Ventromedial Hypothalamic Lesions Research Articles

Ventromedial hypothalamic lesions inhibit corticosteroid feedback regulation of basal ACTH during the trough of the circadian rhythm.

We have determined the effects of bilateral electrolytic lesions of the ventromedial hypothalamus (VMH) on activity in the hypothalamo-pituitary-adrenal (HPA) system. Acutely, during the first 5 days, lesions of the anterior-medial VMH caused loss of the diurnal rhythms in food intake and plasma corticosterone (B) levels. Plasma B concentrations were elevated during the time of the normal trough of the basal diurnal rhythm in HPA axis activity and the diurnal rhythm in food intake was abolished, in agreement with the results of others. Consistent with hyperactivity in the HPA axis, lesioned rats had increased adrenal weight, decreased thymus and body weights and decreased plasma transcortin concentrations. To determine how lesions of the VMH provoke these increases in activity of the HPA system, the sensitivity of ACTH in adrenalectomized, lesioned rats to replacement with exogenous B was determined under basal conditions during the trough (morning-AM) and peak (evening-PM) of the diurnal rhythm in HPA axis activity. ACTH in lesioned rats in the AM was insensitive to feedback over the very low range of plasma B of 1-4 micrograms/dl, whereas sham-lesioned controls exhibited the normal, high sensitivity of ACTH to B at this time of day. There was no difference between the sensitivity of ACTH to this low range of B in the PM in VMH- and sham-lesioned rats. Two to 5 weeks after VMH lesions, as found by others, mean daily plasma B levels did not differ from sham-lesioned controls; however, plasma B during the AM was still mildly elevated in these rats. Inhibition of plasma B in the PM by dexamethasone was less effective in lesioned rats. Although HPA system responses to hypoglycemia, corticotropin-releasing factor and ACTH were normal, the lesioned rats exhibited obesity, hyperinsulinemia, hyperglycemia, hypertension and tachycardia, all signs consistent with mild hyperactivity of the PHA axis. Occupancy of type I, high-affinity corticosteroid receptors is known to control basal activity of the HPA system during the trough of the diurnal rhythm and to interact with glucocorticoid receptors to affect basal activity during the peak of the diurnal rhythm and during AM stress. We conclude that VMH lesions disrupt transmission of inhibitory signals, mediated by occupancy of type I corticosteroid receptors, that are initiated by a B feed-back site.

Bombesin-induced hypothermia in rats tested at normal ambient temperatures: Contribution of the sympathetic nervous system

Rats infused centrally with bombesin become hypothermic at normal ambient temperatures when acutely deprived of food, but not while allowed unrestrained access to food. Ad lib-fed rats, tested at normal ambient temperatures, become hypothermic after receiving intracerebroventricular (ICV) bombesin when they have ventromedial hypothalamic lesions or when administered insulin or 2-deoxy- d-glucose peripherally. All of these conditions have been linked to reductions of sympathetic nervous system activity to brown adipose tissue (BAT), a major thermogenic mechanism of many homeotherms. A between group design was used to examine the effects of ICV bombesin infusions on the response to peripheral injections of a) the sympathetic ganglionic blocker chlorisondamine (2.5 mg/kg, IP) in ad lib-fed rats, b) the nonspecific β-agonist isoproterenol (30 mg/kg, IP) in food-deprived rats, and c) the combination of isoproterenol and chlorisondamine in ad lib-fed rats. Ad libfed rats receiving ICV bombesin (100 ng/5 μl), in combination with peripheral chlorisondamine injection, became hypothermic 60 min postbombesin administration (−2.84 ± 0.33°C), while ad lib-fed rats receiving ICV bombesin infusion and peripheral injections of saline did not (−0.08 ± 0.37°C). Isoproterenol blocked hypothermia in ad lib-fed rats injected with chlorisondamine and ICV bombesin. Food-deprived rats receiving ICV bombesin infusion and peripheral saline injection exhibited hypothermia 60 min postbombesin administration (−2.51 ± 0.29°C). Peripheral injections of isoproterenol prevented bombesin-induced hypothermia in food-deprived rats. These data suggest that bombesin induces hypothermia at normal ambient temperatures when the sympathetic nervous system drive to BAT cannot be (or is not) activated.

