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Biomedical subjects

J Seydoux

Publications and source records attributed to J Seydoux.

At least 73 records · Page 4Linked to original sources
PubMed1988

Discrepancies between the affinities of binding and action of the novel beta-adrenergic agonist BRL 37344 in rat brown adipose tissue.

The novel brown adipose tissue (BAT) selective beta-adrenergic agonist, BRL 37344, is 31-fold more potent than (-)-isoproterenol in stimulating the respiratory rate of interscapular BAT fragments. BRL 37344 is also more potent (9-fold) than (-)-isoproterenol in stimulating adenylate cyclase activity of IBAT purified plasma membranes whereas, in the same preparation, it is 81-fold less potent than (-)-isoproterenol in competition displacement studies with the beta-adrenergic ligand, [125I]cyanopindolol. We have previously demonstrated that the photoaffinity reagent [125I]cyanopindolol-diazirine selectively labels a 62 kDa protein in IBAT plasma membranes that displays pharmacological properties of a beta 1-adrenergic subtype. Relatively high concentrations of BRL 37344 (10 microM) are required to displace [125I]cyanopindolol-diazirine binding to the 62 kDa protein. Taken together, the results suggest that two different populations of beta-adrenergic receptors may co-exist in BAT plasma membranes: a small population (about 15%) of atypical beta-receptors and a large population of beta 1-receptors that exhibit high and low affinities for BRL 37344, respectively.

Adenylyl Cyclases↗
PubMed1988

Prepontine knife cut-induced hyperthermia in the rat. Effect of chemical sympathectomy and surgical denervation of brown adipose tissue.

The effect of brown adipose tissue (BAT) denervation on the prepontine knife cut-induced hyperthermia was studied. The knife cut has earlier been shown to induce a steady state hyperthermia of 3 to 4 degrees C, as a result of marked activation of the BAT. Before the lesion, the interscapular BAT (IBAT) temperature was lower than the colonic temperature, but the temperature gradient reversed a few minutes after the lesion and the fractional blood flow increased 12-fold. Bilateral sectioning of the 5 nerves supplying IBAT did not modify either the magnitude or the kinetics of the IBAT hyperthermic response. The IBAT fractional blood flow, which was 15 times higher in denervated than in intact tissue before the lesion, scarcely increased following the lesion despite the sharp increase in the tissue's metabolic activity. Chemical sympathectomy with 6-hydroxydopamine suppressed the hyperthermic response. Propranolol or hexamethonium injected i.v. during the steady state hyperthermia resulted in a rapid drop in IBAT temperature and in a reversal of the gradient between IBAT and colonic temperature both in denervated and in intact IBAT. Injection of desipramine, an inhibitor of noradrenaline reuptake, resulted in itself in an increase of temperature in both intact and denervated tissue, which is circumstantial evidence for the presence of a functional residual innervation in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1988

Evidence for a modulating effect of Na+/H+ exchange on the metabolic response of rat brown adipose tissue.

Membrane potential and intracellular pH (pHi) were simultaneously monitored in rat perifused brown adipose tissue fragments by means of double-barrelled microelectrodes. In parallel experiments, the respiratory rate was measured. The cytosolic pH of unstimulated brown adipocytes was about 0.5 units higher than the value expected for a passive transmembrane distribution of H ions. Isoproterenol (5.10(-10)M) had no effect on pHi and membrane potential while it induced a 3.1 +/- 0.5-fold increase of the respiratory rate. Clonidine (10(-7)M) alone was followed by a cytosolic alkalinization of 0.14 +/- 0.05 pH units with no concomitant increase in the respiratory rate. A mirror image of the intracellular alkalinization induced by clonidine, i.e. an acidification of 0.09 +/- 0.03, was noted by monitoring the extracellular pH. Addition of clonidine in the presence of isoproterenol induced an alkalinization of 0.17 +/- 0.03 pH units and a 7.7 +/- 1.0-fold increase of the respiratory rate. Thus the alkalinizing effect of clonidine developed despite a massive increase in CO2 production. Pretreatment of the preparation with amiloride (10(-3)M), an inhibitor of Na+/H+ exchange, completely prevented the alkalinization and markedly reduced the potentiating effect of clonidine on the isoproterenol-induced respiratory rate. The results obtained are compatible with the hypothesis of a modulating effect of Na+/H+ exchange on the brown adipocyte metabolic response to catecholamine stimulation.

