Hypothalamic Hyperphagia Research Articles

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.

Effects of hypothalamic knife cuts on feeding induced by paraventricular norepinephrine injections

The relationship between the fiber systems involved in the hypothalamic noradrenergic feeding response and the medial hypothalamic (MH) hyperphagia syndrome was appraised in male rats using knife cuts. Parasagittal knife cuts in the perifornical hypothalamus produced hyperphagia and excessive weight gain but failed to disrupt feeding in response to paraventricular hypothalamic injections of norepinephrine (NE). Coronal knife cuts in the posterior hypothalamus which extended from the midline to the lateral perifornical region also failed to disrupt NE feeding. These findings indicate that the output of the noradrenergic feeding system does not follow the feeding pathway implicated in the MH hyperphagia syndrome. They also suggest that the output of the noradrenergic feeding system is not directed laterally beyond the level of the fornix nor caudally into the lower brainstem over the medial forebrain bundle.

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.

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.

Influence of diet palatability on the noradrenergic feeding response in the rat

Adult male rats which displayed a reliable feeding response to intrahypothalamic injections of norepinephrine (NE) on a chow diet were subsequently tested on one of three diets: an unpalatable quinine-adulterated meal, a palatable fat-adulterated meal, or a “neutral” unadulterated meal. The quinine diet completely blocked the NE feeding response, while the fat diet produced a small and unreliable reduction in the feeding response. When food deprived all groups increased their food intake, although the fat diet group tended to overeat, and the quinine diet group tended to undereat relative to the unadulterated diet group. The failure of the palatable fat diet to potentiate the NE feeding response does not support the hypothesis that this response mimics the ventromedial hypothalamic hyperphagia syndrome. The blocking effect of the quinine diet on NE feeding is consistent with other evidence which suggests that NE mediates the eating behavior induced by glucoprivation.

Metabolic effects of hypothalamic hyperphagia

In order to test the hypothesis that the enhanced gluconeogenesis of hypothalamic obesity remains responsive to changes in food intake, we have measured gluconeogenesis in two models of hypothalamic obesity under both hyperphagic and normophagic conditions. The results show that hyperphagia partially decreases gluconeogenesis and fully restores liver glycogen in both models. The discussion section relates our present findings to the enhanced glucose utilization previously noted after VMH destruction and to the recent hypothesis that hyperphagia is a response to body protein depletion.

The role of hyperinsulinema and the vagus nerve in hypothalamic hyperphagia reexamined.

Three series of experiments investigated the role of hyperinsulinemia and the vagus nerve in the hyperphagia and obesity syndrome produced in female rats by knife cuts in the ventromedial hypothalamus (VMH). The findings of the first series revealed that VMH cuts do not produce hyperinsulinemia when the rats are prevented from overeating, but insulin levels are elevated in rats allowed to overeat. The second series of experiments demonstrated that VMH-cut rats overconsume sweet sugar solutions during daily short-term tests, and that pharmacological blockade of vagal efferent activity with atropine methyl nitrate fails to inhibit this overconsumption. The third study revealed that subdiaphragmatic vagotomy completely blocks VMH hyperphagia and obesity on a chow diet, but does not prevent overeating and rapid weight gain in rats fed an assortment of highly palatable foods. These findings indicate that vagally mediated insulin release is not an essential component to the VMH knife cut syndrome.

Effects of gastric vs complete subdiaphragmatic vagotomy on hypothalamic hyperphagia and obesity

Complete subdiaphragmatic vagotomy totally reversed pre-existing VMH lesion induced hyperphagia and obesity independent of the magnitude of the brain lesion effects, suggesting vagal participation in the VMH syndrome. However, complete vagotomy also reduced food and water intake and body weight in brain unlesioned controls. The specificity to VMH lesion obesity of the vagotomy effect is therefore questioned. Complete subdiaphragmatic vagotomy also reversed the obesity produced by prior hypothalamic knife cuts, and prevented the development of knife cut effects in rats which received knife cuts and vagotomies concurrently, or were permitted to recover from the acute effects of vagotomy before receiving knife cuts. Section of the gastric vagus, sparing the hepatic and coeliac branches, had no effect on knife cut-induced obesity, but did reduce water/food ratios and block increases in fasting gastric acid secretion. Thus, upper gastrointestinal effects cannot alone account for the blockade of obesity seen after complete vagotomy. This implicates the coeliac and/or hepatic vagal branches as important to the expression of hypothalamic obesity.

