Hypothalamic obesity: comparison of radio-frequency and electrolytic lesions in weanling rats

Female rats were subjected to radio-frequency or anodal electrolytic lesions of the ventromedial hypothalamus (VMH) when 28 days old. Blood samples for determination of basal plasma insulin and glucose levels were taken on postoperative day 30 (Experiment 1) and on day 10 (Experiment 2). Body weight and daily food intake of rats with either type of lesion did not differ from unoperated animals during the first 10 days, but rats with electrolytic lesions, unlike radio-frequency lesioned animals, displayed excess food intake and weight gain starting in the third postoperative week. Both types of lesions produced stunted linear growth and a higher than normal Lee Obesity Index. Only the rats with electrolytic VMH lesions were significantly hyperinsulinemic on postoperative day 30, with a mean plasma insulin level that was at least double that observed in unoperated or radio-frequency lesioned animals. On day 10, however, the animals with electrolytic lesions had markedly lower plasma insulin and glucose levels compared to the other two groups, which did not differ from one another. There was no apparent difference in the size of the lesions produced by the two techniques, and it is therefore concluded that some of the endocrine dysfunctions resulting from electrolytic VMH lesions are due to metallic ion deposits (stimulating adjacent tissue) rather than to tissue ablation.     

Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions

The effects of adrenalectomy in rats with ventromedial or paraventricular hypothalamic lesions have been studied in two experiments. Rats with ventromedial hypothalamic lesions or lesions in the paraventricular nucleus were allowed to gain weight for fourteen days at which time they were adrenalectomized. Before adrenalectomy, animals with VMH lesions ate more, gained significantly more weight than animals with lesions in the paraventricular nucleus, and both were significantly heavier and consumed more food than sham-operated controls. Following adrenalectomy, food intake decreased and both groups of lesioned animals lost weight. The animals with VMH lesions stabilized at weights above the control animals. Implantation of corticosterone enhanced weight gain and food intake in animals with lesions in either the paraventricular nucleus or the ventromedial hypothalamus. In the second experiment, one subgroup of rats with VMH lesions was adrenalectomized, and allowed to eat ad lib. Two other groups of sham-operated rats with VMH lesions served as controls. One group ate ad lib and one group was pair fed to the food intake of the adrenalectomized VMH-lesioned rats. Weight gain in the adrenalectomized VMH-lesioned rats and the pair-fed VMH-lesioned controls was similar and less than the VMH-lesioned rats eating ad lib. GDP binding to interscapular brown adipose tissue was related to the degree of weight gain, not to the presence of the VMH lesion. These data show that corticosterone is essential for the expression of obesity in both PVH- and VMH-lesioned rats. They also argue that the reduction in the activity of the sympathetic nervous system of VMH-lesioned rats as estimated by the GDP binding to mitochondria from brown adipose tissue is associated with hyperphagia.     

Lack of diet-induced thermogenesis in brown adipose tissue of obese medial hypothalamic-lesioned rats

Radiofrequency heat lesions were made in the medial hypothalamus of 12-week old male and female Holtzman rats. Two to three days later rats were offered a palatable cafeteria diet in addition to chow or were fed chow alone for the next 3-4 weeks. Male lesioned rats were only slightly hyperphagic on the chow diet and gained little extra weight. When fed the cafeteria diet, energy intake of male lesioned rats almost doubled in comparison with chow-fed lesioned rats and a very rapid extra weight gain occurred. Despite the marked hyperphagia, thermogenesis in brown adipose tissue was suppressed in the cafeteria-fed lesioned rats, as indicated by low mitochondrial guanosine diphosphate (GDP) binding. In female rats, lesions induced much greater hyperphagia and body weight gain than in male rats, particularly when they ate the cafeteria diet. Again, thermogenesis in brown adipose tissue was suppressed in the cafeteria-fed female lesioned rats. The proportion of energy derived from carbohydrate was not altered by the cafeteria diet in either male or female rats, whether lesioned or not, but there was an increase in the proportion of energy derived from fat at the expense of protein. No sex differences in food selection were observed. The accumulation of body fat was always greater in female lesioned rats than in male lesioned rats for similar food intakes. It is concluded that medial hypothalamic lesions prevent the normal occurrence of diet-induced thermogenesis in brown adipose tissue despite extreme overeating by the rats of a palatable cafeteria diet.     

