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F Rohner-Jeanrenaud

Publications and source records attributed to F Rohner-Jeanrenaud.

At least 91 records · Page 5Linked to original sources

Role of the oropharynx in regulation of glycemia.

Previous studies have demonstrated that reflexes originating from the oral cavity at the start of food intake are necessary to ensure a normal glucose tolerance. In our experiment, the underlying mechanisms of these reflexes were studied in conscious, freely moving rats bearing chronic catheters. A double-isotope technique was used to measure, under non-steady-state conditions, rates of total glucose appearance (total Ra), total glucose disappearance (Rd), gut glucose absorption (gut Ra), hepatic glucose production (HGP), and the metabolic clearance rate of glucose (MCRg). In random order, 1 wk apart, rats either spontaneously drank 1 ml of a 60% glucose solution or were given the same dose into the stomach via a chronic gastric catheter. Glycemia and insulinemia were lower when glucose was taken orally than when the same amount of the substrate was administered intragastrically. Total Ra after glucose administration was the same in both groups throughout the experiment. Despite lower insulin and glucose values, the increase in Rd was initially higher in the oral group than in the intragastric group. This was accompanied by initial higher MCRg values in the oral group than in animals that received the glucose load directly into their stomachs. We conclude that a series of reflexes elicited by oral glucose ingestion improve glucose tolerance by increasing the efficiency of glucose disposal in the early stages after a glucose load, with a smaller amount of insulin released.

Animals↗

[Interactions between the central nervous system, the endocrine pancreas and metabolism].

1. The importance of nervous circuits including neural afferences, their integration by the central nervous system and the resulting efferents is illustrated by comparing glucose tolerance following the spontaneous ingestion or the intragastric administration of a glucose load. When these circuits are by-passed (intragastric glucose administration), glucose tolerance is impaired and accompanied by an increased insulin output compared to the situation of normal glucose ingestion. This is due to a decreased glucose utilization in the absence of the numerous reflexes that are elicited by the presence of glucose in the oropharynx. 2. In normal animals, insulin secretion by the B cell of the endocrine pancreas is under an inhibitory tonus by the sympathetic nervous system while the parasympathetic system has no stimulatory tonus. After acute bilateral destruction of the ventromedial hypothalamic nuclei (VMH), such a situation is reversed and there is an activation of the parasympathetic outflow leading to hyperinsulinemia. This hyperinsulinemia is partly responsible for the development of the obesity of VMH-lesioned animals and is accompanied by a decreased activity of some sympathetic efferents amongst which those innervating brown adipose tissue. Analogous data have been obtained when studying genetically obese fa/fa rats. 3. A peptide of around 1'000 daltons extracted from the rat hypothalamus and having insulin secretion promoting activity could possibly be an insulin-releasing factor since it is present not only in the hypothalamus but also in the plasma.

Animals↗

In vivo metabolic changes as studied longitudinally after ventromedial hypothalamic lesions.

Ventromedial hypothalamic (VMH)-lesioned rats were tested 1 and 6 wk after the lesions to determine, by euglycemic-hyperinsulinemic clamps, their tissue response to insulin. One week after the lesions, total glucose metabolism was more sensitive and responsive to insulin than in age-matched controls. In the two groups, hepatic glucose production was suppressed at almost identical insulin concentrations (approximately 550 microU/ml). Six weeks after the VMH lesions, the increased insulin responsiveness of total glucose metabolism disappeared and glucose metabolism became less insulin sensitive (right, shifted dose-response curve) than that of control animals. Furthermore, hepatic glucose production of VMH-lesioned rats was now inhibited by 45% at most and at the supraphysiological insulin concentration of 16,000 microU/ml, while it was totally suppressed by 550 microU/ml of the hormone in age-matched controls. This defect was accompanied by a lack of decrease in plasma glucagon levels during the clamps carried out at maximal insulin concentration. In summary, in a first phase after VMH lesion, rats are hypersensitive and hyperresponsive to insulin; and in a later phase, when obesity is well established, VMH-lesioned rats become insulin resistant and are characterized by a decreased in vivo sensitivity and responsiveness of liver and muscles to the hormone.

Animals↗

Mechanism of abnormal oral glucose tolerance of genetically obese fa/fa rats.

