Hypothalamic hyperphagic rats overeat bitter sucrose octa acetate diets but not quinine diets.

Female rats were made hyperphagic with knife cuts or lesions in the ventromedial hypothalamus (VMH) and their aversion to food made bitter by adulteration with quinine or sucrose octa acetate (SOA) was examined. In short-term choice tests VMH obese rats, as well as controls, strongly preferred a 0.1% quinine diet to a 1.0% SOA diet. Yet, in 24 hr intake tests VMH obese rats overate, relative to controls, the 1% SOA diet, but underate the 0.1% quinine diet. VMH rats in both dynamic and static stages also overate SOA diets in concentrations up to 16%. However, VMH obese rats underate a 1% SOA diet when previously fed a 0.1% quinine diet. The results indicate that the VMH rat's finickiness to quinine diets may not be due to bitter taste alone, but may result from toxic postingestive effects of quinine and the development of a conditioned taste aversion.     

Sham feeding in rats after ventromedial hypothalamic lesions and vagotomy

Sham feeding was examined in female rats with ventromedial hypothalamic (VMH) lesions with or without abdominal vagotomy. In Experiment 1, intact rats consumed more than twice as much sweet milk during 1-hr tests of sham feeding (M = 13.0 ml) as they did when feeding normally (M = 5.5 ml). Rats with VMH lesions showed exaggerated sham feeding, which was elevated almost fourfold (M = 56.6 ml) over their already high normal feeding baseline (M = 15.1 ml). In Experiment 2, vagotomy substantially reduced sham feeding in rats with VMH lesions. After vagotomy, VMH rats sham fed half as much (M = 23.7 ml) as nonvagotomized VMH rats did (M = 46.8 ml). Vagotomy did not, however, reduce sham feeding to control levels (M = 13.1 ml). These results are consistent with the hypothesis that VMH hyperphagia arises from exaggeration of orosensory responsiveness, which is, in part, a consequence of perturbed vagal function.     

Taste reactivity alterations after IL-1beta microinjection into the ventromedial hypothalamic nucleus of the rat

The ventromedial hypothalamic nucleus (VMH) is a central site of action of interleukin-1beta (IL-1beta) induced feeding disturbances. This study was designed to elucidate taste-related perceptual and motivational processes potentially contributing to the anorexia and adipsia seen after bilateral IL-1beta microinjection into the VMH. A saccharin conditioned taste aversion (CTA) paradigm was tested after the central IL-1beta administration. To further investigate whether gustatory deficits are involved in development of the feeding alterations, IL-1beta induced changes of taste responsiveness were also studied in taste reactivity tests. Administration of the cytokine into the VMH did not cause the development of CTA. During taste reactivity tests, however, IL-1beta treated rats displayed significantly poorer ingestive reactions to pleasant taste stimuli than did animals of the control group. In addition, the aversive responses of IL-1beta injected rats to pleasant tastes were significantly more robust than those of control animals. The cytokine treated animals also showed stronger aversion than ingestion to hedonically positive tastes. The present findings indicate that (1) anorexigenic and adipsogenic consequences of IL-1beta microinjection into the VMH are not due to development of cytokine induced CTA; and (2) hedonic responsiveness to palatable tastes is processed by IL-1beta mediated neural mechanisms in the VMH.     

Enhanced responses of the chorda tympani nerve to sugars in the ventromedial hypothalamic obese rat

Sweet taste sensitivity in obese rats with lesions of the ventromedial hypothalamus (VMH) was studied by examining chorda tympani nerve responses to various taste stimuli including sugars. In the early progressive phase of obesity (2 wk after creating VMH lesions), there was no significant difference in the nerve responses to any taste stimulus between sham-operated and VMH-lesioned rats. In contrast, in the late phase of obesity (15-18 wk after VMH lesions), the magnitude of responses to sugars (except for fructose) was prominently greater than that in age-matched controls. High-fat diet-induced obese rats and streptozotocin-diabetic rats also showed greater chorda tympani nerve responses to sugars as was observed in VMH-lesioned obese rats, indicating that VMH lesions might not be specifically related to the enhanced gustatory neural responses to sugars. Although it has been demonstrated that the enhanced responses of the chorda tympani nerve to sugars in genetically diabetic db/db mice is largely attributable to the lack of the direct suppressive effect of leptin on the taste receptor cells, plasma leptin levels were not correlated with the changes in chorda tympani responsiveness to sugars in these models of obesity and diabetes. Accordingly, our results suggest that some chronic factors, including high blood glucose, inefficiency of insulin action, or leptin resistance may be related to the enhancement of chorda tympani nerve responses to sugars.     

Does the ventromedial hypothalamus inhibit the lateral hypothalamus?

