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Biomedical subjects

B Jeanrenaud

Publications and source records attributed to B Jeanrenaud.

At least 73 records · Page 4Linked to original sources
PubMed1991

Effects of a peroxisome proliferator on beta-oxidation and overall energy balance in obese (fa/fa) rats.

The aim of the study was to examine in the obese Zucker (fa/fa) rats the effect of a peroxisome proliferator nafenopin on liver and brown adipose tissue peroxisomal and mitochondrial beta-oxidation enzyme activities and on the overall energy dissipation. A 17-day nafenopin treatment increased liver wet weight 2.1-fold and liver total acyl-CoA oxidase and mitochondria beta-oxidative activities 32- and 4.6-fold, respectively. It increased the interscapular brown adipose tissue (IBAT) acyl-CoA oxidase activity 2.1-fold but had no effect on the mitochondria beta-oxidative activity. Because nafenopin was found to decrease food intake by 22%, obese nafenopin-treated rats were compared with a group of obese pair-fed rats. Both food restriction and nafenopin treatment decreased body weight gain, but a decrease (14%) in fat content was only observed in nafenopin-treated rats. Food restriction of obese rats decreased the mean metabolic rate by 13%, and nafenopin treatment prevented this decrease. Both food restriction and nafenopin treatment decreased the mean daily respiratory quotient (RQ). However, the RQ of nafenopin-treated rats was steadily lower than that of control, whereas that of food-restricted rats was the same as that of control animals during the feeding period and decreased when food supply was exhausted. The increase in liver and IBAT fatty acid beta-oxidative activities may be the cause of the decreased lipid accretion measured in obese rats.

Adipose Tissue↗
PubMed1991

Insulin secretory response to secretagogues by perifused islets from chronically glucose-infused rats.

Perifused islets from rats infused for 7 days with 40% glucose exhibited an altered secretory response to selected stimuli. Both phases of insulin release were blunted when 20 mM L-leucine was tested; the secretory response to a subsequent leucine stimulation was also blunted compared with the control group. The ability of 20 mM alpha-ketoisocaproate to stimulate the release of insulin was also greatly diminished in islets from glucose-infused rats. The secretory response to 50 microM tolbutamide plus 7 mM glucose by perifused islets from glucose-infused rats was 45% lower than in the control group. In addition, the response to a subsequent 10 mM glucose stimulation was lost. On the other hand, islets from glucose-infused rats responded to 20 microM forskolin plus 16.7 mM glucose with on significant change in the amount of insulin released during both phases of stimulation compared with the control group. The response to 100 nM phorbol 12-myristate 13-acetate was 3.1-fold higher in islets from glucose-infused compared with saline-infused rats. The finding that chronic infusions of glucose lead to selective impairment of the secretory response to fuel stimuli and agents such as tolbutamide that act on metabolically regulated K+ channels gives support to the notion that alterations in the generation of metabolic coupling signals might be involved in the phenomenon described here.

Animals↗
PubMed1991

Evolution of insulin secretory response to glucose by perifused islets from lean (FA/FA) rats chronically infused with glucose.

Chronic infusion of nondiabetic rats with glucose for up to 7 days modified the insulin secretory response by subsequently perifused islets. Thus, on the 1st day of infusion with 40% glucose, the islets responded to 16.7 mM glucose with a 3.9-fold increase in insulin release during the first 10 min with no significant change during the second-phase insulin output compared with the control group. On the 2nd day, there was a 2-fold enhancement of insulin release during the initial 10 min of stimulation, the second phase being a similar to control islets. On the 5th day of infusion, the pattern of insulin release was not significantly different from the control group. After 7 day of infusion, there was a 46% decrease in first-phase and a 33% decrease in second-phase insulin response to glucose. The response to 10 mM arginine plus 5 mM glucose was not modified by chronic glucose infusion. Priming experiments indicate that islets from rats infused for 7 days were not able to recover the normal pattern of secretion in vitro. Islets from 7-day glucose-infused rats contained 75% more protein and had a significantly higher insulin content than control islet, suggesting that insulin synthesis is not involved in the loss of the response observed. Glucose metabolism by the islets was modified by glucose infusion with a significant increase in glucose utilization and no changes in glucose oxidation, suggesting that alterations in mitochondrial oxidative events are involved in the phenomenon of desensitization.

Animals↗
PubMed1991

Aspects of neuroregulation of body composition and insulin secretion.