The genetically obese fa/fa rat is glucose intolerant when tested in a conscious state after the spontaneous ingestion of a glucose solution. The aim of this study was to investigate the mechanism(s) underlying the abnormal oral glucose tolerance test of obese animals with the non-steady-state measurement of glucose turnover proposed by Steele et al. in 1968. Our results show that the total rate of glucose appearance is enhanced in obese compared with lean animals. This abnormality is not due to an increased gut glucose absorption but to a lack of suppression and even a transient stimulation of hepatic glucose production after the ingestion of glucose. The rate of glucose utilization by the obese animals is somewhat increased compared with controls or unchanged when expressed as glucose metabolic clearance rate, thus excluding this parameter from the factors contributing to the observed glucose intolerance. The results obtained with genetically obese rats agree with those reported for type II diabetes in humans. The observed defect of the obese group could be related to an abnormal regulation of insulin counterregulatory hormone(s) or of hepatic innervation as well as to other defects of hepatic glycogen handling.

Animals↗

Insulin: its relationship to the central nervous system and to the control of food intake and body weight.

This article describes the close relationship among the hormone insulin, the central nervous system, and the regulation of food intake and body adiposity. The initial section documents the control of insulin output from the pancreas by the central nervous system, and a later section describes the relationship of insulin levels in the blood to the degree of adiposity. Another section documents the ability of insulin to gain access to the brain and to elicit responses there. Finally, the behavioral effects of insulin added to the brain, and especially its ability to reduce food intake and body weight, is discussed. The implications to obesity are stressed throughout.

Adipose Tissue↗

Involvement of the cholinergic system in insulin and glucagon oversecretion of genetic preobesity.

The etiology of the abnormal secretion of hormones from the endocrine pancreas of genetically obese (fa/fa) rats is unknown. In this study, we tested the postulate that there is an early occurrence of increased efferent parasympathetic activity to the endocrine pancreas of these rodents. Unweaned female 17-day-old pups were anesthetized and tested by an iv bolus of arginine to stimulate insulin and glucagon output. At the time of the tests, pups were indistinguishable from each other. They were, therefore, kept to adulthood to allow for their separation into an obese (25% of total animals) and a lean (75%) group. Those animals that became obese were retrospectively referred to as preobese. Basal insulinemia and glucagonemia were identical in the two groups, as were the dynamics of arginine-induced hormone release. However, arginine-induced insulin as well as glucagon output were higher in preobese than in lean pups. These two abnormalities were abolished by acute atropine pretreatment. It is concluded that the substrate-induced insulin and glucagon oversecretion of preobese pups is an early defect that is mediated via the vagus nerve.

Age Factors↗

A role for the vagus nerve in the etiology and maintenance of the hyperinsulinemia of genetically obese fa/fa rats.

It is demonstrated that pre-obese Zucker rats, studied before weaning (17 days of age), at a time when they were indistinguishable from lean controls, do hypersecrete insulin in response to glucose or arginine administration when compared to their lean littermates in spite of normal basal insulin levels. When arginine is used as the stimulus, it is shown that pre-obese pups hypersecrete glucagon as well as insulin, the net result of insulin and glucagon oversecretion being probably the observed normoglycemia of these animals. Furthermore, these early substrate-induced increases in pancreatic hormonal secretion could be reduced toward normal values by acute pre-treatment of the pre-obese rats with the cholinergic inhibitor, atropine. It is suggested the parasympathetic nervous system plays a role in genetically obese fa/fa rats in bringing about an early increased substrate-induced insulin release, a defect which could be one of the causes involved in the development of their obesity syndrome. In adult animals, the involvement of the parasympathetic nervous system in insulin oversecretion is less clear probably due to the presence of an increased B cell mass. However, using three different experimental approaches, it could be seen that an increased vagal tone acting at the B cells in obese animals participate to their insulin hypersecretion.

Animals↗

Oversecretion of glucagon by pancreases of ventromedial hypothalamic-lesioned rats: a re-evaluation of a controversial topic.

