND: Many physiological functions including nycthemeral rhythm, reproductive cycles, body temperature and body mass are controlled by photoperiodic changes in different species. In the hibernating garden dormouse, both energy intake and body mass increase with the duration of the night. This seasonal mass gain is spontaneous and reversible. AIM: We have studied the occurrence of the increase of body mass by taking into account the endogenous variations of melatonin due to changing photoperiod or to pharmacological treatment. RESULTS: A single daily administration of either a melatonin agonist or antagonist just before night mimics the short day and long day effects, respectively. Compared to the control animals (natural photoperiod), the mass gain was greater and occurred earlier in animals under short days (6 h light (L)/18 h dark (D)) and in those receiving the melatonin agonist (S 20304). The animals treated with the antagonist (S 20928) during the same period exhibited no mass gain and their response was similar to that of the long-day group (16L/8D). Solely agonist treatment acted on metabolic rate. CONCLUSION: These results demonstrate that the duration of melatonin-receptor exposure per day determines the onset of seasonal obesity in garden dormice and, on the other hand, that restriction of melatonin-receptor exposure by pharmacological treatment prevents it.

Animals↗

PubMed1995

Characterization of beta 1- and beta 3-adrenoceptors in intact brown adipocytes of the rat.

1. The binding properties of beta 1-, beta 2- and beta 3-adrenoceptors were determined in isolated brown adipocytes of the rat rather than in membrane preparations from tissue homogenates, because typical brown adipocytes represent only about 40% of the various cells present in brown adipose tissue. Binding characteristics were assessed with the hydrophilic beta-adrenoceptor radioligand, (-)-[3H]-CGP 12177. The potent beta-antagonist, bupranolol (100 microM) was used to determine nonspecific binding. Characterization was essentially performed by saturation and competition studies. 2. The saturation curve of (-)-[3H]-CGP 12177 was clearly biphasic (Hill coefficient, nH = 0.57 +/- 0.11, P < 0.01) indicating the presence of two different beta-adrenoceptor populations of high (KD = 0.24 +/- 0.04 nM) and low (KD = 80 +/- 7 nM) affinity. The low affinity sites were more numerous (Bmax = 121,000 +/- 30,000 sites/cell) than the high affinity sites (Bmax = 12,000 +/- 1,000 sites/cell). 3. (-)-[3H]-CGP 12177 (25 nM) was displaced by adrenaline (Ad), noradrenaline (NA), isoprenaline (Iso), phenylephrine (Phe) and by the new beta 3 agonist, CL 316,243 (CL) in a biphasic pattern. The order of potency for (-)-[3H]-CGP 12177 displacement from the small population of high affinity sites (Iso >> NA > Ad >> CL >> Phe was in agreement with a beta 1/beta 2-classification. In contrast, the potencies of the same agonists for displacing the radioligand from the low affinity binding sites (CL >> Iso > NA > Ad >> Phe) revealed the presence of a distinct population of adrenoceptors obeying a beta 3-classification. 5-HT did not displace (-)-[3H]-CGP 12177 (25 nM) when used at concentrations as high as 0.1 mM.4. The beta-adrenoceptor antagonist, (-)-bupranolol, was more effective than (-)-propranolol for displacing(- )-[3H]-CGP 12177 (25 nM) from the high (Ki= 0.029 =/- 0.011 and 0.19 +/- 0.07 nM, respectively and low (Ki= 0.27 +/- 0.04 microM and 1.6 +/- 0.2 lM, respectively) affinity binding sites. The selective beta 1 antagonist CGP 20712A efficiently displaced the radioligand from a small population (Ki = 65 +/- 19 pM)of binding sites, confirming the presence of beta 1-adrenoceptors.5. To evaluate whether beta 2-adrenoceptors could be identified in the population of high affinity binding sites, displacement studies were performed at a low concentration of (- )-[3H]-CGP 12177 (4 nM) that mainly labelled beta 1/beta 2-adrenoceptors. ICI 118 551 ( a selective beta 2-antagonist) and procaterol (a selective beta 2-agonist) displaced (- )-[3H]-CGP 12177 from its binding sites with very low affinity (Ki = 0.17 +/- 0.02 micro M and Ki = 11 +/- 2 micro M respectively).6. From these observations, we conclude that: (1) two kinds of binding sites with low and high affinities for (-)-[H]-CGP 12177 can be detected in intact brown adipocytes, (2) there are 10 times more low than high affinity beta-adrenoceptors, as determined by saturation or competition curve analysis, (3) the high affinity binding sites mainly correspond to beta1-adrenoceptors, whereas the low affinity sites represent beta 3-adrenoceptors, and (4) beta 2-adrenoceptors are undetectable.7. It is suggested that the low affinity beta 3-adrenoceptors represent the physiological receptors for noradrenaline secreted from sympathetic nerve endings when the concentration of the neurohormone in the synaptic cleft is very high and/or when the high affinity beta 1-adrenoceptors are desensitized by prolonged sympathetic stimulation such as chronic cold exposure.

Adipocytes↗

PubMed1995

Regional variation in adipose tissue metabolism of severely obese premenopausal women.