Perturbances in the autonomic nervous control of different target tissues (e.g. endocrine pancreas, brown adipose tissue) are present in the genetically obese (fa/fa) rat. These disorders are probably secondary to central dysregulation(s). In view of the reported effects of CRF in stimulating sympathetic nerve-mediated mechanisms while inhibiting vagus nerve-mediated ones, ovine CRF (oCRF) was administered for 7 days into the cerebral ventricles of fa/fa rats. oCRF treatment stopped the excessive weight gain of the obese animals. The oCRF effect was unrelated to changes in food intake, as the two groups were pair-fed. oCRF-treated obese rats were characterized by a decrease in basal hyperinsulinemia, increases in brown adipose tissue weight and activity, and decreases in hepatic glycogen content and epididymal fat pad weight. It is suggested that intracerebroventricular oCRF administration to obese fa/fa rats prevents the increase in body weight observed in vehicle-infused obese rats by modulating the impaired autonomic nervous control of different target tissues. This does not occur in lean rats.

Adipose Tissue↗
PubMed1990

Contribution of glycerol and alanine to basal hepatic glucose production in the genetically obese (fa/fa) rat.

Increased hepatic glucose production has been reported to occur in the insulin-resistant genetically obese fa/fa rats. The possible existence of an increased basal gluconeogenesis in obese rats was investigated, upon comparing the metabolic fate of glycerol and alanine in liver of fed anaesthetized lean and genetically obese (fa/fa) rats. Glycerol turnover rate in obese animals was 3 times that of the lean. This increase in glycerol turnover rate was associated with an increase in blood glycerol levels in obese animals. The contribution of glycerol to glucose production was significantly increased in obese animals. In contrast, the contribution of alanine to the hepatic glucose production was similar to lean and obese animals. A higher incorporation of glucose, glycerol and alanine into hepatic lipids was observed in obese animals than in controls. It is concluded that in fed genetically obese (fa/fa) rats the high blood glycerol concentrations is a major driving force for the increased basal hepatic conversion of this substrate into glucose.

Alanine↗
PubMed1990

Insulin activates 6-phosphofructo-2-kinase and pyruvate kinase in the liver. Indirect evidence for an action via a phosphatase.

The effect of insulin on hepatic glucose production has been studied in anesthetized rats in the postabsorptive state. Insulin decreases significantly hepatic glucose production within 5-10 min. It also increases the level of fructose 2,6-bisphosphate, via an increase in the Vmax of 6-phosphofructo-2-kinase and concomitantly decreased the activity of fructose-2,6-bisphosphatase, resulting in a 5-fold increase in the ratio of kinase/phosphatase. Insulin also increased the apparent Kd of pyruvate kinase for phosphoenolpyruvate. The changes in the activity of 6-phosphofructo-2-kinase and pyruvate kinase were measured after separation from possible modulators, and suggest a decrease in their phosphorylation state which cannot be attributed to a decrease in the level of cAMP or in the activity of cAMP-dependent protein kinase since these two parameters were not modified by insulin. In addition, neither the activity of phosphorylase a nor that of glycogen synthase were modified. The data strongly suggest that the increase in the glycolytic rate plays a role in the effect of insulin on hepatic glucose production and that insulin mediates its effect on the activity of these enzymes via one or more phosphatases.

Adenosine Triphosphate↗
PubMed1990

Metabolic consequences of hyperinsulinaemia imposed on normal rats on glucose handling by white adipose tissue, muscles and liver.

The effects of hyperinsulinaemia imposed on normal rats on the subsequent insulin-responsiveness in vivo of 2-deoxy-D-glucose uptake of white adipose tissue and of various muscle types were investigated. This was done by treating normal rats with insulin via osmotic minipumps, and by comparing them with saline-infused controls. Hyperinsulinaemia produced by prior insulin treatment resulted in a well-tolerated hypoglycaemia. At the end of the treatment, the glucose utilization index of individual tissues was determined by euglycaemic/hyperinsulinaemic clamps associated with the labelled 2-deoxy-D-glucose method. Prior insulin treatment resulted in increased insulin-responsiveness of the glucose utilization index of white adipose tissue, and in increased total lipogenesis in white adipose tissue and fat-pad weight. In contrast, prior insulin treatment resulted in a decreased glucose utilization index of several muscles. These opposite effects of hyperinsulinaemia on glucose utilization in white adipose tissue and muscles persisted when the hypoglycaemia-induced catecholamine output was prevented (adrenomedullectomy, propranolol treatment), as well as when hypoglycaemia was normalized by concomitant insulin treatment and glucose infusion. Insulin suppressed hepatic glucose production during the clamps in insulin-treated rats as in the respective controls, whereas total hepatic lipid synthesis and liver fat content were greater in rats treated with insulin than in controls. It is concluded that hyperinsulinaemia itself could be one of the driving forces responsible for producing increased glucose utilization by white adipose tissue, increased total lipid synthesis with fat accumulation in adipose tissue and the liver, together with an insulin-resistant state at the muscular level.