Glucagon secretion by perfused pancreases of control and ventromedial hypothalamic-lesioned rats was studied in response to a mixture of 20 different amino-acids used at physiological or pharmacological concentrations, and under experimental conditions near to or different from physiological situations. When experimental conditions are too extreme (lack of glucose with 5 or 15 mmol/l final amino-acid concentration), there was no difference of glucagon secretion between pancreases of control and ventromedial hypothalamic-lesioned animals. However, when experimental conditions are as close as possible to those prevailing in vivo (presence of 5 mmol/l glucose with 2.5 or 5 mmol/l amino-acid concentration), pancreases from ventromedial hypothalamic-lesioned rats clearly oversecrete glucagon when compared with control rats (with 2.5 mmol/l amino-acid: controls: 7.9, ventromedialhypothalamic-lesioned: 17.1 ng/20 min, p less than 0.05; with 5 mmol/l amino-acid: controls: 12.6, ventromedialhypothalamic-lesioned: 31.0 ng/20 min, p less than 0.025). Upon extrapolating these results to a situation in vivo, this study indicates that ventromedial hypothalamic-lesioned rats secrete more glucagon than controls in response to physiological stimuli, at least at the level of the portal vein. This could explain why the lesioned rats, known to be hyperinsulinaemic, are nevertheless normoglycaemic and have increased plasma urea levels.

Amino Acids↗

Role of ventromedial hypothalamus on sympathetic efferents of brown adipose tissue.

Previous studies have suggested the presence, in hypothalamic obesity, of an impairment of the energy-dissipating capacity of brown adipose tissue ascribed to a functional disconnection of the sympathetic innervation of this tissue. The following observations demonstrate, with electrophysiological techniques, the presence of a functional link between the ventromedial hypothalamic (VMH) area and the interscapular brown adipose tissue (IBAT) in the rat: the spontaneous activity of the efferent sympathetic nerves reaching the IBAT of normal rats was increased in response to an acute cold stimulus, whereas this increase failed to occur in nerves of VMH-lesioned rats studied 4-7 days after the lesions; and the spontaneous activity of the efferent sympathetic nerves of IBAT decreased rapidly (by greater than or equal to 80% within 30 min) after acute lesions of the VMH area. It is suggested that the VMH area plays a role in increasing the activity of the efferent sympathetic nerves of IBAT during an acute cold stimulus and that alone or in relationship with other, as yet undetermined, central nervous system sites, it has a tonic stimulatory effect on the final common pathways that innervate the IBAT via the efferent sympathetic nerves.

Adipose Tissue, Brown↗

The origins and role of efferent vagal nuclei in hyperinsulinemia in hypothalamic and genetically obese rodents.

The main brainstem parasympathetic efferent neurons that ultimately reach the pancreas and facilitate insulin secretion are located in the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus nerve (DMX). With regard to insulin secretion, hypothalamic (produced by ventromedial hypothalamic (VMH) lesions) and genetic obesities have features in common: (a) insulin oversecretion is an early abnormality in both syndromes; and (b) this abnormality is vagus nerve-mediated. VMH lesions and possible, spontaneously occurring (i.e. genetic) CNS-located abnormalities appear to result in an increased parasympathetic efferent tone together with decreased sympathetic efferent tone that is likely to be responsible for the occurrence of hyperinsulinemia, obesity and, eventually, insulin resistance.

Animals↗

Hyperinsulinemia of preobese and obese fa/fa rats is partly vagus nerve mediated.

In vivo glucose-induced insulin secretion was greater in preweaned preobese 17-day-old Zucker rats than in the corresponding controls. This hypersecretion of insulin was reversed to normal by acute pretreatment with atropine. A short-lived (30 s) electrical stimulation of the vagus nerve preceding a glucose load potentiated the in vivo glucose-induced insulin release in adult animals (6-9 wk) and more so in obese Zucker (fa/fa) than in lean rats. This suggested the existence of enhanced sensitivity and/or responsiveness of the B cells of obese animals to the parasympathetic system. That the parasympathetic tone was increased in adult obese Zucker (fa/fa) rats was corroborated by the observation that acute vagotomy of these animals resulted in a significant decrease in glucose-induced insulin secretion, whereas no such effect was seen in lean rats. Also, perfused pancreases from adult obese (fa/fa) rats oversecreted insulin during a stimulation by arginine when compared with controls, an oversecretion that was restored toward normal by superimposed infusion of atropine. It is concluded that a) the increased insulin secretion of preobese Zucker fa/fa rats is an early abnormality that is mediated by the vagus nerve, and b) increased secretion of insulin in adult obese fa/fa rats continues to be partly vagus-nerve mediated, although a decreased sympathetic tone and other unknown defects could conceivably play a role as well.