Ventromedial hypothalamic lesions increase gastrointestinal DNA synthesis through vagus nerve in rats

Ventromedial hypothalamic lesions increase gastrointestinal DNA synthesis through vagus nerve in rats

Activation of the rat melanin-concentrating hormone neurons by ventromedial hypothalamic lesions

The occurrence of a melanin-concentrating hormone-like peptide (MCH) was previously reported in the lateral hypothalamus of the rat. The sequence of this peptide was determined but its role as well as its regulation remain unclear. In the present study, we examined the effects of minor electrolytic lesions of the ventromedial nuclei (VMN) on MCH neurons by using immunocytochemical and in situ hybridization procedures. We report that VMN lesions resulted in (1) a clear elevation in the number and staining intensity of MCH immunoreactive perikarya and fibres, (2) a significant increase in the level of hybridocytochemical signal obtained with an oligonucleotide probe complementary to rMCH mRNA. These data provide evidence for a role of VMN in modulating the MCH gene and peptide expression.

Facilitation of liver regeneration after partial hepatectomy by ventromedial hypothalamic lesions in rats.

Whether or not the hypothalamus is involved in initiating hepatic DNA synthesis after partial hepatectomy is unclear. To determine the role of the ventromedial hypothalamic nuclei in liver regeneration after partial hepatectomy, we studied hepatic DNA synthesis during liver regeneration in rats with bilateral lesions of these nuclei. Lesions of the ventromedial hypothalamus accelerated the increase in hepatic DNA synthesis and raised the peak level of thymidine incorporation after partial hepatectomy. These effects of hypothalamic lesions were completely inhibited by hepatic vagotomy. Thus, lesions of the ventromedial hypothalamus appear to promote hepatic regeneration by increasing vagal stimulation of the liver.

The biphasic changes in splenic natural killer cell activity following ventromedial hypothalamic lesions in rats

The cytotoxic activity of natural killer (NK) cells in the spleen was measured by a standard 4-h chromium release assay following electrical lesioning of the ventromedial hypothalamic nucleus (VMH) in rats. The splenic NK cell activity of VMH lesioned rats was found to be significantly suppressed at effector: target cell ratios of 100:1 and 50:1 compared with that of sham lesioned rats on day 4 after the lesion. On the other hand, on day 49, the VMH lesioned animals that had become hyperphagic and obese showed an enhancement of splenic NK cell activity compared with sham lesioned animals. The mechanisms of the biphasic change in NK cell activity following the VMH lesions are discussed.

Effects of intraventricular administration of neuropeptide Y on feeding behavior in fasted female rats with ventromedial hypothalamic lesions

The role of ventromedial hypothalamic nucleus (VMN) in feeding behavior induced by central administration of porcine neuropeptide Y (NPY) in fasted female rats was investigated focusing on the effect of the intracerebro-ventricular (i.c.v.) injection of NPY on food intake in rats with VMN lesions after 24 h of food deprivation. Cumulative food intake was measured 1, 3 and 6 h after injection. In Exp. 1, the i.c.v. injection of NPY into intact rats stimulated food intake compared with the injection of saline 1 and 3 h after the injections in a dose dependent manner (1 h; NPY 1 μg, 3.29 ± 0.43, 2 μg, 4.64 ± 0.88, 5 μg, 5.15 ± 0.61 vs. saline 2.48 ± 0.42 g , P<0.05 in 2 and 5 μg). 5 μg of NPY significantly stimulated food intake 6 h later. In Exp. 2, i.c.v. injection of NPY (2 μg) in VMN-lesioned rats showed no significant effect on food intake compared with the injection of saline 3 weeks after VMN lesioning (1 h; NPY 2 μg, 2.46 ± 0.58 vs. saline 2.39 ± 0.12 g ). These results suggest that central administration of NPY enhances food intake in fasted female rats and that the VMN is one of the crucial sites of NPY induced feeding.

