VMH Rats Research Articles

Cardiovascular vagosympathetic activity in rats with ventromedial hypothalamic obesity.

Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long-term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart beta-adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic-acting drugs showed an increase in heart vagal tone and responsiveness to a beta-agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart beta-adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. These results show the following in this model of massively obese rats with sympathetic impairment: 1). adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2). cardiac responsiveness to beta-agonist stimulation is increased; and 3). despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.

Leptin Resistance of Adipocytes in Obesity: Role of Suppressors of Cytokine Signaling

Liver-derived hyperleptinemia induced in normal rats by adenovirus-induced gene transfer causes rapid disappearance of body fat, whereas the endogenous adipocyte-derived hyperleptinemia of obesity does not. Here we induce liver-derived hyperleptinemia in rats with adipocyte-derived hyperleptinemia of acquired obesity caused by ventromedial hypothalamus lesioning (VMH rats) or by feeding 60% fat (DIO rats). Liver-derived hyperleptinemia in obese rats caused only a 5–7% loss of body weight, compared to a 13% loss in normoleptinemic lean animals; but in actual grams of weight lost there was no significant difference between obese and lean groups, suggesting that a subset of cells remain leptin-sensitive in obesity. mRNA and protein of a putative leptin-resistance factor, suppressor of cytokine signaling (SOCS)-1 or -3, were both increased in white adipose tissues (WAT) of VMH and DIO rats. Since transgenic overexpression of SOCS-3 in islets reduced the lipopenic effect of leptin by 75%, we conclude that the increased expression of SOCS-1 and -3 in WAT of rats with acquired obesity could have blocked leptin's lipopenic action in the leptin-resistant WAT population.

Ventromedial Nuclei of the Hypothalamus are Involved in the Phase Advance of Temperature and Activity Rhythms in Food-Restricted Rats Fed During Daytime

Daily rhythms are synchronized to the light-dark cycle (LD) via a circadian clock located in the suprachiasmatic nuclei. A timed caloric restriction phase advances daily rhythms of body temperature and wheel-running activity in rats kept under LD. Because lesions of the ventromedial hypothalamic nuclei (VMH) prevent the fasting-induced changes in the day-night pattern of activity, it was hypothesized that the VMH might participate in the caloric restriction-induced phase changes. To test this hypothesis, rats with electrolytic or ibotenic acid lesions of VMH and control rats were fed 2 h after lights on 50% of ad lib food intake. During the preceding fed state, rats with electrolytic lesions of VMH displayed a less marked day-night difference in locomotor activity and a phase-advanced acrophase of temperature rhythm (2 h) compared to those of sham-operated rats. These effects were not found in fed rats with ibotenic lesions of VMH, suggesting that these effects of electrolytic lesions were due to disruption of undetermined fibers of passage. In response to a timed caloric restriction, the nocturnal peak of temperature rhythm was phase advanced by 7 h in sham-operated rats. Their day-night pattern of activity was also phase advanced towards the time of feeding. In both groups of food-restricted VMH-lesioned rats, the acrophase of temperature rhythm plateaued 3 h later than in sham-operated group. The phase advance of body temperature was, therefore, reduced to 4 h by ibotenic lesions of VMH and to 2 h by electrolytic lesions. Except for a feeding-associated component of activity expressed in control and VMH-lesioned rats, no significant change in day-night pattern of activity was detected in VMH-lesioned rats, either by electrolytic or ibotenic lesions. These results indicate that neuronal damage of the VMH limits the phase-advancing properties of a timed caloric restriction on the daily rhythms of temperature and locomotor activity.

Insulin receptor kinase activity in muscles and white adipose tissue during course of VMH obesity.