Adipose Tissue↗
PubMed1990

Ocular complications in the old and glucose-intolerant genetically obese (fa/fa) rat.

Genetically obese fatty (fa/fa) male rats with abnormal oral glucose tolerance associated with initial hyperinsulinaemia as well as control lean (FA/FA) rats were investigated for the development of retinal microangiopathies. The animals were kept on a standard or sucrose supplemented diet. When tested at 60 weeks, the glucose intolerance of fa/fa rats was accompanied by an insulin response that was now either comparable to that of lean rats (standard diet) or close to nil (sucrose supplemented diet). At killing (68 weeks of age), retinal vasculature was examined by electron microscopy and morphological changes were quantitatively assessed by ultrastructural morphometry. A retinal microangiopathy was observed in all mutant animals which was more pronounced in the sucrose fed group, and which was characterized by: (1), an increase in focal thickenings and in nodules of the basement membrane adjacent to the perivascular glial cells: (2), a decrease in the number of pericyte nulei with concomitant signs of early degenerative cytoplasmic changes of pericytes; (3), an increase in the pinocytic activity of endothelial cells, indicative of presumptive changes in vascular permeability; (4), an increase in the number of intercellular endothelial junctions; (5), the presence of numerous stimulated platelets within capillaries. The fa/fa rat may thus be considered as a suitable model for studying the pathophysiology of ocular complications, in particular retinopathy accompanying non-insulin-dependent diabetes.

Animals↗
PubMed1990

Neuro-humoral control of insulin secretion.

Hypothalamic extract from normal rats was shown to contain a principle able to stimulate insulin secretion both in vivo and in vitro. This substance, whose peptidic nature was demonstrated by enzymatic digestion, has a molecular weight of about 1000 Daltons. An active release of this peptide was obtained when incubating hypothalamic fragments under appropriate stimulatory conditions (i.e. KCl 50 mmol l-1 in the incubation medium) (i.e. molecular weight and insulin secretion stimulating activity) similar to the hypothalamic peptide was evidentiated in the plasma of normal rats. Since manipulations of hte hypothalamus (i.e. electrical lesions or stimulations) could respectively decrease or enhance the plasma concentration of this substance, the hypothalamic origin of the insulin secretion stimulating principle present in the plasma was strongly suggested. The possible participation of this hypothalamic peptide to the neural control of insulin secretion is suggested.

Animals↗
PubMed1990

Vagal mediation of corticotropin-releasing-factor-induced increase in insulinemia in lean and genetically obese fa/fa rats.

The effects of intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) on plasma glucose and insulin levels were investigated in lean Zucker (FA/FA) rats; i.c.v. CRF induced a rapid (within 1 min), marked, but transient increase in insulinemia that was not accompanied by any change in glycemia. At a time when insulinemia already returned toward basal values, glycemia started to increase. The effect of i.c.v. CRF in stimulating plasma insulin levels was dose-dependent and could be blocked by pretreatment of the animals with atropine methylnitrate. Similar results were obtained when studying the acute effects of i.c.v. CRF in genetically obese (fa/fa) rats. Although, in absolute values, the amount of insulin released in response to i.c.v. CRF was higher in obese than in lean animals, it was similar in both groups of rats, when expressed as fold increase over basal insulin levels. In summary, i.c.v. CRF elicits a rapid, vagally mediated stimulatory effect on insulin secretion both in lean and genetically obese fa/fa rats with no qualitative or quantitative difference between the two groups of animals. The site(s) of action of this CRF effect on insulinemia remains to be elucidated.

Adrenocorticotropic Hormone↗
PubMed1990

Abnormal regulation of the hypothalamo-pituitary-adrenal axis in the genetically obese fa/fa rat.

