Dual effects of 2-deoxy-D-glucose on food intake in the rat: inhibition at night and stimulation in the day-time

The effect of 2-deoxy-D-glucose on food intake in rats has been reexamined. The effects were compared following administration of 2-DG IP (250, 500, 750 mg/kg and saline) either at the beginning of a 12-hr dark or 12-hr light period. Ad lib food intake was recorded during the subsequent 24 hours. In the day-time 2-DG enhanced food intake. The increase was not dose-dependent. It was apparent only during the first four hours and was compensated during the following eight hours. At night, an inhibition in food intake was observed. This inhibition was mainly manifested during the first four hours and was not dose-dependent. However, a dose related compensation during the subsequent hours resulted in a dose-dependent inhibition of the nocturnal intake. A second expermient indicated that after an overnight fast 2-DG also inhibited the high food intake induced in the day-time. In a third experiment, insulin 10 IV SC combined to 2-DG was shown to further increase food intake in the day-time. At night the combined administration of insulin and 2-DG cancelled their respective opposite effects and no change of food consumption was observed. The results are interpreted in terms of the contrasted neuroendocrine and metabolic patterns prevailing in the two parts of the diurnal cycle.     

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.     

Intraventricular insulin reduces food intake and body weight of marmots during the summer feeding period

The study presented below describes experiments that investigate the ability of insulin to inhibit food intake in awake, active marmots during the summer season. Our results suggest that increasing intraventricular insulin concentration during the summer active feeding period will cause a decrease in food intake and body weight of marmots. When infused with insulin into their lateral ventricles (Alzet #2002 minipumps), animals had significantly lower food intake as compared to their food intake during the control period. In addition, these animals lost body weight during the period of the insulin infusion. We suggest that during the summer when marmots are not hibernating and are actively feeding, brain insulin levels may play a role in regulating food intake.     

Spontaneous obesity and weight loss: insulin action in the dormouse

Dormice (Glis glis) undergo spontaneous cyclic changes in food intake and body weight. These infradian cycles with a periodicity of about 2 mo are endogenously controlled, since they persist in conditions of constant temperature and photoperiod. To evaluate the role of insulin as an effector of hyperphagia and fattening in dormice, experiments were conducted to study pancreatic function and adipose tissue metabolism during several phases of the infradian cycle. During the weight loss phase, peripheral insulin resistance occurs in the absence of hyperinsulinism. This resistance is not corrected by weight loss. Weight loss phase animals showed poor glucose tolerance and an impaired in vitro glucose-stimulated insulin secretion; these were not attributable to reduced pancreatic insulin content. Although basal glucose transport and basal, as well as insulin-stimulated, glucose utilization in isolated adipocytes were depressed during the weight loss phase, insulin-stimulated transport was significant. The data offer no evidence that insulin has a direct causal role in the development of spontaneous obesity in this species.     

Central insulin potentiates eating elicited by 2-deoxy-D-glucose

2-Deoxy-D-glucose (2DG) elicits glucoprivic food intake whether administered centrally or systemically. Insulin, on the other hand, elicits glucoprivic food intake when administered systemically but reduces food intake when administered centrally. The purpose of these experiments was to determine the interaction of centrally administered insulin with systemically administered 2DG on feeding. In the experimental condition, male Sprague-Dawley rats were administered 5 mU insulin into the third cerebral ventricle (i3vt) followed 2 h later by a subcutaneous injection of 250 mg/kg of 2DG. Contrary to expectations, third ventricular insulin significantly increased 2DG-induced hyperphagia. A replication using doses of insulin ranging from 1 to 10 mU revealed a dose-dependent response. Whereas the lowest dose of insulin (1 mU) did not reliably change food intake, doses of 2.5, 5, and 10 mU significantly enhanced 2DG-induced feeding. Consistent with previous reports, centrally administered insulin, when given alone, caused a significant reduction of 24-h body weight and chow intake. To assess if the insulin-induced hyperphagia was a result of leakage from the ventricles, we peripherally administered 5 mU of insulin and observed, if anything, a slight decrease of food intake. These studies suggest that in the presence of central glucoprivation, a distinct anabolic action of centrally administered insulin overrides the normally observed catabolic response and increases the hyperphagic feeding response induced by 2DG.     