Early after lesion of the ventromedial hypothalamus nuclei (VMH), insulin-induced glucose utilization is increased in white adipose tissue (WAT), whereas oxidative and glycolytic muscles are, respectively, normoresponsive or resistant to insulin. Five weeks later, all of the muscles are resistant, whereas WAT returns to normal responsiveness. The aim of this study was to characterize the insulin receptor kinase activity in WAT and muscles 1 and 6 wk after lesion. The number and affinity of insulin receptors were not modified in any of the tissues studied. Autophosphorylation and phosphorylation of an exogenous substrate were similar in oxidative and glycolytic muscles of VMH and control rats both 1 and 6 wk after the lesion. Insulin receptors from WAT of 1-wk VMH rats exhibited a 2.5-fold increase in insulin-stimulated autophosphorylation and phosphorylation. Six weeks after the lesion, both autophosphorylation and phosphorylation returned to normal values. This suggests that insulin receptor tyrosine kinase activity does not play a significant role in the insulin resistance of skeletal muscles but has a crucial role in mediating the variations of insulin action on WAT observed during the development of VMH obesity.

Ventromedial hypothalamus vs. lateral hypothalamic D2 satiety receptors in the body weight increase induced by systemic sulpiride

Two experiments were conducted in order to see if dopamine satiety receptors in the lateral hypothalamus or satiety mechanisms in the ventromedial hypothalamus were involved in the hyperphagia and body weight increase induced by systemic sulpiride. In the first experiment, it was shown that systemic sulpiride (20 mg/kg) does not block the anorexia caused by intraperifornical injections of amphetamine. In the second experiment, sulpiride (20 mg/kg during 18 days) did not produce an additional increase in body weight in previously VMH-lesioned female rats. This last fact cannot be explained by a ceiling effect since insulin (5 U/day during 7 days) increased body weight in the same VMH rats in which sulpiride was not effective. These results do not support the hypothesis that systemic sulpiride reaches the perifornical dopamine D2 receptors to disinhibit feeding, but suggest instead an involvement of the ventromedial hypothalamus. This last suggestion is more in agreement with the hypothesis that sulpiride alters feeding and body weight gain through the induction of a functional gonadectomy.

Effect of mazindol on insulin and glucagon secretion in ventromedial hypothalamic obese rats

The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.

Energy metabolism in rats with ventromedial hypothalamic lesions.

Rats with ventromedial hypothalamic lesions (VMH) have increased ability to accumulate energy. The aim of this investigation was to characterize the main processes responsible for the reduced energy expenditure, using indirect calorimetry, nitrogen, and energy balance techniques. Metabolism was studied during different metabolic conditions created by a strict feeding regimen with concentrated feeding periods. A computerized system for indirect calorimetry enabled continuous study of individual animals for prolonged time periods. We found a mean decrease of 15.5% in total energy expenditure and decreased nitrogen retention in VMH rats. Calculation of respiratory quotient (RQ), energy expenditure, and the metabolic mixture demonstrated fluctuations in metabolism in accordance with the feeding regimen. The same percent reduction in resting postabsorptive energy expenditure was found as in total expenditure. Quantitatively, this main finding means that metabolic processes that occurred both in the resting and postabsorptive state were responsible for two-thirds of the total reduction in energy expenditure, whereas only one-third could be attributed to differences in dietary-induced thermogenesis and/or physical activity. It is concluded that VMH-animals spent as much as 10.3% of their total energy expenditure on liponeogenesis compared with 2.5% in controls.

The dopaminergic mediation of a sweet reward in normal and VMH hyperphagic rats

The role of dopamine in mediating the rewarding quality of a sweet saccharin-glucose (SG) solution was investigated by comparing the effects of the dopamine receptor blocker pimozide, the bitter adulterant quinine, and solution dilution on the consummatory response to the solution in normal and VMH rats. Experiments 1 and 2 demonstrated that pimozide and quinine caused a dose/concentration dependent dependent reduction in the intake of and the licking response to a SG solution. Pimozide treatment caused an equivalent suppression in the intake of the normal and VMH rats, in both the dynamic and static phases, whereas quinine adulteration caused a greater suppression in the intake of the VMH rats. The effects of pimozide and quinine on initial lick rate were also different. Experiment 3 demonstrated that dilution of a SG solution produced a concentration related decrease in intake and licking response. Dilution of the SG solution, like pimozide treatment, affected the intake of the normal and VMH rats in an equivalent manner. The effects of solution dilution and pimozide treatment on the licking response were also similar. The results suggest that the mechanisms by which pimozide and quinine reduce the hedonic quality of natural rewards are functionally dissimilar. The similarity between pimozide treatment and solution dilution suggests that pimozide reduces the positive affective quality of natural reinforcers. The results are discussed in terms of the dopamine theory of reward, the role of dopamine in hypothalamic hyperphagia, and VMH finickiness.