Lipolytic and lipoprotein lipase (LPL) activities were studied in isolated human adipocytes obtained from two intraabdominal depots (round ligament and omental) and from the subcutaneous abdominal region of nine severely obese premenopausal women (with body mass indices ranging from 37 to 51 kg/m2), aged 36 +/- 3 yr, undergoing gastrointestinal surgery. Both fat cell weight and LPL activity were significantly greater in round ligament adipose cells than in subcutaneous abdominal or in omental adipocytes (P < 0.05). The antilipolytic effect of insulin and the sensitivity to this hormone were also higher in round ligament adipose cells than in omental adipocytes (P < 0.05). Although epinephrine initiated a similar biphasic profile of response in all cell types, the catecholamine promoted a weaker inhibition of lipolysis in omental adipocytes than in subcutaneous abdominal adipose cells (P < 0.05). In addition, a lack of regional variation was found in the maximal antilipolysis initiated by UK 14304 and the alpha 2-adrenoceptors was higher in both subcutaneous abdominal and round ligament fat cells than in omental adipocytes. Moreover, the maximal lipolytic response to isoproterenol or to agents acting at post-receptor levels was not different among fat depots. Finally, a lower beta-adrenergic lipolytic sensitivity associated with a reduced beta-adrenoceptor density was observed in round ligament as compared to omental adipose cells. These data suggest that in massively obese premenopausal women, omental and round ligament adipose tissues show distinct metabolic properties that may contribute to limit the impact of intraabdominal obesity.

Adipocytes↗

PubMed1994

Comparison of the lipolytic effects of norepinephrine and BRL 37344 in rat brown and white adipocytes.

The lipolytic effects of norepinephrine (a non-selective beta-agonist) and BRL 37344 (a selective beta3-agonist) were compared in isolated rat brown and white adipocytes. Norepinephrine and BRL 37344 maximally stimulated lipolysis in brown and white adipocytes, approximately 10 times above basal values. However, adipocyte sensitivity for BRL 37344 was greater than that for norepinephrine, particularly in brown adipocytes [the EC50 values (nM) for BRL 37344 and norepinephrine were 5 +/- 1 and 103 +/- 31 in brown adipocytes (P < 0.01) versus 56 +/- 9 and 124 +/- 17 in white adipocytes (P < 0.05), respectively]. On the other hand, the lipolytic effects of norepinephrine were totally blocked by 20-40 times superior concentrations of propranolol or bupranolol in brown as well as in white adipocytes. In contrast, the lipolytic effects of BRL 37344 were fully inhibited by concentrations of propranolol or bupranolol that were 200-1000 superior to the beta3 agonist concentration. The results demonstrate that: (1) the beta3-agonist BRL 37344 is as effective as norepinephrine for maximally stimulating lipolysis in rat brown and white adipocytes, (2) both adipocyte types are more sensitive to the lipolytic effects of BRL 37344 than to those of norepinephrine, (3) although bupranolol is a better antagonist than propranolol on BRL 37344-stimulated lipolysis, it cannot be considered as a specific beta3-antagonist, (4) brown adipocytes are 10 times more sensitive than white adipocytes to the lipolytic effects of BRL 37344, suggesting an important role of beta3-receptors in brown adipose tissue.

Adipocytes↗

PubMed1993

Specific decrease of mitochondrial thermogenic capacity in brown adipose tissue of obese SHR/N-cp rats.

The metabolic properties of brown adipose tissue (BAT), liver, and skeletal muscles were compared in lean and obese diabetic SHR/N-cp rats (a new model of type II diabetes) to test whether the severe insulin resistance of obese animals is specifically associated with a thermogenic defect in BAT. The respiratory response of brown adipocytes to norepinephrine and to agents bypassing the adenylate cyclase complex (dibutyryl cyclic AMP and palmitate) was decreased by two-thirds in obese rats, thereby indicating the presence of a major postreceptor defect. Significantly, total BAT cytochrome oxidase activity, uncoupling protein content, and mitochondrial guanosine 5'-diphosphate binding (3 indexes of BAT thermogenic capacity) were also decreased by two-thirds. The specific activities of these parameters expressed per total BAT mitochondrial protein were not altered either. This indicates that the total number of mitochondria per cell is decreased in BAT of obese rats. In contrast, total tissue cytochrome oxidase activity, protein content, and DNA content all increased by two to three times in the liver of obese SHR/N-cp rats, but these parameters remained unchanged in skeletal muscles (vastus lateralis and soleus). Such a remarkable liver hypertrophy may have occurred as a consequence of the persistent hyperphagia-hyperinsulinemia of obese rats that induced a hyperplasia and/or a hepatocyte polyploidization. This observation together with the fact that daily energy expenditure associated with food intake was markedly increased in obese rats (representing as much as 25% of the total energy expenditure) strongly suggests that the liver plays a major role in energy balance in these animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗

PubMed1993

Differential regulation of GLUT1 and GLUT4 glucose transporters in skeletal muscle of a new model of type II diabetes. The obese SHR/N-cp rat.

The obese diabetic SHR/N-cp rat is a newly developed strain that inherits obesity as an autosomal recessive trait. These rats display early-onset hyperinsulinemia and hyperglycemia, which are hallmarks of type II diabetes. This study was undertaken to determine the expression and the subcellular distribution of the GLUT1 and GLUT4 glucose transporters in skeletal muscle of obese diabetic SHR rats. D-glucose-protectable cytochalasin-B binding to subcellular membrane fractions of hindlimb muscles was used to determine glucose transporter number. GLUT1 and GLUT4 glucose transporter isotypes were detected using antibodies to the COOH-terminal region of the GLUT1 and GLUT4 proteins. Glucose transporter number was significantly lower (-40%) in crude unfractionated membranes of obese diabetic SHR than of lean SHR muscles. When crude membranes were fractionated to separate plasma membranes and the intracellular membranes containing glucose transporters, the number of cytochalasin-B binding sites was found to be markedly lower (-50%) in intracellular membranes and slightly but not significantly reduced (-20%) in plasma membranes of muscle from obese diabetic SHR compared with lean SHR rats. Western blot analysis revealed that a lower GLUT4 protein abundance (-40%) accounts for the reduced glucose transporter number in intracellular membranes of obese diabetic SHR compared with lean SHR muscles. GLUT4 protein content was also reduced by 50% in plasma membranes from obese SHR muscles relative to lean rat muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