Marked reduction of pancreatic insulin content in male ventromedial hypothalamic-lesioned spontaneously non-insulin-dependent diabetic (Goto-Kakizaki) rats

The effects of ventromedial hypothalamic (VMH) lesions were examined in male and female non-obese non-insulin-dependent diabetic (Goto-Kakizaki [GK]) rats with respect to glucose metabolism and pancreatic insulin content. VMH lesions produced hyperphagia and hyperinsulinemia in both male and female GK rats. In male rats, plasma glucose levels of VMH-lesioned GK rats (22.7 ± 3.1 mmol/L) were significantly greater than the levels of sham-operated GK rats (10.6 ± 1.0 mmol/L, P < .001) at 7 weeks after the operation, although there were no differences in these levels between VMH-lesioned and sham-operated groups in Wistar rats. Plasma insulin levels in male VMH-lesioned GK rats tended to be lower at 7 weeks than at 1 week. VMH lesions caused a significant decrease in the pancreatic insulin content of male GK rats (12.0 ± 2.3 nmol/L/g pancreas) compared with male sham-operated rats (15.8 ± 1.4 nmol/L/g pancreas, P < .05) 9 weeks postoperatively. In contrast to the results in male rats, female GK rats showed no differences in plasma glucose levels between VMH-lesioned and sham-operated groups at 7 weeks. Female VMH-lesioned GK rats also showed no difference in plasma insulin levels between 1 week and 7 weeks. The pancreatic insulin level of female VMH-lesioned GK rats was unchanged from that of female sham-operated GK rats. The insulin content was significantly greater in the VMH-lesioned Wistar group than in the sham-operated Wistar group, regardless of sex. These observations suggest that the increased requirement for insulin secretion caused by VMH lesions may lead to B-cell exhaustion, producing, at least in part, marked hyperglycemia in male GK rats. Male VMH-lesioned GK rats might be a good model for obese Japanese patients with the genetic predisposition to non-insulin-dependent diabetes mellitus (NIDDM).

The influence of exercise on energy balance changes induced by ventromedial hypothalamic lesion in the rat

The effects of a hypothalamic ventromidial area lesion on energy balance were tested in exercising rats and in sedentary rats to add further information about the type of obesity developed after ventromedial lesion. Four groups of six male Sprague-Dawley rats were used. Group 1: sham-lesioned and sedentary rats, which were utilized as control rats (C); group 2: sham-lesioned and exercising rats (E); group 3: lesioned and sedentary rats (L); group 4: lesioned and exercising rats (LE). The exercise consisted of daily swimming for 30 min. Resting oxygen consumption, food intake, and body weight were measured before any treatment and 3 weeks after the lesion or/and the exercise period. The results showed that the oxygen consumption increased in the E and LE groups but not in the C and L groups. Food intake increased more in E and LE groups than in L group. The increases in body weight were higher in L and LE than in the E and C groups. These findings suggest that exercise modifies resting oxygen consumption and food intake in lesioned rats, but does not influence the degree of obesity. Thus, the ventromedial syndrome can be considered a type of obesity not completely unregulated.

Determinants of fasting hypertriglyceridemia in ventromedial hypothalamic obesity in rats.

The present study investigated the mechanism of fasting hypertriglyceridemia in ventromedial hypothalamic (VMH) obesity by measurement of post-heparin plasma lipoprotein lipase (LPL) activity, triglyceride secretion rate (TGSR), and plasma insulin. One week after VMH lesions, when the lesioned rats were gaining weight rapidly (the dynamic phase), they showed normal plasma triglyceride levels with increased plasma LPL activity and TGSR. There was a positive correlation between hyperinsulinemia and elevated plasma LPL activity or TGSR in VMH-lesioned rats, while no correlation was observed in control rats. Ten weeks after VMH lesions, when the rats had become obese and reached a steady-state weight gain (the static phase), they showed hypertriglyceridemia with increased plasma LPL activity and TGSR. There was, again, a positive correlation between hyperinsulinemia and elevated plasma LPL activity or TGSR in VMH-lesioned rats. These results suggest a possible mechanism of fasting hypertriglyceridemia in these rats; in the dynamic phase adipose tissue adequately takes up circulating triglyceride because the tissue has sufficient take-up capacity and hence hypertriglyceridemia does not develop. In the static phase the tissue cannot adequately take up circulating triglyceride because of a limitation of its capacity, resulting in hypertriglycemia despite enhanced triglyceride secretion and increased LPL activity in both phases.

Responses to catecholamines in perfused livers of hypothalamic-lesioned rats.