The ingestion of food and the recovery of body weight following fasting in the naive rat

The total food consumption of experimentally naive rats following 24, 48, 72, and 96 hr fasts was observed during the period of the recovery of body weight. The total amount of food consumed in excess of prefast food consumption was found in all groups to be equivalent to 24 hr intake and was, therefore, independent of degree of fast and body weight lost. Moreover, it was found that rats recover lost body weight following a fast even when intake is held to prefast levels. These findings suggest that the regulation of body weight may be under the control of mechanisms in addition to the control of food intake.     

Effects of food restriction on glucose tolerance, insulin secretion, and islet-cell proliferation in pregnant rats

Pregnancy is associated with increased glucose-stimulated insulin secretion and increased pancreatic islet-cell proliferation. In the present study it was investigated whether increased food intake, as occurs during pregnancy, is involved in the regulation of these phenomena. From Day 0 of pregnancy, rats received each day the mean amount of food they consumed daily during the estrous cycle prior to conception. This food restriction regime resulted in lower maternal body weight, and in lower fetal weight on Day 20 of gestation, but did not affect fetal survival. Food-restricted rats showed decreased insulin responses to an i.v. glucose challenge on Day 13, and lower islet-cell replication rates on Day 14 of pregnancy than pregnant rats fed ad lib. Plasma lactogenic activity in food-restricted animals was increased on Days 11 and 13; plasma progesterone levels were unchanged, but plasma leptin concentrations declined progressively during food restriction. Glucose tolerance was normal, suggesting that food restriction improved insulin action. On Day 20 of pregnancy, insulin responses were similar in food restricted and ad lib-fed rats; glucose tolerance was still unchanged. It thus seems that the improved insulin action as present on Day 13 had disappeared on Day 20. Also on Day 20, lactogenic activity as well as progesterone concentrations were similar in food-restricted and ad lib-fed rats. It was concluded that increased food intake plays an important role in the stimulation of islet-cell proliferation and insulin secretion, as well as in the diminished insulin action during the second week of rat pregnancy.     

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.     

Control of food intake in the lactating rat: role of suckling and hormones.

The research described was designed to study the relative contributions of the process of milk synthesis, the suckling stimulus, and the hormones of lactation to the hyperphagia and body weight gain occurring during lactation. In the first set of studies the role of the suckling stimulus was considered. Nursing mother rats in whom a milk withdrawal was precluded by injections of ergocornine or by galactophore ligation continued to show a modified hyperphagia in response to suckling stimulation. However, cycling females induced to respond maternally through pup-induction did not exhibit elevated food-intake in response to suckling by foster young. These results suggested that suckling stimulation is able to stimulate increased food intake only in animals possessing functional secretory mammary glands. In the second group of experiments the role of hormones associated with lactation was considered. Mothers whose pups had been removed and then injected with either prolactin alone or prolactin, hydrocortisone acetate and oxytocin showed the same pattern of lower food intake as that of saline-injected controls. Similarly, virgin animals injected with the same triad of hormones showed no elevation of food intake. These data suggest that the hormones associated with lactation do not exert a direct facilitatory effect on food intake independent of their effect on lactation.     

Feeding in response to repeated protamine zinc insulin injections

Sustained overeating was induced in rats with repeated daily injections of protamine zinc insulin. The hyperphagia and hypophagia upon termination of insulin treatment were directly related to the amount of insulin that had been administered. The intake was regulatory since animals adjusted food consumption appropriately to compensate for caloric intake from glucose solutions, and they maintained stable caloric intake by reducing the weight of food ingested from a high fat diet. Overeating was unmodified by the use of an equicaloric high protein diet even though total weight gain was reduced. Injections of cycloheximide and dexamethasone prevented protamine zinc insulin induced overeating.     