Adipose Tissue, Brown↗
PubMed1988

Increased plasma clearance rate of thyroxine despite decreased 5'-monodeiodination: study with a peroxisome proliferator in the rat.

In euthyroid rats a 17-day treatment with nafenopin, a hypolipidemic agent and peroxisome proliferator, decreased serum total and free T4 concentrations to 32 +/- 5% and 62 +/- 8% (mean +/- SEM; n = 10), respectively, with no change in serum T3 and TSH concentrations. In methimazole-treated rats infused with 3 nmol T4/day/100 g BW, the nafenopin inhibitory effect was not significantly different from that in euthyroid rats. Nafenopin treatment had the following effects on peripheral T4 and T3 metabolism in euthyroid rats. The plasma clearance rate of T4 (PCR), which was measured by Alzet minipump infusion of tracer, was increased 2-fold (1.58 +/- 0.09 vs. 0.82 +/- 0.06 ml/h.100 g BW; P less than 0.001; n = 5), while the PCR of T3 was decreased (37.5 +/- 1.3 vs. 53.8 +/- 1.8; P less than 0.001; n = 5). The fecal clearance rate of radioactivity derived from T4 was increased 2-fold (1.93 +/- 0.10 vs. 0.77 +/- 0.07 ml/h.100 g BW), whereas the urinary clearance rate was not significantly modified. The 5'-deiodinase (5'D) activity, measured by deiodination of labeled rT3, was strongly inhibited in liver and kidney, not modified in brown fat and anterior pituitary, and increased in cerebral cortex. In methimazole-treated rats substituted with isopropyl-diiodothyronine only hepatic 5'D activity was decreased. It is concluded that the decrease in serum total and free T4, without alteration in serum T3 and TSH concentrations, resulting from nafenopin treatment is mainly due to changes in peripheral T4 and T3 metabolism, since it is also observed in T4-substituted animals. The increased PCR of T4 cannot be explained by an increase in deiodination activity, since the major 5'D pathways are inhibited after nafenopin treatment, and the urinary clearance rate is not modified. It can partly be explained by an increase in the fecal clearance rate of T4, which could be due to an increase in glucoronoconjugation. In addition, nafenopin was found to be a weak competitor of T4 binding to serum proteins, leading to a small increase in the free T4 fraction which might also contribute to the increased T4 PCR. The decrease in T3 PCR remains to be explained.

Adipose Tissue, Brown↗
PubMed1987

Hyperthermia induced by pre-pontine knife-cut: evidence for a tonic inhibition of non-shivering thermogenesis in anaesthetized rat.

Temperature of colon, interscapular brown adipose tissue (IBAT) and paw skin (index of vasomotor activity) were monitored before and after microwire knife lesions at the pre-pontine or/and the post-mammillary levels in the urethane-anaesthetized rats at room temperature of 23-24 degrees C. Following the pre-pontine, but not the post-mammillary cut, colonic and IBAT temperatures increased by 3-4 degrees C within 90-240 min. IBAT temperature rose faster with a shorter latency and attained a higher steady-state value than colonic temperature; skin temperature, however rose by only 0.8 degrees C. A procaine microinjection into the pre-pontine area transiently increased by more than 1 degree C both colonic and IBAT temperatures, with similar kinetics as for the knife cut. Cardiac output distribution was measured using radiolabelled microspheres. Brown adipose tissue (BAT) was found to be the only organ to which the fractional blood flow increased dramatically (12 times over baseline value) during the development of hyperthermia. Propanolol, injected after the hyperthermia had fully developed, decreased IBAT and then colonic temperatures. Hexamethonium decreased both colonic and IBAT temperatures with a concomitant rise in skin temperature while tubocurarine was without effect. It is concluded that the hyperthermia observed after the pre-pontine lesion results from an increased sympathetic stimulation of BAT thermogenesis triggered by the release of a tonic inhibitory control on its heat production. Such an inhibitory system would be located somewhere between the lower midbrain and the upper pons.