The responses of hepatic glycogenolysis to catecholamines in ventromedial hypothalamus (VMH)-lesioned male rats were examined in perfused livers. Seven days after bilateral electrical lesioning of the VMH, the livers were perfused. Isoproterenol, a beta-agonist, stimulated greater glucose production in VMH-lesioned rats than in controls (32.8 vs. 5.6 mumol glucose.h-1.g liver-1), while responses to phenylephrine, an alpha-agonist, decreased significantly compared with controls (44.4 vs. 69.8 mumol glucose.h-1.g liver-1). There were no significant differences in responses of livers to glucagon and vasopressin between control and VMH-lesioned rats. Adrenodemedullation showed the same effect on beta-responses as lesions in the VMH, but no effect on alpha-responses. Plasma epinephrine levels were not detectable with the high-performance liquid chromatography analysis in VMH-lesioned rats. The periodicity of plasma corticosterone levels was observed in both VMH-lesioned and control rats, although daytime increases in plasma corticosterone were blocked by VMH lesions. These results suggest that the lesions in the VMH cause changes in the levels of adrenergic receptor and that the increase in beta-responses is caused mostly by the reduction of plasma epinephrine.

Hypergastric acid secretion in rats with ventromedial hypothalamic lesions

This study was designed to investigate abnormal gastric acid secretion in ventromedial hypothalamic (VMH)-lesioned rats. Basal secretion and secretion stimulated by pentagastrin (25 μg/kg, IP) or histamine (2 mg/kg/h, IV) were significantly higher in VMH-lesioned rats than in sham VMH-lesioned rats. Subdiaphragmatic vagotomy and methyl atropine treatment (5 mg/kg, IV) remarkably decreased both basal (about 36–44%) and stimulated secretion (about 36–67%) in VMH-lesioned rats, but did not completely reverse it to normal. Serum insulin and glucose levels were significantly higher in VMH-lesioned rats, but serum gastrin levels were not. VMH-lesioned rats showed significantly heavier gastric dry weight; however, no difference in the mucosal layer/total layer ratio of the gastric wall and the density of the parietal cells was observed between the two groups, indicating that the total number of parietal cells might have increased in VMH-lesioned rats because the increase of gastric dry weight can be presumed to be due to increase of the gastric mucosal layer as well as total layer. These results suggest that vagal activation is one of the main contributors to hypergastric acid secretion in VMH-lesioned rats, but that other factors such as increase of parietal oxyntic cell number may also contribute.

Ventromedial hypothalamic lesions increase gastrointestinal DNA synthesis through vagus nerve in rats

Background: It was recently reported that ventromedial hypothalamic (VMH) lesions produced an increase in gastrointestinal DNA content in rats. In the present study, the mechanism of this alteration was examined. Methods: The DNA content and synthesis after VMH lesioning in rat gastrointestinal tracts were determined. Results: Total content of DNA in stomach and small intestine began to increase at 3 days and continued to increase for 7 days, whereas DNA content in the large intestine began to increase at 3 days and maintained the same level until 7 days after VMH lesioning. DNA synthesis of these organs increased and reached maximum at 3 days and then decreased to the initial level 7 days following the lesions. This increase in DNA content and synthesis in these organs was largely inhibited by bilateral subdiaphragmatic vagotomy or the administration of atropine, a cholinergic blocker, but not by the administration of anti-insulin antibody. Conclusions: VMH lesions induce cell proliferation in the rat gastrointestinal tract by the firing of vagus nerve activity mainly through the cholinergic receptor mechanism.

Bombesin-induced hypothermia in VMH-lesioned rats

Microinfusion of bombesin into the lateral ventricles (LV) of rats pretreated with insulin or acutely deprived of food has been demonstrated to reduce core body temperature. Lesions of the ventromedial hypothalamus (VMH) have been shown to produce hyperphagia, hyperinsulinemia, and to alter serum metabolic fuels. The present study examines VMH lesions as a permissive event in bombesin-induced hypothermia in rats tested at normal ambient temperature. A between-group design was used to evaluate the effect of microinjections of bombesin (1, 10, 100 ng) into the LV of rats with bilateral VMH lesions or sham lesions. Core body temperature was recorded over a 240-min period. In animals with lesions of the VMH, hypothermia was demonstrated by 30 min after injection of the 10 ng and 100 ng doses; the hypothermia persisted for 120 min. The 1 ng dose had no effect on body temperature in VMH-lesioned animals. Animals that received sham lesions of the VMH did not demonstrate a reduction in core body temperature at the maximum effective dose (100 ng) of bombesin. These results suggest that some event(s) associated with bilateral VMH lesions acts as a permissive factor in the production of bombesin-induced hypothermia at normal ambient temperature.