Metabolic concomitants of hypophagia during recovery from insulin-induced obesity in rats

Rats were given daily injections of protamine-zinc insulin (PZI) that increased food intake and body weight. Termination of insulin treatment resulted in transient hypophagia and weight loss. Simultaneously with the weight loss, plasma levels of glycerol, free fatty acids, glucose, and ketones increased, whereas adipose tissue lipoprotein lipase activity and liver glycogen decreased. These changes in food intake and metabolism after termination of PZI treatment were accentuated in streptozotocin-diabetic rats. Two antilipolytic drugs (nicotinic acid and 3,5-dimethylpyrazole) blocked the elevation in plasma glycerol while having no effect on food intake. A 1-day fast after termination of insulin treatment equalized insulin-treated and control groups for plasma glycerol and ketones and reversed group differences in free fatty acids; the elevation in plasma glucose persisted despite starvation. Following starvation, previously PZI-treated rats ate less than controls on refeeding. The results show that enhanced lipolysis does not invariably accompany hypophagia during excess weight loss and suggest that a disturbance in carbohydrate metabolism or an increase in hepatic fatty acid oxidation may underlie this decrease in food intake.     

Sleep deprivation of rats: the hyperphagic response is real

STUDY OBJECTIVES: Chronic sleep deprivation of rats causes hyperphagia without body weight gain. Sleep deprivation hyperphagia is prompted by changes in pathways governing food intake; hyperphagia may be adaptive to sleep deprivation hypermetabolism. A recent paper suggested that sleep deprivation might inhibit ability of rats to increase food intake and that hyperphagia may be an artifact of uncorrected chow spillage. To resolve this, a palatable liquid diet (Ensure) was used where spillage is insignificant. DESIGN: Sleep deprivation of male Sprague Dawley rats was enforced for 10 days by the flowerpot/platform paradigm. Daily food intake and body weight were measured. On day 10, rats were transcardially perfused for analysis of hypothalamic mRNA expression of the orexigen, neuropeptide Y (NPY). SETTING: Morgan State University, sleep deprivation and transcardial perfusion; University of Maryland, NPY in situ hybridization and analysis. MEASUREMENTS AND RESULTS: Using a liquid diet for accurate daily measurements, there was no change in food intake in the first 5 days of sleep deprivation. Importantly, from days 6-10 it increased significantly, peaking at 29% above baseline. Control rats steadily gained weight but sleep-deprived rats did not. Hypothalamic NPY mRNA levels were positively correlated to stimulation of food intake and negatively correlated with changes in body weight. CONCLUSION: Sleep deprivation hyperphagia may not be apparent over the short term (i.e., < or = 5 days), but when extended beyond 6 days, it is readily observed. The timing of changes in body weight and food intake suggests that the negative energy balance induced by sleep deprivation prompts the neural changes that evoke hyperphagia.     

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.     

Absence of post-fast food compensation in the golden hamster (Mesocricetus auratus).

Ad lib food intakes and body weights were measured for hamsters fed one of 4 different diets. Animals were then placed on an intermittent starvation (IS) schedule in which food was available ad lib on alternate days only. Hamsters of both sexes showed little or no post-fast food compensation, i.e., after 24 hr of food deprivation their daily food intake was no greater than their daily intake during baseline testing. These animals lost a large percentage of their initial body weight and many of them died. Other hamsters restricted daily to half-day feeding periods that nearly coincided with the light (L) or dark (D) phases of the illumination cycle also failed to show food compensation; they generally ate no more during D- or L-periods that followed a half day of food deprivation than during D- or L-periods that succeeded a half day of ad lib feeding. These animals lost substantial portions of their initial body weight and many died. Hamsters refed after a 96-hr fast and an 18% loss in body weight also did not increase their food intake substantially above baseline values. In each of these experiments substantial portions of the body weight lost during starvation were not regained during extended ad lib refeeding regimens. These findings contrast strikingly with the behavior of rats tested concurrently; rats showed a dramatic post-fast hyperphagia, rapid recovery of body weight lost during starvation, and a reversal of the normal nocturnal feeding pattern when refeeding began during L-periods. Hamsters' nocturnal rhythms of eating and drinking were remarkably stable in the face of all the experimental manipulations. However, hamsters, as well as rats, were quite effective in compensating for changes in diet density; a 1:1 dilution of a liquid diet produced a prompt doubling in the volume of diet ingested. Impressive but less complete compensation was recorded when solid diets were diluted with inert substances (kaolin, cellulose). Hoarding and perhaps hibernation rather than compensation may have evolved as adaptations to periods of food scarcity. Noncompensation may be related to hamsters' nonresponsiveness to some signal of energy depletion. The possibility of lipogenesis being a rate-limiting step is considered. The desirability of adequate field data as a prerequisite to laboratory analysis of feeding behavior is emphasized.     