Adipose Tissue, Brown↗
PubMed1986

Effect of nafenopin, a peroxisome proliferator, on energy metabolism in the rat as a function of acclimation temperature.

The effects of the peroxisome proliferator, nafenopin, on body temperature, apparent gross food efficiency and activity of interscapular brown adipose tissue (IBAT) peroxisomes and mitochondria of rats acclimated at 23 degrees C or at 32 degrees C have been studied. In 23 degrees C-acclimated rats, nafenopin treatment induced an atrophy of IBAT characterized by a decrease of tissue wet weight, of amounts of mitochondrial and peroxisomal proteins and of mitochondrial total succinate dehydrogenase activity to 67%, 67%, 65% and 57%, respectively of control values. It also resulted in a 1.9-fold stimulation of peroxisome total acyl CoA oxidase activity and had no effect on apparent gross food efficiency or colonic temperature. Acclimation at 32 degrees C per se induced an atrophy of IBAT and a decrease of total catalase and acyl CoA oxidase activities to 23% and 35%, respectively of values obtained in rats acclimated at 23 degrees C. Nafenopin treatment had no effect on IBAT wet weight, on the amounts of mitochondrial and peroxisomal proteins or on total succinate dehydrogenase activity; it resulted in a 2.9- and a 3.7-fold stimulation of the catalase and acyl CoA oxidase activities, respectively with no change in IBAT oxygen consumption. Apparent gross food efficiency was decreased to 54% of control value and colonic temperature increased by 0.91 degrees C. These results may be interpreted in the following way: nafenopin may, at 23 degrees C ambient temperature, induce an extra-heat production in other tissues than IBAT. This extra-heat production is fully compensated via the thermoregulatory feedback control. This compensation cannot occur at thermoneutrality.

Acclimatization↗
PubMed1985

Hypothalamic opioids and the acute-phase glycoprotein response in guinea pigs.

Endogenous opioids (EO) probably do not modulate endotoxin (LPS)- or interleukin 1 (IL1)-induced fever because naloxone does not prevent its development. Yet, increases in CSF and hypothalamic levels of beta-endorphin have been reported during LPS-and IL1-induced fevers. Since IL1 also reduces the specific binding of opioids to their receptors in guinea pig brain, the opioids could be involved in modulating nonfebrile effects of IL1. To determine whether EO might have a role in the IL1-induced acute-phase glycoprotein response of guinea pigs, (1) naloxone (5 and 10 mg/kg, SC) was injected prior to LPS (S. enteritidis 2 micrograms/kg, IV; N = 5), and (2) morphine (MOR, 10 micrograms/microliter), [D-ala2]-met-enkephalinamide (DAME, 5 micrograms/microliter), or dynorphin A (DYN, 5 micrograms/microliter) was injected into the preoptic area (1 microliter, bilaterally; N = 8/treatment) or into the 3rd ventricle (N = 4/treatment); pyrogen-free saline was the control injection. Measurements were: core temperature (Tco) and, as indices of acute-phase glycoproteins, plasma levels of copper (Cu) and N-acetylneuraminic acid (NANA). Naloxone did not prevent the fever or the increases in plasma Cu and NANA levels evoked by LPS. The intracerebral administration of opioid agonists by either route induced variable rises in Tco, each with a different pattern, but no increases in plasma Cu and NANA levels. Thus, EO do not participate in the central modulation of acute-phase glycoprotein synthesis, but may have a role in influencing other nonthermal IL1 effects in the CNS.

Acute-Phase Proteins↗
PubMed1984

Modulation of beta-oxidation and proton conductance pathway of brown adipose tissue in hypo- and hyperinsulinemic states.

The metabolic capacity of interscapular brown adipose tissue of hypoinsulinemic (diabetic) rats is decreased and a reduced beta-oxidative capacity contributes to this metabolic alteration. It was thus of interest to compare, in diabetic and in chronically (8 days) insulin-infused rats, the beta-oxidative capacity and indices of the thermogenic state (GDP-binding and 32 000 Mr protein) in this tissue. Mitochondrial GDP-binding and 32 000 Mr protein were both decreased in diabetic rats compared to appropriate controls and markedly increased as was also the beta-oxidative capacity in hyperinsulinemic rats.