Atropine fails to block the overconsumption of sugar solutions by hypothalamic hyperphagic rats.

Adult female rats given bilateral parasagittal knife cuts in the medial hypothalamus (VMH group) were hyperphagic and became obese on a chow diet, compared with sham-operated controls. The VMH rats also overconsumed, relative to controls, sucrose and glucose solutions during 30 min/day tests. Pretreating the VMH and control rats with atropine methyl nitrate (1.0, 5.0, or 10.0 mg/kg) reduced their intake of the sugar solutions in three out of five experiments, and in all experiments it suppressed their 24-hr chow intake. However, the VMH rats continued to drink more of the sugar solutions than did the controls after all atropine treatments, and in three out of four experiments their hyperphagia on the chow diet was not blocked by the atropine. The results do not support the hypothesis that vagally stimulated insulin release or other cholinergically mediated cephalic responses of digestion are essential for the expression of hypothalamic hyperphagia and finickiness.

Vagotomy blocks hypothalamic hyperphagia in rats on a chow diet and sucrose solution, but not on a palatable mixed diet.

Adult female rats were given ventromedial hypothalamic parasagittal knife cuts (VMH treatment) or control surgery (Con treatment), followed 10 days later by subdiaphragmatic vagotomy (Vag treatment) or sham vagotomy (Sham treatment). The hyperphagia and obesity produced by the VMH cuts to rats on a chow diet was completely blocked by vagotomy (VMH-Vag group). Vagotomy also inhibited the VMH rats' overconsumption of a 20% sucrose solution during 1 hr/day and 24 hr/day tests, which contrasts with the effects of atropine treatment. However, when offered a selection of palatable foods (cookies, sweet milk, high-fat ration) in addition to chow, the VMH-Vag rats overate and gained considerably more weight than did the Con-Vag rats or the Con-Sham rats. The Con-Vag rats, on the other hand, gained less weight than did the Con-Sham rats on the palatable diet. The results indicate that intact subdiaphragmatic vagi are not essential for the expression of VMH hyperphagia and finickiness, and they therefore question the role of vagally mediated cephalic responses in the hypothalamic hyperphagia syndrome. On the other hand, the results indicate that in brain-intact animals vagotomy suppresses the development of diet-induced obesity.

2-deoxy-D-glucose inhibits food intake in rats after ventromedial hypothalamic lesions

Changes in food induced by 2 deoxy-D-glucose (2 DG) have been investigated in newly lesioned rats during the two parts of the diurnal cycle. In a first experiment rats were injected with saline or 2 DG (250, 500, 750 mg/kg) at the beginning of the light or the dark period. In a second experiment rats were injected with saline or 2 DG (250 mg/kg) in the middle of the two periods after 0, 2, 4 or 6 hr of fasting. Results show that 2 DG exerts an inhibitory effect on food intake at night, as it does in intact rats, under ad lib conditions or after a short deprivation time. The stimulating effects of 2 DG on diurnal food intake observed in intact rats is not replicated in VMH rats. On the contrary an inhibition of intake follows a short food deprivation. The data suggest that 2 DG stimulates food intake only under metabolic and feeding conditions characteristic of the diurnal phase in intact rats. Since lipogenesis and hyperphagia are observed 24 hr a day in VMH animals, only inhibition could follow 2 DG.

GABA levels and synthesis index in different brain areas of two obese rat models

1. 1. GABA levels and synthesis index were measured in different brain areas of ventromedian hypothalamic lesioned rats (VMH) and in genetically obese rats (Fatty) compared to lean controls. 2. 2. GABA level was decreased in VMH rats' hypothalamus. 3. 3. GABA synthesis was accelerated in VMH rats' hypothalamus as well as in the hypothalamus, the striatum and the medulla oblongata-pons of Fatty rats. 4. 4. These data are related to the role of GABA in food intake.