Effects of insulin on food intake and plasma glucose level in fat-fed diabetic rats

Schedules of insulin treatment which reliably increased eating in fat-fed diabetic rats were studied for their effect on plasma glucose concentrations. An inverse correlation between intake and plasma glucose was observed in fat-fed diabetics given long-term treatment with protamine-zinc insulin (PZI); however changes in glucose did not account for the differential effect of insulin on food intakes in normal controls or normal and diabetic rats fed a low-fat food. A single injection of 1 U PZI which increased eating in fat-fed diabetics but not normal controls 17–23 hr later did not reduce glucose concentrations from hyperglycemic levels in diabetics during the same time period. Injections of regular insulin increased eating in fat-fed diabetic and normal rats in a comparable fashion, but did not reduce plasma glucose in diabetics as low as in normal animals. The results show that the effect of exogenously administered insulin on food intake in fat-fed diabetics is largely unrelated to changes in circulating glucose levels and suggest that metabolic consequences of insulin treatment other than hypoglycemia may underlie the effect of the hormone on feeding in these animals.     

Effect of naltrexone on food intake and body weight in Syrian hamsters depends on metabolic status

Opioids are a family of neuropeptides involved in the control of food intake and regulation of body weight. In general, nonselective opioid antagonists have inhibited food intake in a variety of paradigms in rodent species. Syrian hamsters may be an exception to the general findings. In a previous report, we showed that systemic administration of an opioid antagonist, naltrexone, for 2 days increased body weight in female Syrian hamsters. To confirm the extent of these finding we designed the present experiment testing the effect of a chronic 6-day infusion of naltrexone on food intake, water intake, and body weight in freely feeding male hamsters. In addition, we examined the effect of acute administration of naltrexone on food intake in both ad-libitum-fed and food-deprived hamsters. We found that chronic systemic administration of naltrexone caused a significant increase in food intake and body weight. Second, acute administration of naltrexone decreased food intake after a 48-h fast but had no effect in ad-libitum-fed hamsters. Water consumption was not altered in any experimental paradigm. Our results suggest that opioid circuits in Syrian hamsters may function tonically to suppress food intake and body weight when Syrian hamsters are in positive energy balance. Paradoxically, opioids may enhance food intake after a sustained fast.     

Adipose tissue lipoprotein lipase activity in rats with obesity-inducing hypothalamic knife cuts

Three experiments examined the effects of obesity-inducing parasagittal hypothalamic knife cuts on adipose tissue lipoprotein lipase (LPL) activity in female rats. Knife cuts induced a 4-fold increase in adipose tissue LPL activity. Knife-cut rats with controlled insulin levels were hyperphagic but showed no increase in adipose tissue LPL activity or body weight gain. Prevention of the hyperphagia by food restriction also blocked the changes in LPL activity and weight gain. Finally, exogenous insulin treatment increased adipose tissue LPL activity in the absence of hyperphagia in neurologically-intact rats. We conclude that increased adipose tissue LPL activity may play a permissive role in the development of hypothalamic obesity, with the increase in enzyme activity being secondary to knife-cut-induced hyperinsulinemia.     

Effect of chronic insulin administration on food intake and body weight in rats.