Effects of selective vagotomies on knife cut-induced hypothalamic obesity: Differential results on lab chow vs high-fat diets

Asymmetrical hypothalamic knife cuts were used to produce obesity in rats fed lab chow pellets. When the brain surgery was accompanied by selective section of the coeliac branch of the abomdinal vagus nerve, only 57% of the expected weight gain was observed. Additional section of the gastric branches of the vagus further reduced the knife cut effects, and complete subdiaphragmatic vagotomy suppressed body weight below control levels. Conversely, all vagotomies that spared the coeliac branch did not by themselves attenuate hypothalamic knife cut obesity. These results suggest that some function(s) under coeliac vagal control are specifically involved in mediating hypothalamic hyperphagia and obesity. When, after 30 days, the rats were switched to high-fat diet, all the knife cut rats overate and became obese (or more obese) irrespective of vagotomy status. This overeating despite vagotomy indicates that the vagus nerves must not be the exclusive mediator of hypothalamic obesity.

Changes in the Principal Fatty Acids of Total Lipids and Various Other Constituents of the Blood Plasma after Hypothalamic Hyperphagia and Forced Feeding in Geese

Force-fed Landes breed geese were pair fed for 25 days with Landes geese made hyperphagic by bilateral electrolytic lesioning of the ventromedian hypothalamus (VMH). We studied the effects of each tre

Hypothalamic hyperphagia and obesity in rats with jejunoileal bypass

Jejunoileal bypass or sham surgery was performed in adult female rats followed 35 days later by ventromedial hypothalamic (VMH) knife cut or sham surgery (forming groups Bypass-VMH, Bypass-Sham, Sham-VMH, and Sham-Sham). Bypassed rats receiving VMH cuts (Bypass-VMH group) ate more food and gained more weight than did either Bypass-Sham or Sham-Sham groups. The hyperphagia and obesity of the Bypass-VMH rats was, however, substantially less than that of the sham bypass VMH cut rats (Sham-VMH group). Bypass-VMH rats that had their intestinal tract reconnected increased their food intake and ultimately became as obese as the Sham-VMH rats. Two additional groups received VMH knife cut or sham surgery followed 50 days later by jejunoileal bypass surgery (VMH-Bypass and Sham-Bypass groups). At the time of the bypass the VMH-Bypass group was hyperphagic and obese, but after surgery they underate and lost weight until they eventually stabilized their body weight at a level below that of the Sham-Bypass group. The body weight of the VMH-Bypass group was also 167 g less than that of the Bypass-VMH group. Thus, the order of surgery significantly influences the food intake and body weight level of rats with VMH knife cuts and jejunoileal bypass.

Hypothalamic knife cut obesity in hyper or hypothyroid rats

Recent evidence indicates that the paraventricular nucleus of the hypothalamus (PVN) contains both neurons that produce thyrotropic releasing hormone (TRH) and neurons that are destroyed or disconnected by the knife cuts that produce hypothalamic hyperphagia and obesity. This, and other evidence, suggested linkage between thyroid regulation and appetite control. As predicted, hyperthyroidism potentiated and hypothyroidism tempered the weight gains of knife cut rats. However, these effects were due entirely to increased and decreased, respectively, linear growth, not to differences in the degree of obesity. Enhanced linear growth and elevated growth hormone levels are a minor component of the enhanced weight gain of hypothalamically knife cut rats. Most of the weight gain is due to fat deposition. Only the enhanced linear growth and growth hormone aspect appear to possibly be mediated via the thyroid. In addition, obesifying knife cuts did not reduce goiterogenesis in PTU treated rats, as would be expected if the elaboration of TRH were blocked by obesifying knife cuts. Thus, neither TRH nor thyroxine is involved in the etiology of hypothalamic obesity.

Hypothalamic demyelination induced by gold thioglucose

The effect of hypophysectomy in mice previously treated with gold thioglucose (GTG) was studied with respect to changes in food intake and development of obesity. As expected, all mice treated with GTG alone exhibited lesions in the ventromedial hypothalamus (VMH), hyperphagia and obesity. Hypophysectomy of GTG treated mice prevented the appearance of hyperphagia and obesity. Daily administration of the adrenal corticoid, cortisone, completely restored the hyperphagia and obesity in GTG treated hypophysectomized mice. The amounts of cortisone used did not appreciably affect food intake or body weights of normal, hypophysectomized or GTG treated mice. These findings indicate that the hypothalamic hyperphagia and obesity which normally follows the administration of GTG is dependent on a functional pituitary gland. Furthermore, the specific ability of an adrenal corticoid to completely restore the hyperphagia and obesity of GTG treated hypophysectomized mice in the absence of other pituitary factors, suggests that the pituitary adrenal axis serves as an important link in the regulatory mechanism for control of feeding behavior in the mouse.

Effect of induced hypothalamic hyperphagia and forced-feeding on organ weight and tissular development in Landes geese.