Brain catecholamine levels and turnover in various models of obese animals

1. 1. Catecholamine levels and turnover times were measured in several brain areas of two models of obese rats: ventromedial hypothalamic lesioned rats (VMH) and genetically obese rats (Fatty). 2. 2. Norepinephrine (NE) levels were increased only in the hypothalamus and in the remainder of the brain of Fatty rats. Dopamine (DA) levels were not modified. 3. 3. NE turnover time was accelerated in the medulla-oblongata-pons of VMH rats and in Fatty rats hypothalamus. DA turnover time was accelerated in the remainder of the brain of VMH rats while it was slowed in Fatty rats corpus striatum. 4. 4. These data are discussed in regard to the catecholamine hypothalamocentric hypothesis.

Acute hyperkinesia after hypothalamic lesions: A comparison of the time course, level, and type of hyperkinesia induced by ventromedial and lateral hypothalamic lesions in rats

Postoperative hyperkinesia induced by ventromedial (VMH) and lateral hypothalamic (LH) lesions was compared in two experiments. In the first experiment overall motility of the animals was monitored continuously for 20 h after the lesions. Both LH and VMH lesions were found to cause comparably high levels of activity in the first 10 h after the lesion. In the next 10 h VMH rats were more active than LH rats. In a second experiment a detailed analysis of the behaviors displayed by rats with VMH or LH lesions at 4, 8, and 24 h after the lesions revealed that different behavioral components contributed to the overall hyperactivity in the two cases, with a predominance of locomotion, rearing, jumping, and gnawing for VMH lesion rats, and rearing, rotations, and forelimb movements for LH lesion rats during the acute hyperactivity stage. These results indicated that acute motor effects of hypothalamic lesions are specific to lesion placement. Relations to other types of hyperkinesia and possible mechanisms involved are discussed.

Development of VMH obesity in vagotomized rats

In 3 different experiments, vagotomy failed to reverse or prevent the development of hyperphagia and obesity following VMH lesions. In the first experiment, previously vagotomized male rats were given bilateral VMH lesions after testing for completeness of vagotomy. In a second experiment on male rats, vagotomy preceded or followed VMH lesions, and testing for completeness of vagotomy was not carried out until the end of the experiment. In a third experiment obese VMH female rats were vagotomized before or after VMH lesions, and completeness of vagotomy was assessed histologically. In each experiment, vagotomized VMH rats displayed hyperphagia and became obese. Discrepancies between these results and those reported by others are discussed in terms of diet offered, surgical procedures, and the possibility of continuing malaise after vagotomy.

Effects of a Diazoxide inhibition of insulin release on food intake of normal and hyperphagic hypothalamic rats

In order to clarify the role of endogenous insulin in generating normal and pathological feeding behaviors, the effect of an anti-insulin drug, Diazoxide, on the meal pattern has been investigated in both normal and VMH rats. A dose-dependent reduction of food intake under Diazoxide treatment was found in normal rats. The same percentage reduction was obtained at night with a higher dose than required in the daytime. Conversely, hyperphagic VMH rats exhibited a dose-dependent reduction which was identical in the two portions of the diurnal cycle. The dose effective in entirely suppessing eating in VMH rats was twice that required for normal rats in the daytime period and identical at night. The results are discussed in relation to earlier findings concerning the diurnal insulino-secretory pattern in normal and VMH rats.

Infant rats: VMH damage and the ontogeny of obesity and neuroendocrine dysfunction

The VMH was bilaterally destroyed in preweanling (Day 10) or postweanling (Day 40) male and female rats. Growth parameters (body weight, body length, Lee indices) were measured until 200 days of age, nutrient intake was measured during maturity, and an analysis of endocrine gland weights and adenohypophyseal morphology was performed on preweanling rats. When compared with controls, growth was abnormal for VMH rats after 50–80 days of age. Bilateral preweanling females displayed elevated body weights, normal body lengths, and elevated Lee indices, while bilateral preweanling males had normal body weights, stunted linear growth, and elevated Lee indices. Postweanling VMH rats exhibited elevated body weights and elevated Lee indices; however, postweanling VMH males displayed augmented linear growth. VMH rats were normophagic and demonstrated finickiness to taste-aversive fluids. Endocrine gland analysis revealed that preweanling VMH males had neuroendocrine deficits related to somatotrophic hormone (low pituitary weight, decreased adenohypophyseal acidophils), while female VMH rats had neuroendocrine pathology related to metabolic dysfunction (all gland weights were low, decreased adenohypophyseal basophil size).