Neurons in the hypothalamic paraventricular nucleus mediate the serotonergic stimulation of renin secretion

The aim of the present study was to resolve which hypothalamic nucleus is necessary for the serotonergic control of renin secretion. RU 24969 is considered a serotonin (5-HT 1A/5-HT 1B) agonist, while p-chloramphetamine is a 5-HT releaser. Both drugs reliably elevate plasma levels of renin when injected peripherally. Previous studies suggest that serotonergic neurons, projecting to the hypothalamus, mediate the effect of p-chloroamphetamine on renin secretion. Discrete cell-selective lesions were made with ibotenic acid in three hypothalamic sites: the paraventricular, the dorsomedial or the ventromedial nuclei. Two weeks after surgery rats were injected with RU 24969 (5 mg/kg, i.p.) or p-chloroamphetamine (8 mg/kg, i.p.). The renin response to both RU 24969 and p-chloroamphetamine was significantly reduced in rats with histologically verified paraventricular lesions compared to vehicle treated controls. In contrast, the renin response to p-chloroamphetamine remained unchanged in rats with either dorsomedial or ventromedial hypothalamic lesions. Thus, these results are consistent with the hypothesis that 5-HT receptors located on cell bodies in the paraventricular nucleus mediate the renin response to a serotonin agonist and releaser. Furthermore, they confirm previous studies that suggest that 5-HT neurons regulate renin secretion through central receptors.

Molecular and metabolic changes in white adipose tissue of the rat during development of ventromedial hypothalamic obesity.

We have previously shown that rats made obese by lesion of ventromedial hypothalamus (VMH) nuclei, demonstrate an hyper-responsiveness to insulin with regard to whole-body glucose utilization one week after injury. This is mainly due to an increased glucose uptake in white adipose tissue. Six weeks after the lesion, glucose utilization in white adipose tissue returns to normal values. These modifications in insulin responsiveness could be mediated by altered activity and/or concentration of intracellular insulin effectors. In this study, we have measured the expression of the insulin-sensitive glucose transporter, Glut 4 and the activities and expression of key lipogenic enzymes (fatty-acid synthase and acetyl-CoA carboxylase) in white adipose tissue, one and six weeks after the lesion. All these parameters, as well as glucose transport and metabolism determined in white adipocytes, were markedly increased one week after the lesion. They returned to control values within six weeks in VMH-lesioned rats. These results indicate the existence of an increased expression of Glut 4 and lipogenic enzymes in white adipose tissue of VMH-lesioned rats which decreased with time and were parallel to glucose utilization determined in vivo.

Elevated content and secretion of gut GLI in VMH-lesioned rats

Gut glucagon-like immunoreactivity (GLI), a supposed intestinal growth factor in the plasma and gastrointestinal tract, and weight of the gastrointestinal tract, an intestinal growth indicator, were examined in ventromedial hypothalamic (VMH)-lesioned rats 1 week after VMH lesions. Postprandial plasma gut GLI in VMH-lesioned rats was significantly higher than that in control rats. The content of gut GLI in all gastrointestinal sections except the duodenum in VMH-lesioned rats was significantly greater than that in control rats. Gel chromatography in the lower portion of the small intestine in which GLI content was the highest of all sections revealed the same pattern in both VMH-lesioned and control rats with two peaks of similar molecular size. Weight of all gastrointestinal sections except the cecum in VMH-lesioned rats significantly increased. These results demonstrated that both gut GLI secretion and production were enhanced in VMH-lesioned rats. The elevated gut GLI release may accelerate growth of the gastrointestinal tract in these animals.

Insulin and glucose transporter gene expression in obesity and diabetes.