Effects of ventromedial hypothalamic lesions on restricted feeding behavior in rats

Previous research has shown that VMH lesioned rats overeat when given free access to food yet undereat when daily access is restricted. In the present study VMH lesioned female rats in Experiment 1 and male rats in Experiment 2 consumed more food than controls during both free and restricted access feeding schedules. The factor that most likely accounts for the contrasting outcomes is the extent of hyperphagia displayed by the lesioned rats prior to restricted access feeding. The present data are consistent with the interpretation that VMH lesions increase hunger motivation.     

The ventromedial hypothalamic nucleus is not essential for the prefeeding corticosterone peak in rats under restricted daily feeding

The role of the ventromedial hypothalamic nucleus (VMH) in the generation of the prefeeding corticosterone peak was examined in rats under restricted daily feeding, under which daily meal supply was restricted to a fixed time in the early light period. Rats were lesioned in the VMH bilaterally and subjected to restricted daily feeding during two different post-operative phases and with two different durations of food presentation. A restricted feeding with free access to meal for 4 hr was imposed on the VMH-lesioned rats from 2 to 4 weeks after the lesion, when the daily food intake increased significantly (dynamic phase). The restricted feeding induced the prefeeding hormone peak in sham operated rats, but failed to develop it in the VMH-lesioned rats. On the other hand, the hormone peak appeared in the VMH-lesioned rats subjected to the feeding schedule from 8 to 10 weeks after the lesion, when the daily food intake was not different from the control (static phase). Moreover, the VMH-lesioned rats showed the hormone peak even in the dynamic phase when the access to meal was shortened to 1 hr. These results indicate that the VMH is not essential for the generation of the prefeeding corticosterone peak under restricted daily feeding, and suggest that a special metabolic state observed during the dynamic phase of VMH lesion prevents the development of the feeding-associated oscillation or its expression upon plasma corticosterone level.     

Body weight regulation in ground squirrels and hypothalamically lesioned rats: slow and sudden set point changes

Golden-mantled ground squirrels. Citellus lateralis, have a near annual cycle in body weight. In the present experiments their weights were temporarily forced off the usual levels either by food deprivation during a phase of weight gain or by offering extra palatable food during a phase of weight loss. When these treatments ceased the weights returned to levels appropriate for that time of year rather than to pretreatment values. Therefore the cycle of body weight in uniform and ad lib conditions reflects an underlying cycle in slowly climbing or sliding set points for body weight. In contrast to fattening ground squirrels, lesioned rats in the dynamic phase of hypothalamic hyperphagia did not compensate well for weight losses incurred during food deprivation. Weight gain during the dynamic phase appears to be roughly proportional to the discrepancy between actual and set weights, the latter being suddenly much elevated by the lesion.     

Transplantation of pancreatic beta-cells prevents development of hypothalamic obesity in rats.

The present experiments have tested the hypothesis that ventromedial hypothalamic (VMH) lesions enhance insulin secretion by neural mechanisms. Rats were made diabetic by injecting streptozotocin to destroy their own pancreatic beta-cells. Subsequently, transplants of fetal pancreatic tissue were placed under the renal capsule. VMH lesions were placed in rats whose diabetes was cured with transplants as well as sham-transplanted animals. The animals were followed for 4 wk. The lesioned rats with pancreatic transplants gained no more weight than the sham-operated controls. There was no significant rise in insulin in the transplanted rats after VMH lesioning, but the VMH lesioned rats with intact pancreatic tissue showed the expected rise in insulin. Food intake rose 71% in the VMH lesioned rats with intact beta-cells, but only 23% in the VMH lesioned rats with transplants. Hypertrophy of the pancreatic islets was also observed in the VMH lesioned rats with an intact pancreas, but was not found in the VMH lesioned rats with a transplanted pancreas. Thus, transplantation of pancreatic tissue beneath the renal capsule of diabetic rats prevented the characteristic hyperphagia, hyperinsulinemia, and obesity in VMH lesioned rats whose pancreas was free from intact innervation. The results support the hypothesis that neural mediation of the rise in insulin is the primary factor in the development of hypothalamic obesity.     

