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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 food. These findings indicate that vagally mediated insulin release is not an essential component to the VMH knife cut syndrome.

Animals↗

Patterns and associates of hyperphagia in patients with dementia.

This study examined patterns and associates of excessive eating (hyperphagia) in a community-based registry of patients with dementia. From patients enrolled in the Mayo Clinic Alzheimer's Disease Patient Registry (n = 439), 39 were identified with excessive eating reported on the Behavior Symptom Checklist at some time during their illness. They were matched for age, gender, duration of disease, and Global Deterioration Scale (GDS) score to "normal eaters." Annualized weight change was determined based on weight from the 6 months before the evaluation to weight 6 months after the evaluation. Annualized weight change scores were not significantly different between excessive eaters and normal eaters nor between wanderers and nonwanderers. In cross-sectional analysis, univariate modeling suggested age at onset, GDS, and Mini-Mental State Examination score to be significant predictors of excessive eating. Using multivariate logistic model with backward elimination, only age of onset and GDS were retained as associates of excess eating. Rater type also emerged as a significant predictor for excessive eating with family raters reporting this behavior in 16% of patients compared to 5% for other raters. In chi-square analyses excessive eating was associated with greater frequency of wandering, unpredictable behavior, inappropriate dressing, inappropriate bodily concerns, and threatening self-harm. Associates of excess eating were subsequently examined separately in wandering and nonwandering excessive eaters. Logistic modeling suggested that among nonwanderers, patients who were younger but more severely demented were likely to have reported excessive eating. These results suggest hyperphagia to be present in approximately 10% of a community-based cohort of patients with dementia and associated with increasing functional decline. Excessive eating does not appear to arise from memory dysfunction, but for wanderers may result from needing increased caloric intake because of increased activity levels. Thus, for wandering excessive eaters, it may be appropriate to endure the eating to ensure appropriate caloric intake. Nonwandering excessive eaters were younger, had greater dementia severity, and had more unpredictable behavior. They may have dementia with prominent frontal lobe involvement and may respond to any food stimulus respective of hunger. Restricting food exposure may be an effective management intervention for them.

Aged↗

Chlordiazepoxide-induced hyperphagia in rats: lack of effect of GABA agonists and antagonists.

Because of the evidence that benzodiazepine binding sites are associated with GABA receptors in the central nervous system, it has been suggested that the behavioural effects of benzodiazepines may be mediated by GABAergic mechanisms. In order to investigate this hypothesis in relation to the hyperphagia produced by benzodiazepines, the effects of chlordiazepoxide were compared with those of the GABA agonists progabide and muscimol and the GABA antagonists picrotoxin and bicuculline. In rats adapted to a 22 h/day food deprivation schedule chlordiazepoxide produced a dose-related increase in food intake. Neither progabide nor muscimol produced a similar effect after IP injection, nor did these drugs potentiate the effects of a dose of chlordiazepoxide. Picrotoxin and bicuculline, each given at a sub-convulsant dose, did not affect quantities of food consumed and also did not antagonise the effect of chlordiazepoxide. These results provide no evidence for the hypothesis that chlordiazepoxide-induced hyperphagia in rats is mediated by GABAergic mechanisms.

Animals↗

Reversible hyperphagia and obesity following intracerebral microinjections of colchicine into the ventromedial hypothalamus of the rat.

Colchicine, a drug which produces a reversible inhibition of intraaxonal transport and synaptic transmission, was used as a reversible neural blocker to investigate the role of the ventromedial hypothalamus (VMH) in the control of ingestive behavior and body weight regulation. Male Sprague-Dawley rats received intracranial microinjections of colchicine into the VMH. Volume and concentration of the colchicine solution were varied to assess specificity of action and dose-response relationship. When colchicine (2 and 4 microgram) was microinjected bilaterally into the VMH, there was a dose-dependent increase in food and water intakes and body weight gain which lasted several days. The acute period of hyperphagia was followed by a marked depression in feeding which persisted until body weight was lowered to control levels. This suppression of feeding appeared to be a consequence of the preceding period of hyperphagia and obesity, since colchicine-treated rats which were pair-fed with controls to prevent obesity continued to maintain normal food intake and body weight gain when later fed ad libitum. The results of this study confirm the importance of the VMH in the long term regulation of feeding, and indicate that reversible neuronal blocking with colchicine is a useful technique for investigating the neural substrates of feeding and other behaviors.