The effects of induced hypothalamic hyperphagia and forced-feeding were studied in 30 geese of the Landes breed. They were housed in individual cages under a dark-light cycle of 12 hrs light-12 hrs darkness. Eleven geese with ventromedian hypothalamic (VMH) lesions and 8 controls were fed ad libitum. A third lot of 11 force-fed animals was pair-fed with the operated geese. The study lasted 4 weeks after an adaptation period to the new environmental conditions. The daily food intake of the geese and their weekly liveweight gain were monitored. After VMH lesions, the mean food intake of the geese increased by 169 p. 100 so that after each treatment their liveweight increased and they became obese (P less than 0.001). The tissue distribution of the group with lesions showed a higher amount of subcutaneous fat (P less than 0.05), while the mesenteric fat (P less than 0.05) was more abundant after forced-feeding. The liver weight was much higher in all cases; its increment reached 311 p. 100 in geese with VMH lesions and 193 p. 100 in the force-fed. However, those values were too low when compared to the means obtained by traditional forced-feeding. Hyperphagia in the geese was very marked as compared to that in rats, but it was insufficient to produce a considerable hepatic steatosis.

Hyperphagia and obesity produced by midbrain lesions in the rat: A comparison with hypothalamic hyperphagia and obesity

Bilateral electrolytic lesions were made in female Wistar rats to compare the characteristics of the obesity produced by lesioning the mesencephalon (MES) with those produced by lesioning the ventromedial hypothalamus (VMH). The hyperphagia following VMH lesions was immediate but it developed more slowly in the rats with MES lesions and in several rats there was an initial aphagia. Three weeks after lesioning, however, both groups weighed the same but major differences were found in response to various challenges. The appetite suppressant effect of d -amphetamine hydrochloride (1.5 mg/kg) as well as the circadian rhythm of eating and the response to a quinine adulterated (quinine monohydrochloride 0.25%) diet were not identical in the two groups of animals. MES-Lesioned rats ate much less food than either the VMH-lesioned rats or the controls when a screen baffle was placed over their food jars and increases in their body weights were observed to be diet-dependent. Fat deposition in MES-lesioned rats was almost entirely in the intrascapular area in contrast to fat deposition commonly observed in obese VMH-lesioned rats where it is mostly in the abdominal area. The results of these experiments provide further support to the observations that midbrain and hypothalamic hyperphagias are not identical.

Hypothalamic hyperphagia prevented by damage to brain dopamine-containing neurons

Bilateral damage to the ventromedial hypothalamic region in otherwise intact rats produced hyperphagia and weight gain. Rats which had incurred extensive damage to ascending dopamine-containing pathways as a result of intracerebral 6-hydroxydopamine injections failed to overeat or to gain excessive weight following ventromedial hypothalamic damage. They were, however, hyperactive and hyperemotional shortly after this lesion. We suggest that the integrity of the ascending dopaminergic fibers is critical for the appearance of the hypothalamic hyperphagia syndrome.

The different effects of continuous night and day-time insulin infusion on the meal pattern of normal rats: Comparison with the meal pattern of hyperphagic hypothalamic rats

The different night and day-time effects of continuous intravenous infusion of various doses of insulin on the meal pattern have been investigated in normal rats. In the day-time a dose-response curve was apparent. An 86–220% increase in the 12 hr cumulative intake was due to an increase in the number of meals for the lowest dose and in both the size and number of meals for the highest doses. With the same doses given at night the average increase in 12 hr intake was limited to 27% and was not dose-dependent. The changes in the various features of the meal pattern, observed under the effects of continuous insulin infusion, resembled those observed after VMH lesions. The similarities between these effects can be considered to support the assumption of the role played by hyperinsulinism in hypothalamic hyperphagia.

Maintenance of 24 hour eating rhythmicity during gold thioglucose induced hypothalamic hyperphagia in rats

Lesion were made in the ventromedial hypothalamic area in rats by implantation of cannulas filled with gold thioglucose. Whenever this local application of gold thioglucose resulted in hyperphagia, all animals retained their 24 hr eating rhythm. Although there was an increase in food intake, the ratio of nighttime eating activity to the total 24 hr eating activity remained the same. This supports the hypothesis that cells which are involved in the 24 hr rhythm in eating activity are different from those responsible for the regulation of food intake.

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.

Changes in 24-hour fluctuations of feeding behavior during hypothalamic hyperphagia in rats

Lesions were electrolytically placed in the ventromedial hypothalamic area in rats. Bilateral lesions appear to be more effective in producing hyperphagia than unilateral lesions. Changes in the circadian pattern during the hyperphagic phase are mainly brought about by a variable degree of increase in eating during the light periods. The fact whether or not a rhythm is present is determined by the localization of the lesion. Symmetrically placed lesions result in loss of rhythmicity in most cases but this does not correlate with the degree of hyperphagia. A possible role of connections between the suprachiasmatic nucleus and the ventromedial hypothalamic area is suggested.