Electrical stimulation of the ventromedial hypothalamus inhibited feeding in hungry rats. Neither knife cuts of the VMH-LH connections nor LH electrolytic lesions significantly altered the feeding inhibitory effects of medial stimulation. This suggests that the common assumption that the VMH inhibits the LH feeding system is incorrect. However, electrical stimulation may not be an appropriate method to study VMH feeding pathways, and this problem is discussed.     

Hypothalamic hyperphagia prevented by prior subdiaphragmatic vagotomy: Insulin hyperphagia is unaffected

Male rats were given bilateral subdiaphragmatic vagotomy or a sham operation. Both groups of animals showed equivalent hyperphagia and weight gain during a ten day treatment with long-acting insulin. Despite this ability to increase feeding, the vagotomized rats did not overeat and become obese after VMH lesions.     

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.     

Ventromedial hypothalamic syndrome: Finickiness?

Female rats with lesions of the ventromedial hypothalamus (VMH) underate and lost weight compared to same-diet control rats when fed a 0.2% quinine-adulterated wet-mash maintenance diet, yet overate and gained weight compared to same-diet control rats when fed a 0.4% quinine-adulterated high-fat maintenance diet. Control rats underate and lost comparable amounts of body weight when fed either adulterated diet. These data question the generality of the concept of VMH finickiness and are discussed in terms of an increased hunger hypothesis.     

Caloric compensation in rats with combined lesions in lateral and ventromedial hypothalamus

Compensatory adjustment of caloric intake in response to stomach loading of glucose or vegetable oil was studied in rats with lateral hypothalamic (LH) or with combined lateral and ventromedial hypothalamic (VMH) lesions. The LH lesioned rats as well as the sham operated controls compensated the loaded calories by an adequate reduction of oral intake, but those bearing both LH and VMH lesions tended to undercompensate with increased total caloric intake and body weight during some but not all periods of loading. Some of the rats with combined LH and VMH lesions displayed characteristics of the respective syndrome, such as thirst deficit and hyperphagia.     

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 taste of sickness: lipopolysaccharide-induced finickiness in rats

Decrease in food intake is one of the most documented non-specific symptoms of inflammatory processes. However, attention has been mainly focused on quantitative analysis. The present paper reports studies undertaken to test the possible contribution of changes in taste processes in inflammatory-induced alteration of feeding behavior. In a first experiment, the effects of lipopolysaccharide-induced sickness were assessed on preference for saccharin and aversion for quinine in rats using the two-bottle test paradigm. In a second experiment, effect of lipopolysaccharide (LPS) on the behavioral reactivity to palatable, unpalatable and mixed solutions was analyzed using the taste-reactivity paradigm. Our results show that LPS decreased total fluid intake but did not change taste responses to unpalatable or palatable substances. However, LPS increased aversive reactions and decreased hedonic responses to mixed taste. These LPS-induced changes are interpreted as an increase in finickiness and are discussed in regard to their potential role in the adaptation of individuals to sickness.     

The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight

Early researchers found that lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia and obesity in a variety of species including humans, which led them to designate the VMH as the brain's "satiety center." Many researchers later dismissed a role for the VMH in feeding behavior when Gold claimed that lesions restricted to the VMH did not result in overeating and that obesity was observed only with lesions or knife cuts that extended beyond the borders of the VMH and damaged or severed the ventral noradrenergic bundle (VNAB) or paraventricular nucleus (PVN). However, anatomical studies done both before and after Gold's study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight. Several other important differences have also been found between VMH and both PVN and VNAB lesion-induced obesity. Concerns regarding (a) motivation to work for food and (b) the effects of nonirritative lesions have also been addressed and answered in many studies. Lesion studies with weanling rats and adult pair-tube-fed rats, as well as recent studies of knockout mice deficient in the orphan nuclear receptor steroidogenic factor 1, indicate that VMH lesion-induced obesity is in large part a metabolic obesity (due to autonomic nervous system disorders) independent of hyperphagia. However, there is ample evidence that the VMH also plays a primary role in feeding behavior. Neuroimaging studies in humans have shown a marked increase in activity in the area of the VMH during feeding. The VMH has a large population of glucoresponsive neurons that dynamically respond to blood glucose levels and numerous histamine, dopamine, serotonin, and GABA neurons that respond to feeding-related stimuli. Recent studies have implicated melanocortins in the VMH regulation of feeding behavior: food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor (BDNF) neurons. Moderate hyperphagia and obesity have also been observed in female rats with damage to the efferent projections from the posterodorsal amygdala to the VMH. Hypothalamic obesity can result from damage to either the POMC or BDNF neurons. The concept of hypothalamic feeding and satiety centers is outdated and unnecessary, and progress in understanding hypothalamic mechanisms of feeding behavior will be achieved only by appreciating the different types of neural and blood-borne information received by the various nuclei, and then attempting to determine how this information is integrated to obtain a balance between energy intake and energy output.     