Animals↗

Inhibition of insulin hyperphagia by gamma aminobutyric acid antagonists in rats.

The effects of GABA antagonists, picrotoxin and bicuculline were studied on hyperphagia caused by insulin in free feeding rats. It was found that peripheral administration of GABA antagonists inhibited this hyperphagia. These agents were administered in the VMH and LH through stereotaxically implanted cannulae. It was found that the food intake was inhibited when injected into the VMH, but not in the LH. These findings suggest that LH plays a relatively passive role as compared to VMH, where GABA appears to be an important neurotransmitter.

Animals↗

Failure of naloxone to attenuate fasting induced hyperphagia in broiler chicks.

Subcutaneous administration of naloxone at 1 to 10 mg/kg produced a dose-related decrease in feed intake of broiler chicks. Food deprivation for 3, 6, 12, and 24 hours produced a significant increase in feed intake compared to non-food deprived birds. Subcutaneous administration of naloxone at 1 to 10 mg/kg failed to attenuate hyperphagia of broiler chicks, deprived of food for 12 hrs. These data suggest that opiate receptors are involved in the regulation of spontaneous feeding behavior in broiler chicks. However, in contrast to other mammals and pigeons, a mechanism, other than endorphinergic system, not sensitive to naloxone blockade, might be involved in food deprivation induced hyperphagia in broiler chicks.

Animals↗

Hypophagia follows the initial hyperphagia produced by 2-deoxy-D-glucose in rats.

The glucose analogue 2-deoxy-D-glucose (2DG) inhibits glucose metabolism and causes a rapid increase in food consumption in most species. This increase is most apparent during the first 6 postinjection hours, although it may persist as long as 10 hr. There are no published descriptions of alterations in food consumption subsequent to the hyperphagia. In the present study male and female rats were injected with 2DG (750 mg/kg IP), insulin (regular, 20 U/kg SC) or distilled water, and food intake was compared to baseline levels during the next 1, 6 and 24 hr. Results showed that food intake: (1) was not affected by injections of water: (2) was higher than normal during all 3 time periods following insulin injections: and (3) was higher than normal at 1 and 6 hr following 2DG, but significantly lower than normal by the end of 24 hr. The reasons underlying the development of hypophagia subsequent to the initial hyperphagia produced by 2DG are presently unknown.

Animals↗

Hyperphagia and obesity after olfactory bulbectomy performed at different times of the year in the European hamster.

Olfactory bulbectomy was performed on wild male European hamsters at different phases of their circannual body weight rhythm. Olfactory bulbectomy was always followed by an immediate hyperphagia the magnitude of which varied with the time of the year it was performed. The bulbectomy did not affect the phase of the circannual body weight rhythm, although in certain cases the rhythm is attenuated or apparently phase-shifted. Hyperphagia was delayed by food restriction but reappeared when animals were placed on ad lib food. The possible role of olfactory bulbs in the regulation of body weight, and the possibility that the maintenance expenditure of the bulbectomized animals is higher than that of the controls are discussed.

Animals↗

Hyperinsulinemia and its role in maintaining the hypothalamic hyperphagia in chickens.

Electrolytic lesions of the ventromedial hypothalamus including nucl. hypothalamicus inferior caused the cockerels to become hyperphagic. The plasma insulin level of the control birds was low before feeding and it increased after feeding, while that of the hyperphagic birds was higher before feeding and increased even more after feeding. Under the fasting condition on the 19th day, the insulin secretion of the hyperphagic birds remained at a high level, and there was a high correlation between the insulin value and the food consumption. Hyperactivity of insulin secretion in the hypothalamic hyperphagic birds was inhibited by administration of diazoxide and their insulin levels declined to a level similar to that of the controls. As a result the hyperphagia was interrupted and the daily food consumption declined to the same level as the controls. Therefore, the hyperinsulinemia seemed to be necessary for maintaining the hypothalamic hyperphagia in chickens. The role of glucagon in this phenomenon is also discussed.