Animals↗

Increases in plasma insulin levels in response to electrical stimulation of the dorsal motor nucleus of the vagus nerve.

In order to investigate the physiological counterpart of the anatomical finding showing that the dorsal motor nucleus of the vagus nerve (DMX) is a source of efferent vagal fibers innervating the pancreas, unilateral electrical stimulation using monopolar electrodes (50 microA, 30 Hz, 0.2 msec) at a glycemia of 150 mg/100 ml was performed in normal anesthetized rats. DMX stimulation resulted in rapid (within 1 min) rise in plasma insulin levels (greater than or equal to 200%). Stimulation of the nucleus of tractus solitarius, anatomically connected to DMX, also produced a 50% increase in insulinemia. The effect of DMX stimulation was almost completely abolished by atropine pretreatment or acute bilateral subdiaphragmatic vagotomy. The effect of DMX stimulation was not potentiated by the alpha-adrenergic blocker (infusion of phentolamine) indicating that no inhibitory fiber was recruited during DMX stimulation. It is concluded that DMX is connected to the endocrine pancreas exclusively via vagal fibers and has a role in neurally mediated insulin release.

Animals↗

[The central nervous system-endocrine pancreas axis].

Some results suggesting the existence of gluco- and/or insulin-sensitive sites within the central nervous system (CNS) are recalled. In summary, it seems that when these sites are activated by the presence of glucose or insulin, there is an activation of the parasympathetic nervous system which is responsible for an increased peripheral insulin secretion and/or an hypoglycemia. This could possibly favour glucose disposal. Inversely, when the CNS lacks energy substrates, a cascade of events occurs which tend to increase peripheral glycemia. Bilateral lesions of the ventromedial hypothalamus (VMH) bring about a very early occurring hypersecretion of insulin which can be rapidly and completely abolished by vagotomy. It has also been shown that genetically pre-obese rats (fa/fa) do hypersecrete insulin in response to an i.v. glucose load. This suggests that hypersecretion of insulin of these animals could play a causative role in the development of their obesity. Moreover, this hypersecretion of insulin observed in genetic pre-obesity is abolished by acute atropine administration indicating the involvement of the parasympathetic nervous system in the development of their hyperinsulinemia and subsequent obesity. Cephalic phase insulin secretion seems to "optimalize" insulin secretion that occurs following a meal, as it appears to permit adequate glucose utilization and therefore glucose tolerance. Indeed, animals which are lacking cephalic phase insulin secretion do hypersecrete insulin while remaining hyperglycemic for a longer period of time when compared to animals which have a cephalic phase insulin secretion. Hypothalamic factors present in the ventromedial or the ventrolateral hypothalamus have been shown to have insulin secretion promoting activity when administered in vivo or in vitro to donor rats. It remains to be shown whether such factors are indeed released into the blood (humoral factors) or whether they are neuromodulators and/or neurotransmitters.

Afferent Pathways↗

Possible involvement of the cholinergic system in hormonal secretion by the perfused pancreas from ventromedial-hypothalamic lesioned rats.

Total arginine-induced secretion of insulin, glucagon and somatostatin was studied during a 20 min period in isolated perfused pancreases from control and non-hyperphagic ventromedial hypothalamic (VMH) lesioned rats. Compared to controls pancreases from VMH-lesioned rats secreted more insulin (82 +/- 13 ng vs 36 +/- 9 ng) and more glucagon (130 +/- 23 ng vs 73 +/- 14 ng) but less somatostatin (0.58 +/- 0.18 ng vs 1.12 +/- 0.14 ng). These abnormalities were restored to normal by perfusion with atropine (25 mumol/l). Pancreases of both groups were perfused with the cholinergic agonist methacholine (100 mumol/l). Again pancreases from VMH-lesioned rats secreted more insulin (157 +/- 19 ng vs 33 +/- 6 ng) and more glucagon (95 +/- 13 ng vs 57 +/- 9 ng) but less somatostatin (0.80 +/- 0.15 ng vs 1.30 +/- 0.18 ng). These results support the concept that, in pancreases isolated from VMH-lesioned rats increased "cholinergic activity" may prevail via increased release of endogenous acetylcholine from islet-postsynaptic ganglion cells together with increased numbers of muscarinic receptors on postsynaptic ganglion cells as well as on endocrine cells.

Animals↗

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↗