Adipose Tissue↗
PubMed1983

Fatty acid utilization and purine nucleotide binding in brown adipose tissue of genetically obese (ob/ob) mice.

The activities of the main enzymes involved in fatty acid utilization i.e. palmitoyl CoA synthetase as well as peroxisomal and mitochondrial beta-oxidation were measured in brown adipose tissue homogenates of lean and ob/ob mice kept at 23 degrees C or acclimated at 4 degrees C. The proton conductance pathway, i.e. the number of purine nucleotide (GDP) binding sites and the percentage of 32,000 polypeptide in brown adipose tissue mitochondria were also measured. In the ob/ob mice at 23 degrees C, the specific activities of the palmitoyl CoA synthetase and of the beta-oxidation as well as the number of GDB binding sites were lower than in the lean mice by 26%, 43% and 37%, respectively. The percentage of 32,000 polypeptide, however, was the same in both groups. In the ob/ob mice at 23 degrees C, the lower homogenate beta-oxidation specific activity was due to the fact that the peroxisomal and mitochondrial specific activities were 44% and 37% lower, respectively. Cold acclimation at 4 degrees C was found to cause an increase of the palmitoyl CoA synthetase specific activity, of the palmitoyl CoA synthetase and peroxisomal beta-oxidation total activities and of the number of GDP binding sites, in both lean and ob/ob mice. Cold acclimation increased the percentage of 32,000 polypeptide in the ob/ob mice only.

Adipose Tissue, Brown↗
PubMed1983

Brown adipose tissue metabolism in streptozotocin-diabetic rats.

Defects of both diet-induced thermogenesis and cold tolerance have been reported for streptozotocin-diabetic rats. Since brown adipose tissue (BAT) is a major effector of both diet- and cold-induced thermogenesis in the rat, the possible cause of these defects was investigated by comparing BAT metabolism under basal conditions and during activation by nerve stimulation, norepinephrine (NE), or octanoate addition in both streptozotocin-diabetic rats and in controls. The following metabolic indices were measured in rat interscapular BAT (IBAT): 1) tissue composition, 2) heat production rate as measured by direct microcalorimetry, 3) redox state of flavoproteins linked to the acyl-coenzyme A dehydrogenase pathway as measured by reflection spectrometry, 4) redox state of NAD(P) as measured by surface-emitted fluorescence, and 5) fatty acid activation and beta-oxidation activities in IBAT homogenate. In streptozotocin-diabetic rats, IBAT was atrophied (DNA content unmodified, protein and lipid content decreased). The basal and NE-stimulated total heat production rates showed a 75% and 56% decrease, respectively. The specific activity of fatty acid beta-oxidation as measured by flavoprotein redox state or enzymatically was decreased by 52% and 59%, respectively. The basal redox level of NAD(P) was about 3 times higher than in the controls and NE stimulation resulted in oxidation in contrast to the reduction observed in control tissues. These results show that the metabolic capacity of IBAT from streptozotocin-diabetic rats is decreased and further suggest that the reduced capacity for beta-oxidation contributes significantly to the metabolic alteration.

Adipose Tissue, Brown↗
PubMed1982

Impaired metabolic response to nerve stimulation in brown adipose tissue of hypothyroid rats.

In brown adipose tissue of the rat, chemically or surgically induced hypothyroidism caused the following effects. A large decrease of the magnitude of the metabolic response to electrical nerve stimulation. The deactivation half-time of the response was reduced to 70% of the control value, with no change in catechol O-methyltransferase activity. Pre-incubation of tissues with norepinephrine, 10(-5) M, increased the response to subsequent nerve stimulation almost to that of the controls. The catecholamine analogue dose-response curves were shifted to the right. The shift was very pronounced for isoproterenol (K50 426 nM versus 2 nM), somewhat less marked for norepinephrine (7373 nM versus 194) and very slight for phenylephrine (2803 nM versus 1649); there was almost no change in Emax values. An increase of octanoate oxidative capacity. A decrease of the capacity of the stereoselective binding of (-)-[3H]dihydroalprenolol of the high-affinity (Kd 2.0 nM) sites to a fourth of the control value and an increase by a factor of 2.9 of the Kd of the low-affinity binding sites. This decrease of binding to the beta-receptors was not sufficient quantitatively to explain the decrease in the metabolic response, suggesting the existence of an additional defective reaction which could occur between the binding to the beta-receptors and the activation of the triglyceride lipase. These results show that the sharp decrease of the metabolic response of brown adipose tissue to nerve stimulation has multiple causes. The findings are discussed in the context of the drastic decrease of cold resistance in hypothyroid rats.

