The discovery of leptin and its impact in the understanding of obesity.
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Animals↗
Biomedical subjects
B Jeanrenaud
Publications and source records attributed to B Jeanrenaud.
The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats. Reduced sensitivity compared with lean animals.
The effect of different doses of leptin, given as an intracerebroventricular (ICV) bolus, on body weight gain and food intake was investigated during refeeding, following a 24-h fast in lean (FA/fa) rats. It was observed that ICV leptin resulted in a dose-dependent decrease in body weight gain, compared with vehicle injection, a difference that persisted for at least 6 days. This was associated with a transient reduction in food intake over the first 2 days after leptin injection. More importantly, the effect of leptin was also observed in genetically obese fa/fa rats but at the expense of two to ten times higher leptin concentrations, indicating the presence of decreased leptin sensitivity. Furthermore, ICV leptin injections were able to decrease neuropeptide Y (NPY) levels in the arcuate and paraventricular hypothalamic nuclei in both lean and genetically obese fa/fa rats, although a higher leptin dose was again needed in the obese group. These observations provide further evidence for the implication of NPY and leptin in a regulatory loop controlling body homeostasis. This loop is functional in lean and genetically obese fa/fa rats, provided that leptin levels in the central nervous system are high enough in the obese group, in particular. Since human obesity is frequently associated with elevated circulating leptin levels, a state of decreased leptin sensitivity (i.e., leptin resistance), similar to that described here in fa/fa rats, could possibly occur in human syndromes as well.
Animals↗
Four-day hyperinsulinemia in euglycemic conditions alters local cerebral glucose utilization in specific brain nuclei of freely moving rats.
Although insulin is a well known regulator of peripheral tissue glucose metabolism, there is little agreement over its effects on brain glucose metabolism. Several investigators report that peripheral insulin may enter the brain via several routes. The presence of insulin receptors specific to brain, coupled to diverse reports of the effect of acute insulin administration on brain glucose use, led us to carry out a 4-day hyperinsulinemic euglycemic clamp in freely moving rats with subsequent labelled 2-deoxyglucose metabolic mapping studies. It was found that after 4 days of peripheral insulin infusion, several brain regions (Anterior Hypothalamic area, Suprachiasmatic nucleus, Basolateral Amygdaloid nucleus, Supramammillary bodies, Medial Geniculate nucleus and Locus Coeruleus) had an altered local cerebral glucose utilization. Upon subsequent analysis of their anatomical and functional connections it is proposed that insulin may regulate an integrated circuit of pathways within the central nervous system.
Animals↗
Insulin, corticosterone and the autonomic nervous system in animal obesities: a viewpoint.
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Animals↗
In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues.
Chronic hyperinsulinemia with maintenance of euglycemia was imposed on normal rats for 4 days. In white adipose tissue, hyperinsulinemia resulted in a twofold increase in GLUT4 protein and mRNA and a sixfold to 15-fold increase in fatty acid synthase (FAS) and acetyl coenzyme A (CoA) carboxylase (ACC) activity, respectively. Lipogenic enzyme mRNA was also markedly increased (20- to 30-fold). This was specific for white adipose tissue and was not observed in brown adipose tissue. In the liver, hyperinsulinemia was accompanied by a threefold increase in glucokinase (GK) activity and mRNA and by a threefold to fivefold increase in lipogenic enzyme activities and mRNA. In agreement with the changes in lipogenic activities, lipogenesis was markedly increased in white adipose tissue and liver of hyperinsulinemic rats. The data strongly suggest that in the rat, insulin is a driving force leading to increased lipid synthesis in liver and white adipose tissue.
Acetyl-CoA Carboxylase↗
Effect of sustained physiological hyperinsulinaemia on hypothalamic neuropeptide Y and NPY mRNA levels in the rat.