Recovery of anticipatory activity to restricted feeding in rats with ventromedial hypothalamic lesions

Entrainment of circadian activity rhythms to a fixed daily mealtime was measured in intact and ventromedial hypothalamic (VMH) lesioned rats housed in tilt-cages. Intact rats showed a clear increase in activity for 2–3 hr prior to the 2 hr daytime feeding period. Anticipatory activity in lesioned rats was attenuated or absent during restricted feeding 5–9 weeks after surgery, but was evident in all rats, even those bearing apparently total VMH damage, during a second restricted feeding schedule 14–21 weeks after surgery. These results show recovery of function and argue against a necessary role for the VMH in food entrained rhythms.     

Ventromedial hypothalamic lesions and stomach ulcers: reduction by non-nutritive bulk ingested in the post lesion period

The effects of some dietary properties on stomach ulceration resulting from ventromedial hypothalamic (VMH) brain lesions, were investigated in two experiments. In the first experiment two groups of rats received VMH lesions and one group received sham lesions. One of the lesioned groups was deprived of food and water during the 24 hr post lesion period, as was the sham lesioned group. The other lesioned group was given access to a highly palatable diet and water during the post lesion period. No stomach ulcers were found in the sham lesioned rats. The VMH lesioned group with access to food and water had less glandular stomach ulceration 24 hr after the lesion procedure than the VMH lesioned deprived group (p<0.01). In the second experiment four groups of rats received VMH lesions and were then given access to one of the following diets during the post lesion period: water, 16.7% sucrose solution, non-nutritive bulk (silica and methylcellulose), or bulk containing 16.7% sucrose. A multivariate analysis of variance was applied to five measures obtained in this experiment. The two groups receiving the bulk diets had significantly less stomach ulceration than the two groups given the liquid diets. Addition of the surcose to the liquid or bulk diet had no significant effect on gastric pathology. These experiments demonstrate that the ingestion of bulk diet in the post lesion period results in a reduction in gastric ulceration in the rat. And thus, similar to previous demonstrations that bulk diet has antiulcerogenic effects in other experimental procedures for gastric ulcer production (e.g., starvation, pylorus ligation, or electric shock), the present experiments demonstrate an antiulcerogenic property for bulk diet on stomach ulcers induced by VMH lesions.     

Role of the ventromedial hypothalamus in prolactin-induced hyperphagia in ring doves.

Prolactin (PRL) strongly stimulates feeding activity and body weight gain in ring doves, and of the brain loci tested to date, the ventromedial hypothalamus (VMH) is the most effective site of PRL action in promoting these changes. To determine if the VMH is essential for this response, we examined the effects of VMN destruction on spontaneous feeding and on changes in food intake induced by intracerebroventricular (i.c.v.) injections of PRL. Male birds were selectively destroyed by radiofrequency lesions (n = 6). A group of sham-lesioned males (n = 6) served as controls. Lesioned birds exhibited a transient increase in food intake that peaked around the seventh postoperative day and declined to baseline levels by day 12. In contrast to this pattern, body weights of lesioned birds increased in parallel with food intake, but remained elevated throughout the 3-week postoperative period. During the peak period of hyperphagia in the lesioned group, food intake and body weight increases were two to three times greater in lesioned birds than in controls. After postoperative feed intake had stabilized, each bird received 5 daily i.c.v. injections of ovine PRL. Food intake and body weight increased dramatically in both groups in response to PRL treatment, and no group differences were observed in response to magnitude. We conclude that VMH destruction strongly perturbs feeding and body weight regulation in doves. However, VMH integrity is not essential for the expression of PRL-induced hyperphagia.     

Patterns of weaning and adult response to stress

We have previously shown that excitation of certain neurons in the ventromedial nucleus of the hypothalamus (VMH) of rats induces hyperrunning activity. The present study investigated the involvement of these VMH neurons in inducing excessive running under the activity-stress paradigm. The VMH of 6-week-old male rats was bilaterally lesioned by administration of kainic acid. Control animals received saline in the VMH. They were housed in running-wheel activity cages with free access to food for 6 days of the recovering period, and then fed 1 h each day for 6 days. Control animals exhibited marked increases in both running activity and its light/dark ratio, and developed stomach ulcers. In contrast, animals with bilateral VMH lesions showed a significantly attenuated increase in running activity and no change in light/dark ratio. VMH lesions also suppressed stomach ulceration. These results suggest that VMH neurons play a crucial role in inducing excessive running and stomach ulceration during exposure to the activity-stress paradigm.     