Adipose Tissue, Brown↗
PubMed1982

Alterations of brown adipose tissue in genetically obese (ob/ob) mice. I. Demonstration of loss of metabolic response to nerve stimulation and catecholamines and its partial recovery after fasting or cold adaptation.

Metabolic responses to electrical nerve stimulation or norepinephrine of isolated interscapular brown adipose tissue (BAT) from lean and ob/ob mice were studied using either continuous monitoring of the NAD(P)H/NAD(P) redox state or direct microcalorimetry. The responses to these sympathetic stimuli were not significantly different from zero in BAT of ob/ob mice kept at 22 C and fed ad libitum. The metabolic rate of BAT of lean mice was stimulated 3-fold by norepinephrine. ob/ob mice are hyperglycemic and hyperinsulinemic; cold adaptation further increased their plasma glucose, and fasting decreased the levels of both glucose and insulin to normal values. Both fasting and cold adaptation at 5 C partially restored the tissue metabolic response of ob/ob mice, whereas a decreased sensitivity was observed in the tissue of lean mice. The results of these experiments are compatible with the hypothesis that the impaired capacity of BAT of ob/ob mice to produce heat could be one of the causes of their high food efficiency and their inability to withstand acute cold exposure.

Acclimatization↗
PubMed1982

Alterations of brown adipose tissue in genetically obese (ob/ob) mice. II. Studies of beta-adrenergic receptors and fatty acid degradation.

beta-Receptor number, norepinephrine-stimulated adenylate cyclase activity and lipolysis, octanoate-induced NAD(P) redox changes, and heat production were studied in brown adipose tissue (BAT) of lean and obese (ob/ob) mice. beta-Receptor number was increased 1.54-fold in purified brown adipocyte plasma membrane of ob/ob mice compared to that in lean controls. This increase was reversed by cold adaptation (5 C). Basal and norepinephrine-stimulated adenylate cyclase values were not different in the two groups. Norepinephrine stimulated lipolysis at 10 nM in BAT of lean mice, but only at 10 microM in BAT ob/ob mice. Octanoate produced an increase in the NAD(P) redox state in BAT of lean mice, but it did not modify the NAD(P) redox state in BAT of ob/ob mice. Concomitantly, octanoate increased heat production 3-fold in BAT of lean mice, but did not promote any significant increase in heat production in BAT of ob/ob mice. These two parameters were restored toward values observed in lean mice when the ob/ob mice were adapted to a cold environment. The data indicate that BAT of ob/ob mice exhibits three alterations; one at the level of the beta-receptor, one at the level of the lipolytic response to norepinephrine, and one at the level of fatty acid activation and/or beta-oxidation.

Adenylyl Cyclases↗
PubMed1981

Functional disconnection of brown adipose tissue in hypothalamic obesity in rats.

The metabolic responses to electrical nerve stimulation, norepinephrine or octanoate additions were studied using continuous monitoring of NAD(P)H/NADP redox state by reflexion spectrophotometry of interscapular brown adipose tissues from control and ventromedial hypothalamic (VMH) lesioned rats. The responses to these stimuli were all greatly decreased already 3 days after VMH lesions, indicating a reduced cell capacity to oxidize free fatty acids. Measurements of interscapular brown adipose tissue composition 4-5 weeks after VMH lesions showed a decrease of both DNA concentration and total content, indicating some tissue involution. It is concluded that the involvement of the ventromedial hypothalamus in the activation of brown adipose tissue provided a possible anatomical clue concerning pathways connecting thermal and weight regulations.

Adipose Tissue, Brown↗