Adrenalectomy has been shown to reverse most facets of the syndrome of the genetically obese fa/fa rat. However, a detailed analysis of the hypothalamo-pituitary-adrenal (HPA) axis in these animals is lacking. In the present study, morning corticosteronemia was higher in obese rats of both sexes than in lean ones, whereas evening corticosteronemia was higher only in obese male rats. The HPA axis was further investigated using stressful stimuli. Immobilization, ether, and cold stresses resulted in greater corticosterone levels in obese than in lean animals. These abnormalities consisted in upward shifts of the corticosterone response in obese females and absolute increases in that of obese males, indicating that such alterations were more pronounced in obese male than obese female rats. Due to this, the putative origin of the increased corticosterone output of obese rats was studied in males. Greater levels of ACTH were reached in obese than in lean rats when submitted to a cold stress (6 C). Dexamethasone produced a complete suppression of corticosterone output in both lean and obese rats. During the recovery from such suppression, corticosterone levels rose to higher values in obese than in lean rats. This observation together with the greater cold-induced ACTH output in obese rats suggest that the increased activity of the HPA axis of these animals is of central origin. Whatever its precise etiology within the central nervous system, it is proposed that the increased HPA axis activity in obese rats and its resultant hypercorticism play a role in the establishment and maintenance of their syndrome.

Animals↗
PubMed1990

Changes in the hypothalamo-pituitary-adrenal axis of genetically obese fa/fa rats: a structural, immunocytochemical, and morphometrical study.

Most metabolic disorders of genetically obese Zucker rats are reversed by adrenalectomy and are restored by corticosterone treatment, thus suggesting that a functional hypercorticosteronemic state is involved in the pathogenesis of the obesity syndrome in fa/fa rats. However, the hormone content and morphology of the hypothalamo-pituitary-adrenal axis of this animal model have to our knowledge not yet been described. We, thus, investigated morphologically and morphometrically the hypothalamic regions involved in CRF synthesis and secretion in male fa/fa rats. To ascertain if the brain is selectively or uniformly affected, we studied the main nuclei of the lateral and mediobasal hypothalamus, i.e. arcuate, lateral hypothalamic, and ventromedial nucleus and the parvicellular portion of the paraventricular nucleus. Moreover, after immunocytochemical labeling, we analyzed densitometrically the CRF-bearing axons of the median eminence and the ACTH-containing cells of the anterior and intermediate lobe of the pituitary gland. Finally, we investigated the adrenal glands by qualitative light microscopy. In fa/fa rats most hypothalamic nuclei were structurally changed. Furthermore, hypothalamic CRF and anterior pituitary ACTH contents as well as adrenal weight were increased, the zona fasciculata of the adrenal cortex was hypertrophic, and the ACTH content of the intermediate lobe was reduced. In conclusion, our results demonstrate that the obesity syndrome in genetically obese fa/fa rats is associated with lesions of the hypothalamo-pituitary-adrenal axis consistent with hyperadrenocorticism due to hyperactivity of the whole adrenal axis. Alterations also occur in the hypothalamic nuclei controlling glycemia, insulinemia, and circadian corticosterone secretion.

Animals↗
PubMed1990

Hyperinsulinemia increases the amount of GLUT4 mRNA in white adipose tissue and decreases that of muscles: a clue for increased fat depot and insulin resistance.

To mimick a state of hyperinsulinemia, normal rats were infused with insulin for 4 days via minipumps, and compared to saline infused rats. At the end of the experimental period, the abundance of mRNA was increased in white adipose tissue (WAT) and decreased in muscles of "insulinized" rats compared to controls. These findings were accompanied, in all tissues considered, except the diaphragm, by parallel changes in the amount of the glucose transporter protein and by parallel changes in the in vivo glucose utilization index. Hyperinsulinemia is thus a driving force in stimulating adipose tissue metabolic activity, while bringing about incipient muscle insulin resistance.

Adipose Tissue↗
PubMed1989

Dysregulation of glucose transport and transporters in perfused hearts of genetically obese (fa/fa) rats.

