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F Rohner-Jeanrenaud

Publications and source records attributed to F Rohner-Jeanrenaud.

At least 55 records · Page 3Linked to original sources
PubMed1995

The ob gene and insulin. A relationship leading to clues to the understanding of obesity.

Obesity and non-insulin-dependent diabetes are estimated to affect millions of people in the world. This pathology is multifactorial, comprising complex interactions of genetic and environmental factors and lacking a specific therapy. Great interest arose from the recent discovery of the ob gene expressed only in adipose tissue and coding for a protein that appears to regulate adiposity, potentially by acting as a satiety factor. We report here that in normal rats, ob mRNA is respectively up- or downregulated by a rise in insulinemia (induced by 2-day insulin infusion while maintaining euglycemia) or a decrease in insulinemia (induced by a 3-day fast). Our results also show that in genetically obese fa/fa rats studied longitudinally, white adipose tissue ob mRNA levels increase in parallel with early occurring and steadily increasing hyperinsulinemia. This results in adult obese animals having markedly higher ob mRNA levels than age-matched normoinsulinemic lean rats. Furthermore, in adult obese rats, ob mRNA escapes down-regulation as normalization of hyperinsulinemia due to fasting fails to reduce the high ob mRNA levels.

Adipose Tissue↗
PubMed1994

Alterations of local cerebral glucose utilization in lean and obese fa/fa rats after acute adrenalectomy.

An animal model often used to investigate the aetiology of obesity is the genetically obese fa/fa rat. It has many abnormalities, including hyperphagia, hyper-insulinemia, insulin resistance, low cerebral glucose utilization and an overactive hypothalamo-pituitary adrenal (HPA) axis with resulting hypercorticism. Due to the latter consideration, the aim of this work was to study the impact of acute adrenalectomy (ADX) on the local cerebral glucose utilization (LCGU) of lean and obese fa/fa rats. ADX resulted in discrete increases in LCGU of regions common to both lean and obese rats. These common regions were found to belong to be related to the limbic system. Within this system, the LCGU of the brain of obese rats was either normalized to lean sham operated values or increased by ADX to a similar degree in both groups on a percentage basis. It was concluded that the LCGU of both lean and obese animals appears to be negatively regulated, albeit to different extents, by glucocorticoids. Such negative regulation is particularly salient within the limbic system of the lean rat and even more so in the fa/fa rat. It is suggested that the long-term hypercorticism of obese fa/fa rats due to abnormal regulation of the HPA axis may result in a decreased LCGU in limbic and related regions of the brain of fa/fa rats and contribute to the expression of the obese phenotype.

Adrenalectomy↗
PubMed1994

Effects of corticosterone administration on local cerebral glucose utilization of rats.

The local cerebral glucose utilization (LCGU) of control and 2 day corticosterone-administered rats was investigated using the method of Sokoloff (labelled 2-deoxy-D-glucose). The overall LCGU of both groups was similar, but discrete areas of the corticosterone-administered rat brains displayed both increases and decreases in their utilization of 2-deoxyglucose. These areas were associated with the limbic cortex and included the hippocampus, the septum and some thalamic and hypothalamic nuclei. It is well known that these regions are interconnected and that acetylcholine is one of the main neurotransmitters. Some of these pathways (as measured electrophysiologically) have reportedly inhibitory influences, whilst others have excitatory ones within the limbic region. It was therefore striking to observe that these inhibitory or stimulatory effects were corroborated by a selective, corticosterone-induced decrease or increase in 2-deoxyglucose uptake, respectively. This gives corticosterone a putative role in the regulation of the limbic system. As the latter has been reported to be abnormal in genetically obese hypercorticosteronemic fa/fa rats, it is suggested that these corticosterone-induced changes within the limbic system may contribute to the overall phenotypic expression of this obesity state.

Animals↗
PubMed1994

Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats.

Intracerebroventricular neuropeptide Y (NPY) administration to normal rats for 7 days produced a sustained, threefold increase in food intake, resulting in a body weight gain of more than 40 g. Basal plasma insulin and triglyceride levels were increased in NPY-treated compared to vehicle-infused rats by about four- and two-fold, respectively. The glucose utilization index of white adipose tissue, measured by the labelled 2-deoxy-D-glucose technique was four times higher in NPY-treated rats compared to controls. This change was accompanied by an increase in the insulin responsive glucose transporter protein (GLUT 4). In marked contrast, muscle glucose utilization was decreased in NPY-treated compared to vehicle-infused animals. This change was accompanied by an increase in triglyceride content. When NPY-treated rats were prevented from overeating, there was no decrease in muscle glucose uptake, nor was there an increase in muscle triglyceride content. This suggests that muscle insulin resistance of ad libitum-fed NPY-treated rats is due to a glucose-fatty acid (Randle) cycle. When intracerebroventricular NPY administration was stopped and rats kept without any treatment for 7 additional days, all the abnormalities brought about by the neuropeptide were normalized. A tonic central effect of NPY is therefore needed to elicit and maintain most of the hormonal and metabolic abnormalities observed in the present study. Such abnormalities are analogous to those seen in the dynamic phase of obesity syndromes in which high hypothalamic NPY levels have been reported.