Animals↗

Dietary fat-induced hyperphagia in rats as a function of fat type and physical form.

The influence of dietary fat on food intake and weight gain was assessed by feeding adult female rats diets that differed in the type and form of fat, as well as in the availability of other macro- and micronutrients. Compared to chow-fed controls, the various fat diets increased total food intake by 4% to 27%. Specifically, rats fed chow and a separate source of fat (fat option diet) consumed more fat and total calories, and gained more weight when the fat source was emulsified corn oil rather than pure corn oil or was vegetable shortening rather than corn oil. However, corn oil and shortening had similar effects on caloric intake and weight gain when presented as emulsified gels. Also, pure and emulsified-gel forms of shortening did not differ in their effects on caloric intake and weight gain. Supplementing the vegetable shortening with micronutrients, however, enhanced its hyperphagia-promoting effect. The results of two-choice tests revealed that the rats' preferences for the orosensory properties of the various fat sources did not account for the differential hyperphagias obtained. Rather, it appears that long-term fat selection and caloric intake are influenced primarily by postingestive factors. Fat selection and total intake were determined not only by the fat source itself, but also by the other diet options. That is, rats selected more fat and consumed more calories when chow was the alternative food than when separate sources of carbohydrate and protein were available.

Animals↗

Dietary hyperphagia in rats: role of fat, carbohydrate, and energy content.

Dietary energy, fat and carbohydrate content were varied to determine the nutritional factors responsible for hyperphagia induced by feeding rats high-fat diets. In the first experiment, rats were fed isoenergetic high-fat or high-carbohydrate diets for 2 weeks. Weight gain and energy intake were lower in rats given the high-fat diet. When some of the rats were switched to a diet that was high in fat, carbohydrate and energy, gram food intake was initially unchanged, resulting in a substantial increase in energy intake and weight gain. Energy intake gradually declined over the 4 weeks following the switch to the high-energy diet. In the second experiment, rats were fed high-fat diets that were either high or low in carbohydrate content and either high or low in energy content (kcal/g). Rats fed a high-fat diet that was high in energy and carbohydrate ate the most energy and gained the most body weight and carcass fat. In the third experiment, rats were fed high-carbohydrate diets varying in fat and cellulose content. Energy intake and body weight gain varied directly as a function of caloric density regardless of the fat or cellulose content of the diets. It is concluded that hyperphagia induced by feeding high-fat diets is not due to the high dietary fat content alone. Rather, high levels of fat, carbohydrate, and energy interact to produce overeating and obesity in rats fed high-fat diets.

Animals↗

A new anorexigen assay: stress-induced hyperphagia in rats.

Humans often respond to stress by overeating. A rat model of hyperphagia induced by a stressful tail-pinch has been described. Consumption of sweetened condensed milk by vaive rats was measured durin the stress. This milk drinking was prevented by pretreatment with d-amphetamine, chlorphentermine, diethylpropion, fenfluramine, methamphetamine, morphine, chlorpromazine and haloperidol. The benzodiazepines chlordiazepoxide and diazepam increased the hyperphagia. The relevance of dopaminergic agonistic and antagonist activities to anorexigenic activity are questioned.

Analgesics↗

Estradiol modulation of the hyperphagia induced by the 5-HT1A agonist, 8-OH-DPAT.

Ovariectomized rats were primed with sesame oil or estradiol benzoate followed 48 h later by either sesame oil or progesterone. Four hours later, rats were treated with either saline or 0.25 mg/kg 8-hydroxy-2-9(di-n-propylamino)tetralin (8-OH-DPAT). Rats were allowed to eat for 4 h after this final treatment. Animals in all hormonal conditions showed hyperphagia following 8-OH-DPAT. However, the hyperphagia was significantly attenuated by pretreatment with estradiol benzoate. There was no effect of progesterone on the hyperphagic response. These results suggest that previous findings of an estrous cycle modulation of the hyperphagic response to 8-OH-DPAT arise from the modulatory effects of estradiol, and not progesterone, during the female reproductive cycle.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

A neuronal nitric oxide synthase inhibitor 7-nitroindazole reduces the 5-HT1A receptor against 8-OH-DPAT-elicited hyperphagia in rats.