The regulation of glucose transport in normal and insulin-resistant obese rat hearts have been studied by measuring glucose transport via the efflux of labelled 3-0-methyl-D-glucose. Glucose transporters in obese rat hearts were also investigated using the labelled cytochalasin B-binding assay. Basal, and insulin- or increasing workload-induced stimulation of glucose transport was decreased in obese rat hearts compared to those of normal ones. Total number of glucose transporters (plasma membrane plus microsomal ones) was about half that previously reported for normal rat hearts. Insulin or workload favoured the translocation of glucose transporters from an intercellular pool (microsomes) to the plasma membrane, as they do in normal rats. Due to the measured decrease in total number of transporters of obese rat hearts, those present in the plasma membrane (under basal conditions, or following stimulation by insulin or workload) were less than those previously found in normal rat hearts tested under identical conditions. In obese rat hearts, regulation of plasma membrane transporters was perturbed. The Hill coefficient (an index of positive cooperativity amongst glucose transporters) was paradoxically decreased by insulin while leaving affinity values unaltered. The Hill coefficient was unaltered by workload, although the affinity values were increased compared to respective controls. To sum up, obese rat hearts have decreased total transporter number, and although the two stimuli studied favour the translocation of available transporters, they fail to "activate" them adequately once present in the plasma membrane.

3-O-Methylglucose↗
PubMed1989

The effects of islet activating protein on oral glucose tolerance in the genetically obese fa/fa rat.

When tested in insulin-deficient animal models of diabetes, islet activating protein (IAP) has been shown to increase the secretion of insulin and to improve glucose intolerance. The genetically obese fa/fa rat is an animal model of impaired oral glucose tolerance that does not have reduced insulin secretion. In this model IAP treatment increases basal insulin levels, resulting in lower basal glycemia. However, glucose tolerance following an oral glucose load was worsened by IAP. This was found to be due to an exaggerated stimulation of hepatic glucose production (HGP) following glucose, a defect that is already present in the absence of IAP. IAP has been reported to inhibit (by ADP ribosylation) the inhibitory regulatory protein (Ni) of adenylate cyclase. It is therefore suggested that the increased HGP following oral glucose in fa/fa rats either in the absence or in the presence of IAP treatment may result from a cAMP-mediated mechanism. A beta adrenergic activation or a stimulation of glucagon output could therefore be potential candidates responsible for glucose intolerance in obese fa/fa rats.

Adenylate Cyclase Toxin↗
PubMed1989

Paraventricular nucleus modulation of glycemia and insulinemia in freely moving lean rats.

The effect of norepinephrine (NE) injection (40 nmol) into the paraventricular nucleus (PVN) on plasma insulin and glucose levels was studied in freely moving lean Zucker rats bearing chronic right jugular catheters for blood sampling and unilateral intracerebral cannulas placed just above the PVN. Already 2.5 min after NE injection, plasma glucose levels rose significantly, reaching a peak at 10 min poststimulus, whereas the insulin output was strongly inhibited. This NE-induced hyperglycemia was independent of the corticosterone levels. A ganglionic blockade performed by intravenous chlorisondamine (1 mg/kg body wt) reduced by 80% the 4.5-min NE-induced incremental glucose areas. NE-induced hyperglycemia was reduced to a large extent when the PVN alpha-adrenergic receptors were blocked with phentolamine and to a lesser extent when the beta-adrenergic receptors were blocked with propranolol. NE-induced inhibition of insulin output was not affected by these adrenergic blockers. It is concluded that, when administered locally into the PVN, NE can activate the sympathetic outflow expressed by a neurally mediated hyperglycemia through central alpha- and beta-adrenoreceptor and an inhibition of insulin output through other types of receptors and/or mechanisms.

Animals↗
PubMed1989

Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats.

The genetic obesity of the fa/fa rat is due to or accompanied by perturbances in the autonomic nervous control of different target tissues (e.g. endocrine pancreas, brown adipose tissue). These disorders are likely to be secondary to central dysregulation(s), which could lie somewhere within or in relationship with the hypothalamus. In view of the reported effects of CRF in stimulating sympathetic nerve-mediated mechanisms, while inhibiting vagus nerve-mediated ones, ovine CRF (oCRF) was administered for 7 days into the cerebral ventricles of fa/fa rats at a dose (5 micrograms/day) that did not affect the pituitary-adrenal axis. oCRF treatment stopped the excessive weight gain of the obese animals; oCRF-treated animals gained only 1 g over 6 days, while the vehicle-treated ones gained 29 g (P = 0.044). The oCRF effect was unrelated to changes in food intake, as the two groups were pair-fed. oCRF-treated obese rats were characterized by a decrease in basal hyperinsulinemia, increases in brown adipose tissue weight and activity, and decreases in hepatic glycogen content and epididymal fat pad weight. It is suggested that intracerebroventricular oCRF administration to obese fa/fa rats prevents the 10-15% increase in body weight observed in vehicle-infused obese rats within 1 week by modulating the impaired autonomic nervous control of different target tissues. This does not occur in lean rats.

Adipose Tissue↗