Adipose Tissue↗
PubMed1994

Insulin resistance and hypertension: studies in transgenic hypertensive TGR(mREN-2)27 rats.

The link between hyperinsulinemia and hypertension is imperfectly understood. Recently, a renin gene (the mouse DBA/REN-2d gene) has been transfected into rats, leading to high blood pressure in transgene-positive animals, TGR(mREN-2)27 rats. We tested whether heterozygous hypertensive TGR(mREN-2)27 rats presented evidence of insulin resistance in comparison with the parent strain of Sprague-Dawley rats. Despite their higher blood pressure (203 +/- 8 vs. 112 +/- 6 mmHg, P < 0.001), transgenic rats had normal fasting levels of plasma glucose, insulin, free fatty acids, and triglycerides and had normal fasting rates of hepatic glucose production (by [14C]glucose infusion). During a euglycemic hyperinsulinemic clamp (3 mU/min), stimulation of whole body glucose utilization was equivalent in transgenic and control animals (12.6 +/- 0.6 vs. 10.9 +/- 1.0 mg.min-1.kg-1, respectively). Likewise, suppression of hepatic glucose output by insulin was complete in both groups. The glucose utilization index (as measured by the 2-deoxy-D-[3H]glucose technique) was similar between transgenic and control animals in several skeletal muscles (soleus, extensor digitorum longus, tibialis, diaphragm, white and red quadriceps, and white and red gastrocnemius), in white adipose tissue (periovarian and inguinal), and in brown adipose tissue. We conclude that single gene hypertension does not alter whole body and individual tissue insulin sensitivity.

Adipose Tissue↗
PubMed1994

Intracerebroventricular administration of neuropeptide Y to normal rats has divergent effects on glucose utilization by adipose tissue and skeletal muscle.

Given that several genetically obese rodents characterized by hyperphagia, hyperinsulinemia, and insulin resistance have increased hypothalamic neuropeptide Y (NPY) mRNA and peptide content, the impact of NPY administered intracerebroventricularly (i.c.v.) for 7 days to normal, awake rats was investigated. NPY produced marked hyperphagia, increased body weight gain, increased basal insulinemia, and, more importantly, a much greater insulin response to meal feeding than that of saline-infused controls. NPY administration also resulted in a pronounced increase in the in vivo insulin-stimulated glucose uptake by adipose tissue but in a marked decrease in uptake by eight different muscle types. Increased insulin responsiveness of the glucose transport process by adipose tissue was accompanied by increases in both GLUT4 mRNA and protein levels. In contrast, the decreased insulin responsiveness of glucose uptake in muscles from NPY-administered rats was not related to GLUT4 expression. We conclude that i.c.v. NPY administration to normal rats produces a hormonal-metabolic situation that is similar to that reported in the dynamic phase of the genetic obesity of the fa/fa strain. Thus, NPY could be of primary importance in the establishment of obesity syndromes with incipient insulin resistance.

Adipose Tissue↗
PubMed1993

Lifespan of subcutaneous glucose sensors and their performances during dynamic glycaemia changes in rats.

Performances of a glucose sensor have been investigated during dynamic variations of plasma glucose levels. Subcutaneous glucose concentrations measured by the sensors were calculated by a one-point calibration, performed in basal conditions. A first group of sensors were chronically implanted in the subcutaneous tissue of normal rats. The animals were submitted to glucagon and insulin injection, in order to induce rapid modifications of their glycaemia. This test was repeated at different days after implantation in order to investigate the lifespan and the performance of the sensors. All the sensors were working 1 or 2 days after implantation, and 70% adequately responded to glycaemia variations at day 3 or 4. The quality of the sensors' performance remained constant as a function of the time. With a second group of sensors, we demonstrated that an efficient sterilization procedure did not alter the sensors' characteristics. At the day of implantation, the sterilized sensors' performance, during dynamic variations of plasma glucose levels, was closely similar to that of the non-sterilized sensors. The animals bearing the sterilized devices were rendered diabetic by streptozotocin (STZ) injection. Once the rats had developed a severe hyperglycaemia (1-3 days after STZ), they were injected with intravenous insulin. The subcutaneously implanted glucose sensors correctly followed the decline in plasma glucose levels. We therefore conclude that our sensor could represent a useful tool for short-term continuous blood monitoring.