Neuropeptide Y (NPY) synthesized in the arcuato-paraventricular projection in the rat hypothalamus is thought to play an important role in controlling energy homeostasis. The factors that regulate hypothalamic NPY are not known but, amongst others, insulin has been postulated as an inhibitory modulatory agent. To test this hypothesis, normal male rats were given either insulin (2 units/day) or saline via subcutaneous osmotic minipumps for 3 days. Euglycaemia was maintained by a concomitant glucose infusion in insulin-infused rats which had peripheral insulin levels 5-8 times higher than saline-infused controls. Hyperinsulinaemic rats ate 42% less than controls, but their total energy intake (food intake plus glucose infusion) was higher than that of controls, and they gained more weight than controls during the experimental period. Hyperinsulinaemia had no significant effect on hypothalamic NPY mRNA or NPY levels in the arcuate nucleus. NPY concentrations in the paraventricular nucleus were, however, significantly increased by 73% in hyperinsulinaemic rats, but were closely similar to controls in all other areas. Insulin may act as a satiety factor in that hyperinsulinaemic rats ate less, but the fact that these animals had increased total energy intake and gained excessive weight suggests that insulin may not function as an overall regulator of energy balance. In addition, physiological hyperinsulinaemia does not apparently inhibit NPY gene expression in the arcuate nucleus. Due to the lack of effect of hyperinsulinaemia on NPY synthesis in the arcuate nucleus, the elevated NPY concentrations in the paraventricular nucleus could result from a reduction of its release, which would be in keeping with the reduction in food intake.
Analysis of Variance↗
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↗
[Role of the central nervous system in the development of obesity].
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Animals↗
Endothelial function of the mesenteric arteriole and mechanical behaviour of the carotid artery in rats with insulin resistance and hypercholesterolaemia.
OBJECTIVE: To examine whether insulin resistance and hypercholesterolaemia in obese Zucker rats are associated with a modification of the mechanical behaviour of a conductance (carotid) artery and with an altered endothelium-dependent response to acetylcholine of a small resistance (mesenteric) artery. DESIGN: Male obese Zucker rats, 6-8 months old, were compared with age-matched lean heterozygous and control Zucker rats. METHODS: The mechanical behaviour of the carotid artery was examined in anaesthetized rats by simultaneously monitoring the internal diameter with an A-mode ultrasonic echo-tracking device and the intra-arterial pressure with a computerized data-acquisition system. Furthermore, histometric measurements of the carotid artery were carried out after death. The response to acetylcholine was examined in vitro with a Mulvany dual myograph on precontracted isolated segments of the third-generation mesenteric artery. RESULTS: Obese Zucker rats exhibited high plasma insulin and cholesterol levels. Blood pressure was the same in the obese and control animals. There was no hypertrophy or change in the mechanical behaviour of the carotid arterial wall. Heart weight was slightly higher in the obese rats than in the controls, but smaller in relation to body weight. The relaxation to acetylcholine was significantly attenuated in isolated small mesenteric arteries obtained from the obese strain. CONCLUSION: Hyperinsulinaemia and hypercholesterolaemia in obese Zucker rats are associated with an abnormal response to acetylcholine in the mesenteric arterioles. This metabolic state does not, however, alter the mechanical behaviour or the geometry of the carotid artery.
Acetylcholine↗
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↗
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↗
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↗
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↗
Modifications of glucose and lipid metabolism in cold-acclimated lean and genetically obese rats.
Glucose turnover rate, 2-deoxy-D-[3H]glucose (2-DG) uptake, lipid synthesis in liver, white adipose tissue, and brown adipose tissue (BAT) were measured in lean FA/FA and genetically obese fa/fa rats either kept at 21 degrees C or acclimated to a cold environment (4 degrees C). After 10 days at 4 degrees C, lean rats increased their glucose turnover rate; 2-DG uptake as well as lipid synthesis in BAT were markedly stimulated. After cold acclimation, obese rats also increased glucose turnover; however, BAT glucose utilization was only slightly stimulated. Basal hyperinsulinemia and muscle insulin resistance of the obese group (as assessed by reduced 2-DG uptake in the soleus muscle) were present at room temperature and persisted at 4 degrees C. Total BAT lipid synthesis was increased to the same extent as in lean rats. Obese rat liver lipid synthesis, already much higher than normal at 21 degrees C, was further increased by cold exposure. We conclude that obese cold-acclimated fa/fa rats do not improve their muscle insulin resistance and barely improve BAT glucose utilization. We further suggest that an additional activation of hepatic lipid synthesis and oxidation thereof could participate in the heat production needed by the cold-acclimated obese rats.
Acclimatization↗
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↗
Central nervous system and peripheral abnormalities: clues to the understanding of obesity and NIDDM.