Medial hypothalamic lesions in Syrian hamsters: characterization of hyperphagia and weight gain

Syrian golden hamsters (Mesocricetus auratus) received bilateral lesions aimed at the ventromedial hypothalamus (VMH) or a sham lesion. In the first study, some of the animals in each surgical group were housed in standard sedentary conditions while others had free access to running wheels. The lesions produced a 30% increase in the daily intake of chow, and this was accomplished exclusively by increased meal sizes. As a result, lesioned hamsters gained body weight relative to controls both on the chow diet and in a subsequent high fat diet phase. The effects were comparable in both sedentary and exercising groups. The lesions produced increases in body length and fat content. In the second study, lesions were made in the VMH or in adjacent nuclei and, after an initial period on chow, the hamsters were then given a choice between chow and high fat diet. The lesioned hamsters showed no unusual preference for the high fat diet but, as before, those with damage to the VMH or paraventricular nucleus (PVN) showed exaggerated body weight gain. Hamsters with these lesions were hyperinsulinemic in both fed and fasted conditions at the end of the study.     

Excitotoxic lesions of the lateral hypothalamus made by N-methyl-d-aspartate in the rat: behavioural,histological and biochemical analyses

Summary The purpose of this study was to determine whether the excitotoxin N-methyl-d-aspartate (NMDA) could be used to make lesions within the lateral hypothalamus and what effect they had on regulatory behaviour. Larger doses of NMDA were effective in the lateral hypothalamus but tended to spread into adjacent structures; smaller doses made lesions which were contained within the lateral hypothalamus and zona incerta. Lesions which damaged the lateral hypothalamus and surrounding tissue had no effect on the concentration of dopamine (or its metabolites) in the dorsal or ventral striatum. The large lesions, including extrahypothalamic damage, were associated with long-term deficits in lab chow and water intake, but rats with lesions restricted to the lateral hypothalamus made good recoveries, eating and drinking normally from around the tenth day postoperation. Body weight gain was normal in these rats, though there was a long-term loss of body weight compared to controls. Unoperated rats with food intake yoked to lesioned rats showed identical long-term changes in body weight, suggesting that the changes in body weight of lesioned rats may be a reflection of changes in eating and drinking rather than a disruption of a body weight set-point mechanism. Motor deficits were not found; all rats were able to consume without difficulty saccharin solutions. All lateral hypothalamic lesioned rats failed to respond to dehydrating, dipsogenic or glucoprivic challenges. It is concluded that NMDA is an effective toxin in the rat lateral hypothalamus, sparing ascending dopamine fibres, and that the main effect of such lesions is an impairment in responding to physiological challenges.     

VMH lesions in vagotomized rats: a note of caution

Transections of the vagus nerve immediately below the diaphragm in female rats resulted in a high percentage of deaths by starvation and/or dehydration. Those that did survive had to be chronically maintained on a high fat diet. Transections midway between the stomach and diaphragm usually allowed recovery of normal food intake with a pellet diet, although body weight remained below that of sham-vagotomized animals. VMH lesions in these recovered (90 days) midlevel vagotomized rats caused either marked weight gains, marked weight losses, or wide fluctuations in body weight, results which would not be predicted by hypotheses which attribute VMH obesity to increased vagally mediated insulin secretion. We previously found that VMH lesions in rats with vagal transections just above the stomach resulted in a high percentage of rats that displayed hyperphagia and obesity, and conclude that the level of transection is of critical importance to the manifestation of VMH obesity. Autopsies revealed that midlevel vagally transected rats which failed to gain weight after VMH lesions suffered a loss of esophageal tonus or obstruction at the pyloric sphincter. We believe that the failure to observe hyperphagia in vagotomized rats following VMH lesions is at least partially due to overloading the capacity of the stomach and/or the accumulation of food in the esophagus (resulting in choking) with attempts at overeating.     

Relationship between plasma corticosterone and insulin levels in rats with ventromedial hypothalamic lesions

The effects of ventromedial hypothalamic (VMH) lesions on plasma corticosterone, insulin, and glucose levels were studied in food-restricted and ad lib fed female rats. VMH lesions resulted in significant elevations of corticosterone and insulin levels compared to control values during the first 25 days after surgery. However, unlike insulin values which were generally greater in VMH rats fed ad lib than in food-restricted animals, plasma corticosterone levels were unaffected by level of food intake. Corticosterone and insulin levels were unrelated preoperatively and in sham-operated animals, but were positively correlated (r = .82) by Day 25 in ad lib fed VMH rats. It is concluded that the elevation in plasma glucocorticoids observed in VMH rats is a primary effect of the lesion that is independent of food intake or initial weight gain.     