Animals↗
PubMed1993

Hypothalamic neuropeptide Y messenger ribonucleic acid levels in pre-obese and genetically obese (fa/fa) rats; potential regulation thereof by corticotropin-releasing factor.

Neuropeptide Y (NPY) is a 36 amino-acid peptide. It is localized within the brain but is also present peripherally. It is a well substantiated orexigenic peptide with several other endocrine and behavioural effects. In this study NPY mRNA levels were measured, using the polymerase chain reaction amplification technique, in the hypothalamus of pre-obese (unweaned 13-day-old), young (weaned 28-day-old) and adult (11-week-old) obese fa/fa rats and compared to those of lean age-matched controls. Before weaning, pre-obese pups had the same NPY mRNA levels as controls. After weaning NPY mRNA levels were increased 2-fold in young 28-day-old and 4-fold in adult obese rats, relative to corresponding controls. When adult obese rats were intracerebroventricularly-treated with ovine corticotropin-releasing hormone (oCRF) for 7 days, they stopped gaining body weight relative to vehicle-infused obese controls. Upon measuring NPY mRNA levels in the hypothalamus of these two groups of animals, it was shown that the high NPY mRNA levels of vehicle-treated (control) obese rats were decreased by 3-fold following the intracerebroventricular oCRF administration. It is proposed that: 1) hypothalamic NPY may play a role in the establishment and maintenance of the genetic obesity syndrome of the fa/fa rat, and 2) maintenance of the genetic obesity syndrome of the fa/fa rat, and 2) hypothalamic NPY could be partly regulated by central CRF.

Adipose Tissue↗
PubMed1993

Local cerebral glucose utilization in brains of lean and genetically obese (fa/fa) rats.

The local cerebral glucose utilization (LCGU) of brains from Wistar, lean Zucker (FA/FA), and obese Zucker (fa/fa) rats was investigated using the method of Sokoloff et al. (L. Sokoloff, M. Reiwich, C. Kennedy, M.H. Des Rosiers, C.S. Patlak, K.D. Pettigrew, O. Sakurada, and M. Shinohara. J. Neurochem. 28: 897-916, 1977.). The LCGU of obese Zucker (fa/fa) rats was decreased in comparison to the relatively high values obtained for the lean Zucker (FA/FA) rats in all gray matter areas studied, on average to the extent of 50%. When compared with Wistar rats, several brain areas of lean Zucker (FA/FA) animals had a normal glucose uptake. When these normal areas were assessed for common efferent and afferent pathways, it was found that many of these common connections had normal glucose utilizations. In direct comparison to the obese fa/fa rat, the LCGU rates of these areas were decreased, hinting that this would also be the case for their functional activity. Because these areas (limbic, thalamic, hypothalamic, autonomic) have been reported to be potentially relevant for bringing about the behavioral and neuroendocrine alterations known to occur in obese fa/fa rats, it is proposed that they represent dysfunctions that are partly responsible for the obesity syndrome of the fa/fa strain.

Animals↗
PubMed1993

Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats.

Neuropeptide Y (NPY) is known to be involved in the central regulation of appetite, sexual behavior, and reproductive functions. Whereas central administration of NPY strongly stimulates feeding in satiated animals, diet restriction produces overexpression of NPY in the arcuate and paraventricular nuclei that might reflect behavioral adaptations to shortage of food. Previous studies indicated that central administration of NPY resulted in controversial actions on LH secretion, either stimulatory or inhibitory. In order to analyze the chronic effect on pituitary function of centrally administered NPY, stainless steel cannulae were implanted in the right lateral ventricles of intact 45-day-old Sprague-Dawley female rats. Ten days later, Alzet osmotic minipumps filled with saline or different concentrations of NPY adjusted to deliver 3, 6, 12, or 18 micrograms/day were connected to the intracerebroventricular (icv) cannulae, implanted sc dorsally, and the effects of these treatments evaluated after 7 days. Chronic icv infusion of NPY produced the expected dose-related increase in food intake [25.3 +/- 0.8 g/day (basal) to 47.9 +/- 4.3 g/day (highest NPY dose)] and body wt gain (3.7 +/- 0.4-11.5 +/- 1.4 g/day). Basal insulinemia was highly correlated to the increase in food intake. This orexigenic action of NPY was accompanied by a drastic dose-related decrease in pituitary wt (14.0 +/- 0.5-8.3 +/- 0.3 mg), pituitary concentration of GnRH receptors, a known marker of the activity of the hypothalamo-pituitary gonadal axis (15.2 +/- 1.7-5.2 +/- 0.5 fmol/mg), and ovarian wt (84.0 +/- 4.2-49 +/- 6.7 mg). Ovulation was impaired in NPY-treated animals as seen by daily inspection of vaginal smears. A sharp dose-dependent decrease in plasma levels of insulin-like growth factor I was also observed [934 +/- 64 ng/ml (basal) to 385 +/- 26 ng/ml (highest NPY dose)], probably secondary to a decrease in GH secretion. Whereas these data confirm the central action of NPY to stimulate appetite in satiated animals, they provide the first demonstration that chronic icv administration of NPY unequivocally inhibits gonadotropin secretion and sexual function in intact female rats. These data also confirm that NPY can suppress GH secretion and other anabolic hormones. In conclusion, these results may indicate a physiological role of NPY as an integrator of different adaptive behaviors in periods of unfavorable metabolic conditions such as diet restriction, extending its action to inhibition of sexual functions and anabolic processes.