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).     

Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia

The relation of hyperinsulinemia to hyperphagia was examined in rats with lesions of the ventromedial hypothalamus (VMH). Plasma insulin and glucose levels were assayed after a 4-hr fast and 17 min after the initiation of a meal (6 ml of sweetened milk in 7 min) in animals with sham lesions, VMH animals maintained at preoperative body weight by food restriction, and VMH animals fed ad lib. Both VMH groups displayed basal and postabsorptive hyperinsulinemia, compared with the sham-operated control group, but insulin levels were greatest under the ad lib feeding condition. It is suggested that VMH hyperinsulinemia is due both to a primary effect of the lesion and to hyperphagia and that marked obesity can result in the absence of basal hyperinsulinemia as a result of hyperphagia with consequent postabsorptive hyperinsulinemia.     

Food intake and lateral hypothalamic self-stimulation covary after medial hypothalamic lesions or ventral midbrain 6-hydroxydopamine injections that cause obesity

In rats with perifornical lateral hypothalamic (LH) electrodes that induced feeding, self-stimulation through the same electrodes increased immediately after ventromedial hypothalamic (VMH) lesions and did not return to normal until food intake normalized and the rats had become obese. In a second experiment a unilateral far-LH lesion decreased both feeding and contralateral perifornical LH self-stimulation. In Experiment 3, 6-hydroxydopamine (6-OHDA) injected into the midbrain to destroy the ventral noradrenergic bundle (VNAB) caused hyperphagia and increased LH self-stimulation. In summary, VMH or VNAB damage increased feeding and self-stimulation; contralateral far-LH damage decreased both. These results confirm the earlier suggestion that the VMH region is necessary for normal inhibition of feeding and feeding reward as reflected in self-stimulation rate. Although massive 6-OHDA-induced depletion of the dopamine system that passes through the LH can cause starvation and impair self-stimulation, the results suggest that selective catecholamine depletion of ventral midbrain neurons with sparing of the A9 and A10 dopaminergic cells can disinhibit feeding and self-stimulation. In all three experiments LH self-stimulation and food intake covaried, which suggests that they are functionally related.     

Reduced salivation in rats following ventromedial hypothalamic lesions

Salivation was assessed in normal rats and rats with bilateral lesions of the ventromedial hypothalamus (VMH). VMH lesioned rats demonstrated a reliable reduction of salivation. This hyposalivation occurred during a one month period that animals were maintained on dry rat chow and for a 16 day period that animals were maintained on a palatable liquid diet. VMH rats did not differ from control rats in the amount of saliva secreted in response to Prostigmin or wintergreen solution. Thus, while the VMH rat shows a reduced basal salivation level, such animals salivate normally in response to a strong taste substance.     

Modification of unit responses to gustatory stimuli by conditioned taste aversion in rats

Strong conditioned taste aversion (CTA) was established in rats by associating 0.1% saccharin drinking with subsequent LiCl (0.15 M, 2% body weight) poisoning. Unit reactions (n = 135) to mouth perfusion with saccharin (10 sec) and water (40 sec) were recorded in curarized animals and analysed with a spike detecting computer program. Saccharin induced reactions in the gustatory thalamus of naive and CTA trained rats were equally frequent. The percentage of saccharin induced reactions in lateral and ventromedial hypothalamus (LH and VMH) was affected by CTA training in a reciprocal manner: it decreased from 64 to 38% in LH neurons and increased from 40 to 70% in VMH neurons. It is argued that the modification of hypothalamic reactivity to saccharin reflects the changed signal significance of the sweet taste, which activates the feeding center and inhibits the satiety center in naive animals, but elicits opposite effects after CTA acquisition.     

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.     

Flavor-illness aversions: the role of the amygdala in the acquisition of taste-potentiated odor aversions

In the present experiments the role of the amygdaloid complex and its specific nuclei were tested in the conditioning of taste potentiated odor aversions. In the first experiment two groups of rats were given either large electrolytic lesions in the amygdala (AMX) or sham operations (SH). Postoperatively, these rats were trained to avoid either a taste, an odor, or a taste-odor compound using LiCl illness. Subsequent tests with odor and taste alone showed that the SH group developed strong taste and odor aversions; however, the AMX group failed to display either an odor or taste aversion. In the second experiment, another four groups of rats received either lesions in the medial and basomedial nuclei (M), central nuclei (C), lateral and basolateral (L), or sham operations (SH). The results from postoperative conditioning showed that all groups had strong taste and odor aversions, except group L which displayed a significant disruption of odor aversion learning. In conclusion, these data indicate that the amygdala is involved in the acquisition of taste, odor and potentiated odor aversions learning. Moreover, it is demonstrated that the lateral and/or basolateral nuclei are particularly involved in the development of potentiated odor aversions learning.     

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.