Delayed response to 2-deoxy-D-glucose in hypothalamic obese rats

A dose-response relationship for the effects of 2-deoxy-D-glucose (2-DG) (0–400 mg/kg) on food intake was established in normal and obese ventromedial hypothalamic lesioned rats. In normal animals the lowest dose that produced a statistically significant increase over baseline food intake was 100 mg/kg 2-DG. Larger doses produced a progressively greater effect. Most of the increase in food intake occurred during the first hour after the injection of 2-DG, the latency of the first feeding bout being shorter for higher doses of the compound. Obese VMH rats significantly increased their 4-hr food intake after 150, 200, 250, and 400 mg/kg 2-DG, but the increase in feeding was delayed compared to control animals. During the first hour after the injection, the food intake of obese rats was unaffected by doses of 2-DG up to 250 mg/kg, and inhibited by higher doses (300 and 400 mg/kg). The effects of VMH lesions on 2-DG-induced eating are attributed to the elimination of afferents from peripheral glucoreceptors.

Impaired and enhanced shuttle box avoidance behavior following ventromedial hypothalamic lesions in rats

VMH-lesioned female Long-Evans hooded rats held to preoperative body weight acquired a shuttle box avoidance response only as rapidly as control animals at both a moderate and high shock level when intertrial interval crossings were not punished, and at a moderate shock intensity with punished ITI crossings. Both groups displayed 90–95% asymptotic avoidance behavior under all three conditions. Obese rats with VMH lesions displayed impaired avoidance behavior under these conditions, displaying only 55–60% asymptotic avoidance behavior after 110 trials. The impaired avoidance behavior by obese rats was not due to immobility, for they emitted as many unpunished ITI crossings as control animals. Both lean and obese rats with VMH lesions avoided a significantly greater number of shocks than control animals at a high shock intensity when ITI crossings were punished, with control animals averaging only 20% avoidance responding after 110 trials. Lean VMH rats again performed better than obese rats, displaying 85% and 60% asymptotic avoidance behavior, respectively. Lean VMH rats made more punished ITI crossings than control animals at the high shock intensity, but there was no difference between the unoperated and obese VMH-lesioned animals. Previous discrepant results with shuttle box avoidance experiments are attributed to different testing conditions, although strain differences are also possible.

Passive avoidance behavior in lean and obese rats with ventromedial hypothalamic lesions

Lean and obese rats with ventromedial hypothalamic lesions performed reliably worse than control animals in the acquisition of a step-down passive avoidance task. However, obese rats performed significantly better than lean VMH animals, which consistently leaped off the platform on the second and succeeding trials. While there were no significant differences between groups in the acquisition of a step-through passive avoidance task, lean and obese rats with VMH lesions took reliably longer than control animals to reach criterion when an identical step-through response had previously been reinforced (punishment-extinction of a one-way conditioned avoidance response). Both lean and obese VMH-damaged rats made more punished approach responses to water than control animals following water-deprivation to 88% of body weight, but only lean VMH rats made a significantly greater number of punished approach responses to liquid food than unoperated animals following food-deprivation to 88% of body weight. The number of punished consummatory responses appeared to be influenced by baseline intake. Among the animals tested in more than one paradigm, there was a significant positive correlation between the number of punished consummatory responses and the number of shocks received during punishment-extinction of the one-way CAR, but no relationship was observed between the performances in either of these and the step-down avoidance paradigm. The impaired passive avoidance behavior by rats with VMH lesions is attributed to both an inability to inhibit a previously reinforced response and a change in response tendencies to aversive stimuli.