Animals↗
PubMed1993

Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity.

Chronic intracerebroventricular (icv) administration of neuropeptide-Y (NPY; 10 micrograms/day) was performed in normal female rats to investigate its hormonal and metabolic consequences. Intracerebroventricular NPY produced hyperphagia, increased basal insulinemia, as well as liver and adipose tissue lipogenic activity. It also increased basal morning corticosteronemia. When NPY-induced hyperphagia was prevented by pair-feeding, the icv NPY treatment resulted in the same increases in basal insulinemia and corticosteronemia, and liver and white adipose tissue lipogenesis was still higher than that in respective controls. Under the ad libitum and pair-feeding conditions, icv NPY stimulated glucose uptake as well as total lipoprotein lipase activity in white adipose tissue; it resulted in an increase total activity of hepatic and white adipose tissue acetyl coenzyme-A-carboxylase. As all hormonal and metabolic changes elicited by icv NPY remained present (at the same or to a lesser extent depending upon the parameter considered) when hyperphagia was prevented by pair-feeding, it was, thus, shown that icv NPY per se induces peripheral hormonal and metabolic alterations via efferent routes, which remain to be determined. The effects of icv NPY reported in this study are similar to the defects observed in the early phase of genetic obesity in rodents, the hypothalamus of which has increased NPY levels. NPY could, thus, be of relevance in the occurrence of genetically induced obesity.

Adipose Tissue↗
PubMed1993

Evidence that neuropeptide Y could represent a neuroendocrine inhibitor of sexual maturation in unfavorable metabolic conditions in the rat.

Neuropeptide Y (NPY) is known to be involved in the central regulation of appetite, sexual behavior and reproductive function. Whereas central administration of NPY strongly stimulates feeding, diet restriction produces overexpression of NPY in the arcuate and paraventricular nuclei that might reflect behavioral adaptations to shortage of food. The role of NPY for the regulation of sexual function is still controversial. Whereas NPY is stimulatory during proestrus in the rat, acute administration of NPY is inhibitory in castrated animals and we have shown that chronic administration of NPY inhibits both the gonadotropic and somatotropic axis in adult female rats. In order to further analyse the role of NPY during sexual maturation, a model of delayed sexual maturation imposed by food restriction and return to ad-libitum feeding was used. Young female rats were restricted to 7-8 g food daily starting at 24 days of life (d). This restriction completely prevented sexual maturation. At 50 d, ICV cannulas were placed and at 60 d, Alzet minipumps either delivering NPY (18 micrograms/day) or vehicle into the ICV cannula were implanted dorsally. At 61 d, rats were switched to ad-libitum feeding, a change that produced vaginal opening within 4 days in all vehicle-treated rats. In the rats receiving NPY, significantly increased food intake and weight gain were observed but only one out of the 9 rats studied experienced vaginal opening at 66 d, the other 8 animals remaining sexually immature at 67 d at sacrifice. Sexual immaturity of NPY-treated rats was further confirmed by decreased ovarian weight and reduced number of pituitary GnRH receptors. Plasma IGF-I levels were markedly reduced in NPY-treated rats. Since food restriction has been shown both to increase hypothalamic NPY and to reduce or inhibit sexual function, these data bring evidence for the first time that NPY could be involved in the inhibition of sexual maturation imposed by food restriction, since maintenance of elevated NPY levels in the hypothalamus did prolong this state of sexual immaturity despite restoration of normal food intake.