The effects of the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole on 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT)-induced hyperphagia, which is mediated by the 5-HT1A autoreceptor, were investigated in rats. 7-Nitroindazole suppressed 8-OH-DPAT-elicited increases in food intake. The inhibitory effects of 7-nitroindazole on 8-OH-DPAT-induced feeding were prevented by the NO precursor L-arginine. Although 8-OH-DPAT decreases 5-hydroxytryptamine (5-HT) synthesis, 7-nitroindazole did not reverse the 8-OH-DPAT-elicited decrease in 5-HT synthesis. Therefore, these results indicate that NO formed in the brain is involved in 8-OH-DPAT-induced hyperphagia and that the hypophagic effects of 7-nitroindazole are not dependent on 5-HT synthesis.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes.

The hyperphagia/obesity syndrome produced by paraventricular hypothalamic (PVH) lesions and that produced by medial hypothalamic (MH) knife cuts were compared in adult female rats. Each treatment produced hyperphagia and overweight on a chow diet, although the PVH effect was less than the knife-cut effect. Each treatment also produced qualitatively similar ingestive responses to unpalatable quinine- and sucrose octaacetate-adulterated diets and to palatable dextrose and fat diets during the dynamic and static weight-gain phases. The PVH lesions and MH cuts disrupted day/night feeding patterns and elevated water intakes but not water/food intake ratios. However, PVH lesions, unlike MH cuts, did not increase emotional reactivity. The relation of the PVH syndrome to the classic hypothalamic hyperphagia syndrome is discussed. Also considered is the neuroanatomical substrate responsible for the PVH hyperphagic effect.

Animals↗

Hyperphagia in ruminants induced by a depressant.

Attempts at causing ventromedial hyperphagia in ruminants have been hitherto unsuccessful. In our experiments perfusion of the ventriculocisternal system with pentobarbital caused marked hyperphagia. This suggests that the ventromedial hypothalamic area is functioning in ruminants, probably as in monogastric animals, by inhibiting the lateral area.

Animals↗

Hyperphagia in rats with cuts between the ventromedial and lateral hypothalamus.

Bilateral cuts between the ventromedial and lateral hypothalamus in female rats consistently produced hyperphagia. Hyperphagia occurred slightly less reliably when one of the cuts entered the ventromedial hypothalamus and only infrequently if one entered the lateral hypothalamus. The results are consistent with other evidence that suggests that fibers originating medially stop eating by inhibiting cells in the lateral hypothalamus.

Animals↗

Onset of genetic obesity in the absence of hyperphagia during the first week of life in the Zucker rat (fa/fa).

The aim of this study was to discover which of three major abnormalities of the genetically obese Zucker rat (fa/fa), namely hyperphagia, excess adiposity, and hyperlipidemia, is the first to appear prior to manifest obesity, i.e., before weaning. Suckling fa/fa rats, bred from heterozygous parents, were detected by sizing fat cells obtained from an inguinal fat pad biopsy. Cell hypertrophy was observed in fa/fa rats, compared to Fa/-littermates of the same sex, as soon as 5-7 days after birth. Prediction of fa/fa genotype at this age by this method was assessed using a series of 80 pups and proved to be totally successful. The identity of the "predicted" obese pups was confirmed morphologically at 6 weeks of age. Food (milk) intake was estimated from water turnover rates determined on 86 pups aged 2-8 days using tritiated water. The results show that 7-day-old fa/fa rats had heavier inguinal fat pads with larger adipocytes and higher lipoprotein lipase activity than their lean controls. There was no genotype effect on water intake adjusted to body weight during the first week of life. Moreover weight of stomach contents and triglyceridemia were similar in all animals at 7 days. These results show that excess adiposity develops in the fa/fa rat during the first week of life, before hypertriglyceridemia and hyperphagia, and raises the question of whether this adiposity results from a defect in energy expenditure or an abnormality of fat cell storage capacity, or both.

Adipose Tissue↗