In order to determine the role of insulin and glucose transporter gene expression in the development of diabetes in obesity, we examined insulin and GLUT2-liver type and GLUT4-muscle-fat type glucose transporter mRNA levels in obese and diabetic rats. Ventromedial hypothalamus-lesioned (VMH), Zucker fatty (ZF), and Wistar fatty (WF) rats were used as models. VMH and ZF rats are most frequently used as models for simple obesity. In contrast, WF rats, which have been established by transferring the fa gene of ZF rats to Wistar Kyoto rats, develop both obesity and diabetes. Pancreatic insulin content of VMH rats at 10 weeks after the operation and of ZF rats at 5 and 14 weeks of age was significantly higher than that of controls. On the other hand, insulin content of WF rats at 5 and 14 weeks of age was not significantly different from that of lean littermates. The insulin mRNA levels of VMH rats were increased progressively and were significantly higher than those in sham-operated animals at 4 and 10 weeks after the operation. In ZF rats, the insulin mRNA levels at 5 and 14 weeks of age were significantly higher than those of their lean littermates. In WF rats, by contrast, the insulin mRNA levels were similar to those of lean littermates at 5 and 14 weeks of age. The insulin mRNA levels of WF rats were about 40% of that of ZF rats at 14 weeks of age. On the other hand, at 14 weeks of age, the GLUT2 mRNA levels of liver were significantly higher in ZF and WF rats than those in their respective littermates, but not at 5 weeks of age. The GLUT4 mRNA levels of skeletal muscle in both ZF and WF rats were not significantly different from those of controls. It is suggested that the inability of WF rats to augment insulin gene expression in response to a large demand for insulin is associated with the occurrence of diabetes, and that the activation of GLUT2 mRNA without the activation of GLUT4 mRNA is common to obesity with and without diabetes.

Role of vagus nerve in increased DNA synthesis after hypothalamic ventromedial lesions in rat liver.

We recently reported that ventromedial hypothalamic (VMH) lesions produced an increase in DNA content in rat liver. In the present study, we examined the mechanism of increased hepatic DNA content produced by VMH lesions. Hepatic DNA content began to increase 3 days after VMH lesioning and continued to increase until 7 days after the lesioning. Hepatic DNA synthesis increased and reached maximum 3 days after the lesioning and then decreased to the initial level 7 days after lesioning. The increased DNA content and synthesis after VMH lesioning were completely inhibited by vagotomy (hepatic vagotomy or bilateral subdiaphragmatic vagotomy) and largely inhibited by the administration of atropine but not by administration of anti-insulin antibody. These results suggest that vagus firing produced by VMH lesions stimulates DNA synthesis in rat liver mainly through cholinergic receptor mechanisms.

Mechanism of intrahippocampal neostigmine-induced hyperglycemia in fed rats.

We previously reported that the injection of neostigmine, an acetylcholine esterase inhibitor, into the dorsal hippocampus produced hepatic venous plasma hyperglycemia associated with an increase of epinephrine and glucagon in anesthetized fed rats. To evaluate the relative contribution of these glucoregulatory hormones and the nervous system to the net hyperglycemic response, we unilaterally injected neostigmine (5 x 10(-8) mol) into the dorsal hippocampus in the following groups of rats: intact rats with bilateral adrenalectomy to eliminate the action of epinephrine, and rats receiving a constant infusion of somatostatin and insulin to prevent the glucagon response and to maintain the basal insulin level. Hepatic venous plasma levels of glucose, immunoreactive glucagon, immunoreactive insulin, epinephrine, and norepinephrine were determined. The area under the glucose curve during the 120-min period following the injection of neostigmine was compared between groups. The areas under the glucose curve for rats receiving somatostatin and insulin, adrenalectomy rats, and adrenalectomy rats receiving somatostatin and insulin were, respectively, 82, 31, and 61% of that for intact rats. The fashion of hippocampal stimulated hyperglycemia with neostigmine was similar to that after injection of neostigmine into the third cerebral ventricle. Therefore, we investigated hyperglycemia in rats with lesions of ventromedial hypothalamus and found that the response to hippocampal neostigmine was significantly inhibited by the hypothalamic lesion. These findings suggest that the glucoregulatory hippocampal activity evoked by neostigmine may be transmitted to peripheral organs via the ventromedial hypothalamus.