Animals↗
PubMed1992

Acute intravenous corticotropin-releasing factor administration: effects on insulin secretion in lean and genetically obese fa/fa rats.

The effect of an i.v. administration of different doses (250, 500, and 1000 pmol) of ovine CRF (oCRF) on plasma glucose and insulin levels in lean and genetically obese fa/fa rats was investigated. In both phenotypes, i.v. CRF promoted a rapid (peak at 1 min) transient doubling of basal insulin levels without a concomitant change in glycemia. The dose-dependency of this early insulin response was bell-shaped in both lean and obese animals, with a maximal response at 500 pmol oCRF. After this early rise in insulinemia, glycemia increased in a dose-dependent manner in both lean and obese rats. It was accompanied by a bell-shaped insulin response in lean rats, while such a response was linear in obese rats. The early transient stimulatory effect of CRF on plasma insulin levels could not be prevented by the prior administration of an anti-CRF serum or the alpha-helical CRF-(9-41) antagonist, although administration of either one of these compounds was effective in preventing the CRF-induced changes in the pituitary-adrenal axis. The effect of CRF on the early insulin response was, however, completely suppressed by an acute cholinergic blockade (i.v. injection of atropine). It is suggested that i.v. CRF administration mimics the reflex, cephalic phase insulin secretion. Such cephalic phase insulin output is known to play a role in oral glucose tolerance and may be of physiopathological importance in the Zucker rat strain.

Animals↗
PubMed1992

Beneficial effect of intravenous bolus of corticotropin-releasing factor on glucose intolerance of genetically obese (fa/fa) rats.

The effect of an ovine corticotropin-releasing factor (oCRF) bolus administered intravenously at the onset of glucose ingestion during oral glucose tolerance tests (OGTTs) was evaluated in conscious lean (FA/FA) and genetically obese (fa/fa) rats. When the amount of oCRF was purposely small to not stimulate the hypothalamo-pituitary-adrenal (HPA) axis, it normalized the glucose intolerance of genetically obese rats as tested during OGTTs and decreased their insulin output, whereas it had no effect in lean rats. In obese rats, plasma xylose levels measured after the ingestion of a xylose load were unaltered by the intravenous oCRF bolus, indicating that the beneficial effect of oCRF on glucose intolerance of fa/fa rats was unlikely to be dependent on glucose absorption. When the intravenous bolus of oCRF was doubled at the onset of OGTTs, it stimulated the HPA axis and produced a worsening of glucose intolerance in obese rats together with an increase in their insulin response. Again, it had no effect in lean rats. The abnormal intravenous glucose tolerance of obese rats was unaffected by the administration of an oCRF bolus: This is in keeping with previous data showing that bypassing the oral cavity fails to elicit several sensory reflexes that markedly influence subsequent glucose clearance. It has been suggested that obese rats may have deficient oropharyngeal reflexes that could be reactivated by the oCRF bolus, thereby being responsible for the normalization of their impaired OGTT, which lies in the hepatic glucose production process.

Animals↗
PubMed1992

Hyperinsulinemia and its impact on obesity and insulin resistance.

The impact of hyperinsulinemia on the establishment of insulin resistance was investigated. This was done by treating normal rats with insulin for 3-4 days via osmotic minipumps, and by comparing them with saline-treated controls. Hyperinsulinemia produced by prior insulin treatment (i.e. prior insulinization of the normal rats) resulted in a well tolerated hypoglycemia, increased food intake and body weight gain. Euglycemic-hyperinsulinemic clamps were carried out at the end of the insulinization to assess the acute effects of insulin in control and insulinized rats. It was found that prior insulinization of normal rats resulted in increases in total insulin-stimulated glucose utilization and hepatic lipogenesis, while hepatic glucose production (HGP) was normally suppressed by the hormone. Glucose utilization index by individual tissues was then measured (labelled 2-deoxy-D-glucose method). Prior insulinization of normal rats resulted in increased insulin-stimulated glucose utilization index of white adipose tissue, accompanied by increased insulin-stimulated de novo lipogenesis and glycogen synthesis. In contrast, prior insulinization of normal rats resulted in a decreased insulin-stimulated glucose utilization index of most muscles studied. The decreased insulin-stimulated muscle glucose utilization index brought about by prior insulinization persisted in adrenomedullectomized or propranolol-treated rats, ruling out a role of catecholamines in the effects observed. It is concluded that hyperinsulinemia is a pathological driving force in producing both incipient obesity by overstimulating white adipose tissue and liver metabolic activity, and concomitantly producing incipient muscle insulin resistance.

Adipose Tissue↗