Response to chronic insulin administration: effect of area postrema ablation

The effects of daily administration of protamine zinc insulin (PZI) on plasma insulin and glucose levels and on food intake and body weight of rats with lesions of the area postrema and adjacent caudal-medial portions of the nucleus of the solitary tract (APX rats) were examined. Prior to insulin treatment, APX rats weighted less and had lower plasma immunoreactive insulin (IRI) levels than nonlesioned controls but did not differ from controls in plasma glucose levels. Five daily injections of 5 U/kg PZI raised plasma IRI and lowered plasma glucose levels similarly for both lesioned and nonlesioned rats. When injected with increasing doses of PZI over a 30-day period, both lesioned and nonlesioned rats showed increases of food intake and rate of weight gain in response to 8 U/kg PZI. These data indicate that APX does not affect either physiological or behavioral responses to chronic peripheral insulin administration.     

Seasonal weight gain is attenuated in food-restricted ground squirrels with lesions of the suprachiasmatic nuclei

The role of seasonal hyperphagia in the genesis of prehibernation fattening was assessed in golden-mantled ground squirrels. One group of animals was fed ad lib throughout the weight gain phase of the annual body weight cycle (June-October); a group of neurologically intact animals and one of squirrels with brain lesions incorporating the suprachiasmatic nuclei (SCN) were fed amounts of food equivalent to quantities consumed prior to the body weight trough (May). Part of the seasonal increase of body mass is independent of increases in food consumption; intact animals fed ad lib or restricted to prefattening food intakes underwent similar increases in body mass and possessed equivalent amounts of abdominal white adipose tissue. Food restriction combined with SCN lesions attenuated seasonal weight gain and reduced abdominal fat mass. However, some of the brain-damaged squirrels still evidenced weight gain, a result supporting a previous conclusion that the SCN are involved in circannual body weight rhythm generation but their contribution to this process is not essential for continued rhythmicity in most individuals.     

Influence of type of reinforcement on operant responding by rats with ventromedial lesions

Bar-pressing on FR schedules for sucrose rewards was studied in rats with ventromedial hypothalamic (VMH) lesions. When both VMH and control rats were maintained on ad lib feeding, their bar-pressing performance for sucrose did not differ, but if the VMH group was maintained at control body weight levels, they responded more frequently for sucrose than controls. In a subsequent experiment performance for Noyes pellets and 32% sucrose was directly compared in VMH and control animals maintained at 85% of their respective postoperative body weight levels. Under these conditions controls responded more frequently than lesioned rats for either type of reinforcement, but the magnitude of the difference was greater with the Noyes pellet reward.     

Functional disconnection of brown adipose tissue in hypothalamic obesity in rats

The metabolic responses to electrical nerve stimulation, norepinephrine or octanoate additions were studied using continuous monitoring of NAD(P)H/NADP redox state by reflexion spectrophotometry of interscapular brown adipose tissues from control and ventromedial hypothalamic (VMH) lesioned rats. The responses to these stimuli were all greatly decreased already 3 days after VMH lesions, indicating a reduced cell capacity to oxidize free fatty acids. Measurements of interscapular brown adipose tissue composition 4–5 weeks after VMH lesions showed a decrease of both DNA concentration and total content, indicating some tissue involution.It is concluded that the involvement of the ventromedial bypothalamus in the activation of brown adipose tissue provided a possible anatomical clue concerning pathways connecting thermal and weight regulations.     

DRL performance following ventromedial hypothalamic lesions in rats

Obese ventromedial hypothalamic lesioned rats obtained more reinforcers than control or lean VMH animals when switched from a continuous reinforcement schedule to a differential-reinforcement-of-low-rate (DRL) operant schedule for food reinforcement. There was no significant difference among the three groups in the number of responses emitted on the DRL schedule. An examination of interresponse times revealed that both lean and obese VMH animals suppressed post-reinforcement short-latency responding earlier than control animals. The results do not support the hypothesis that VMH lesions cause a general deficit in response inhibition.