Insulin was chronically administered to rats to determine its effect on the daily changes in food intake and body weight. Animals received regular insulin via 14-day osmotic minipumps in doses of 0.0, 0.5, 1.0, 3.0, and 5.0 IU/day treated either with (+GLU) or without glutamic acid (-GLU). Previous studies have shown that glutamic acid prevents insulin aggregation in the minipumps to provide a more stable flow rate. Food intake and body weights were measured each day of treatment. Chronic insulin treatment was ineffective in promoting changes in animals receiving any dose of insulin except the highest dose. Animals receiving 5.0 IU/day insulin + GLU experienced a transient hyperphagia and weight gain followed by a suppression in food intake and body weight by Day 4 of treatment. Effects were attenuated in animals receiving insulin -GLU. Plasma insulin concentrations on Day 14 were similar for all doses, suggesting a compensation took place either in insulin degradation or endogenous insulin production. Results indicate that glutamic acid treatment enhances the effects of chronic insulin administration via osmotic minipumps.     

Amylinergic control of food intake

Amylin is a pancreatic B-cell hormone that plays an important role in the regulation of nutrient fluxes. As such, amylin reduces food intake in laboratory animals and man, slows gastric emptying and it reduces postprandial glucagon secretion. Amylin deficiency which occurs concomitantly to insulin deficiency in diabetes mellitus, may therefore contribute to some of the major derangements associated with this disorder (hyperphagia, excessive glucagon secretion, accelerated rate of gastric emptying). The described actions of amylin all seem to depend on a direct effect of amylin on the area postrema (AP). As to amylin's satiating effect, the physiological relevance of this action is underlined by studies involving specific amylin antagonists and amylin-deficient mice. In the AP, amylin seems to modulate the anorectic signal elicited by CCK. Subsequent to AP activation, the amylin signal is conveyed to the forebrain via distinct relay stations. Within the lateral hypothalamic area, amylin diminishes the expression of orexigenic neuropeptides such as orexin and MCH. Whether these effects contribute to amylin's short term satiating action remains to be determined. Recent studies suggest that amylin may also play a role as a long-term, lipostatic signal, especially when other feedback systems to the brain are deficient. Obese, leptin-resistant Zucker rats which are hyperinsulinemic and hyperamylinemic, were chronically infused with the amylin antagonist AC 187. AC 187 significantly elevated food intake in obese Zucker rats while having no effect in lean controls. This indicates that at least under certain conditions, chronic blockade of endogenous amylin action may lead to an increase in food intake and/or body weight. As mentioned, the site and mechanism of action for peripheral amylin to reduce food intake seems to be well established. It is less clear how centrally administered amylin reduces food intake although it is well known that 3rd ventricular administration of amylin produces a very strong and long-lasting anorectic action. Amylin receptors have been described in various hypothalamic nuclei but the endogenous ligand of these receptors remains to be investigated. The same holds true as to the physiological relevance of the anorectic effect seen after central amylin administration.     

Effects of chronic intrahypothalamic infusion of insulin on food intake and diurnal meal patterning in the rat

In Experiment 1, rats were chronically infused with insulin (2.7, 27, or 270 ng/hr) or 0.9% saline into the ventromedial (VMH), medial perifornical (PF), or lateral (LH) hypothalamus. VMH infusions of insulin caused a significant, dose-dependent decrease in food intake and body weight; PF infusion of insulin was less effective, but significant; whereas LH infusions of insulin were ineffective. In Experiment 2, rats were chronically infused with insulin (0.54 ng/hr) or 0.9% saline into the VMH, paraventricular (PVN), or posterior (PN) hypothalamic nucleus. Subjects that received VMH or PN infusions of insulin failed to regain weight lost as a result of surgery even 2 weeks after infusion; subjects that received PVN infusions of insulin regained their preoperative weights faster than did controls. All of the groups that received insulin significantly increased their daytime food intake during the infusion period and decreased their night food intake slightly; 24-hr food intake remained unchanged.