To study the impact on glucose handling of the observed hyperinsulinaemia and hypercorticism of the genetically obese fa/fa rats, simplified animal models were used. In the first model, normal rats were exposed to hyperinsulinaemia for 4 days and compared to saline-infused controls. At the end of this experimental period, the acute effect of insulin was assessed during euglycaemic-hyperinsulinaemic clamps. White adipose tissue lipogenic activity was much more insulin responsive in the "insulinized" than in the control groups. Conversely muscles from "insulinized" rats became insulin resistant. Such divergent consequences of prior "insulinization" on white adipose tissue and muscle were corroborated by similar divergent changes in glucose transporter (GLUT 4) mRNA and protein levels in these respective tissues. In the second model, normal rats were exposed to stress levels of corticosterone for 2 days. This resulted in an insulin resistance of all muscle types that was due to an increased glucose-fatty acid cycle, without measurable alteration of the GLUT 4 system. In genetically obese (fa/fa) rats, local cerebral glucose utilization was decreased compared to lean controls. This could be the reason for adaptive changes leading to increased levels in their hypothalamic neuropeptide Y levels and median eminence corticotropin-releasing-factor. Thus, in a third model, neuropeptide Y was administered intracerebroventricularly to normal rats for 7 days. This produced hyperinsulinaemia, hypercorticosteronaemia, as well as most of the metabolic changes observed in the genetically obese fa/fa rats, including muscle insulin resistance. These data together suggest that the aetiology of obesity-insulin resistance of genetically obese rodents has to be searched within the brain, not peripherally.
Animals↗
In vivo regulation of adipose tissue lipoprotein lipase in normal rats made hyperinsulinemic and in hyperinsulinemic genetically-obese (fa/fa) rats.
The objective of this study was to investigate in vivo the effects of various durations of hyperinsulinemia on inguinal white adipose tissue lipoprotein lipase (LPL). Adult genetically-obese (fa/fa) rats were used as a model of chronic hyperinsulinemia. Normal rats infused with insulin as well as with glucose to maintain euglycemia for four days were used as a model of short-term hyperinsulinemia. Normal rats studied during a euglycemic-hyperinsulinemic clamp were used as a model of acute effects of hyperinsulinemia. The levels of LPL mRNA, LPL protein and LPL total activity in inguinal white adipose tissue were measured. In both chronic and long-term hyperinsulinemia, a marked increase in total LPL activity was observed which was associated with an increase in tissue LPL protein abundance. After five hours of hyperinsulinemia, as achieved during the clamps, only total LPL activity was increased. An increase in LPL mRNA was measured only in adipose tissue of obese rats. The differences observed in the regulation of LPL mRNA between insulin-treated rats and genetically-obese animals may be explained either by the large increase in adipose tissue glucose metabolism of insulin-treated rats compared to obese rats and/or by other factors that may be present in genetically-obese (fa/fa) rats.
Acute Disease↗
Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats.
The mechanism by which glucocorticoids induce insulin resistance was studied in normal rats administered for 2 days with corticosterone then tested by euglycaemic hyperinsulinaemic clamps. Corticosterone administration induced a slight hyperglycaemia, hyperinsulinaemia and increased non-esterified fatty acid levels. It impaired insulin-stimulated total glucose utilization (corticosterone 15.7 +/- 0.7; controls 24.6 +/- 0.8 mg.kg-1 x min-1), as well as residual hepatic glucose production (corticosterone 4.9 +/- 1.0; controls 2.0 +/- 0.7 mg.kg-1 x min-1). During the clamps, insulin did not decrease the elevated non-esterified fatty acid levels in corticosterone-administered rats (corticosterone 1.38 +/- 0.15, controls 0.22 +/- 0.04 mmol/l). Corticosterone administration decreased the in vivo insulin-stimulated glucose utilization index by individual muscles by 62 +/- 6%, and the de novo glycogen synthesis by 78 +/- 2% (n = 8-9 muscles). GLUT4 protein and mRNA levels were either unchanged or slightly increased by corticosterone administration. Inhibition of lipid oxidation by etomoxir prevented corticosterone-induced muscle but not hepatic insulin resistance. In conclusion, glucocorticoid-induced muscle insulin resistance is due to excessive non-esterified fatty acid oxidation, possibly via increased glucose fatty-acid cycle ultimately inhibiting glucose transport, or via decreased glycogen synthesis, or by a direct effect on glucose transporter translocation or activity or both.
Animals↗