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.     

Effects of quinine adulterated diets on the food intake and body weight of obese and non-obese hypothalamic hyperphagic rats

Female rats given knife cuts between the medial and lateral hypothalamus overate and became obese on a high fat diet. When switched to a quinine diet the knife cut rats initially underate and lost weight, but their body weights did not fall significantly below that of controls maintained on the same diet. Knife cut rats also maintained weights at control levels when given a moderately bitter quinine diet immediately after surgery, but displayed subnormal weights when switched to a very bitter diet. Cuts lateral to the fornix produced a greater weight suppression on the quinine diet, but a smaller weight gain on a high fat diet than did cuts medial to the fornix. The results indicate that the hypothalamic knife cuts elevate the upper limit of body weight with little or no change in the lower body weight limit, and that obesity rather than hypothalamic damage per se is the major cause of the hyperphagic rat's finickiness to unpalatable quinine diets. A dual lipostatic model of the hypothalamic hyperphagia syndrome is discussed.     

Hypothalamic knife-cut hyperphagia and obesity in weanling rats

In previous reports weanling female rats fed a high-fat diet had a delayed response to hypothalamic knife cuts. In the present report similar cuts in similar rats fed a standard low fat diet became overweight without delay, suggesting that dietary fat is a critical variable in juvenile onset obesity. Adult rats given knife-cuts comparable to those in the weanlings gained weight far more rapidly and achieved higher weights than did those cut as weanlings, suggesting that appetite modulating axons can develop after weaning. Finally, group vs single housing did not influence the age of onset or the magnitude of knife-cut obesity.     

Experimental obesity syndromes in rats: influence of diet palatability on maintenace body weights

Female rats with ventromedial hypothalamic (VMH) lesions, parasagittal hypothalamic knife cuts (KC), or dorsolateral tegmental (DLT) lesions were maintained successively on 0.2 and 0.4% quinine chow, plain chow, pellets, wet mash, and high fat diets (15–45 days each). Only VMH rats overate the 0.2% quinine diet and only KC rats underate the 0.4% quinine diet. Although DLT rats did not overeat the unadulterated chow and pellet diets, as did VMH and KC rats, all three surgical groups attained roughly comparable elevated body weight means after access to the wet mash and high fat diets. Thus, dietary manipulations clearly induce differential patterns of feeding behavior in these three obesity syndromes.     

Overeating, overweight and obesity induced by an unpreferred diet

Rats fed diets containing 50-71% added water (liquid diets) eat more energy and gain more weight than rats fed the same diets without added water (solid diets). The present experiments examined the effects of making a liquid diet less palatable. The first experiment examined the effects of sucrose octaacetate on diet preference. Rats, given a choice of a liquid diet containing 0.5% sucrose octaacetate and a plain solid diet, preferred the plain solid diet for three weeks. When the concentration of sucrose octaacetate was reduced to 0.05%, the rats did not show a reliable preference for either the sucrose octaacetate liquid or plain dry diet. In subsequent experiments, each rat was given only one diet at a time. In the second experiment, rats were fed 0.5% sucrose octaacetate liquid diet for three weeks followed by 0.05% sucrose octaacetate liquid diet for another four weeks. The rats fed the sucrose octaacetate liquid diet overate and became obese compared to the rats fed plain solid diet throughout. In the third experiment, rats fed 0.5% sucrose octaacetate liquid diet for six weeks became obese compared to rats fed plain solid diet throughout. Thus, the overeating and obesity induced by liquid diets cannot be attributed solely to their high palatability.     

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.     

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.     

Consumption of a high-fat diet alters the homeostatic regulation of energy balance

Humans in many countries are currently experiencing what has been called an epidemic of obesity. That is, the average body weight (and amount of fat stored in the body) is increasing over years, carrying with it a multitude of associated medical, psychological, and economic problems. While there is no shortage of possible causes of this epidemic, increased availability and consumption of high-fat (HF), calorically dense and generally quite palatable food is often touted as a likely culprit. In order to better assess the impact of consuming a diet with those qualities, we have developed a well-controlled animal model in which the effects of chronic consumption of a high-fat diet can be dissociated from those of becoming obese per se. Long-Evans rats are fed one of two semipurified pelleted diets, a HF diet that contains 20% fat by weight and a low-fat (LF) diet that contains 4% fat by weight. Pair-fed animals consume the HF diet but are limited to the daily caloric intake of LF rats. Another group receives pelleted chow. Relative to animals consuming diets low in fat, HF animals weigh more, have more carcass fat, are hyperinsulinemic and hyperleptinemic, and are insulin resistant. HF-fed animals, independent of whether they become obese or not, also have central insulin and MTII insensitivity. Finally, HF rats have a down-regulated hypothalamic apo A-IV system that could contribute to their hyperphagia.     

High-fat diet preference in developing and adult rats

Diet preference tests in rats have yielded equivocal results, as some investigators have reported a strong preference for diets high in fat over those containing less fat, while others have failed to see this preference. To further explore this unresolved problem, two diet preference experiments were conducted. In Experiment 1, adult rats were maintained for at least three months on one of three powdered diets (control, high-carbohydrate or high-fat). Rats were then given a preference test with all three diets available. Animals from each group overwhelmingly preferred the high-fat diet. To determine whether this preference was also present in younger, developing rats, in Experiment 2, weanling animals were tested with the same three diets as in Experiment 1. As observed with adult animals, weanling rats also showed a strong preference for the high-fat diet. The idea that rats prefer a diet with a relatively high level of fat is supported. Possible explanations for these findings are discussed.     

Independence of food intake and obesity following ventromedial hypothalamic lesions in the rat

Lesions of the ventromedial nucleus of the hypothalamus that do not cause overeating cause significantly greater accumulations of body fat in male rats maintained on an ad lib diet than in controls. Lesioned rats that overeat show a still greater percentage of body fat. The results indicate that obesity caused by medial hypothalamic lesions can result from both primary metabolic disturbances and overeating; and that experimental obesity consistently results from ventromedial hypothalamic lesions independently of the development of hyperphagia.     

Paraventricular area: Critical focus of a longitudinal neurocircuitry mediating food intake

Hyperphagia, obesity, and excessive linear growth, but not hyperdipsia, were produced by the asymmetrical combination of a parasagittal hypothalamic knife cut and a contralateral coronal knife cut. When the location of the coronal cut was varied systematically, it was found that cuts rostral to the coronal level of the paraventricular nucleus (PVN) neither produced nor prevented overeating, while cuts caudal to the PVN produced a robust hyperphagic response. Thus, the coronal level of the paraventricular nucleus was revealed as the rostral focus of a longitudinal satiety neurocircuitry.     

Effects of dietary dehydroepiandrosterone on food intake and body weight in rats with medial hypothalamic knife cuts

Dehydroepiandrosterone (DHEA) is a steroid which has been reported to have anti-obesity effects when added to the diets of rats and mice. In this report, rats made hyperphagic with medial hypothalamic knife cuts were placed on a diet containing 0.45% DHEA or a control diet. Knife cut rats on the control diet ate more food and gained more weight than sham-operated rats on the control diet. In contrast, knife cut rats fed the DHEA diet weighed the same as shams on the DHEA diet and were only observed to be hyperphagic on one of eight 24 hour measurements taken during a five week period. Dietary DHEA reduced food intake and body weight of both knife cut and sham-operated rats, though the effects were smaller in shams. As these effects of DHEA were reminiscent of the effects of dietary quinine adulteration on intake by knife cut rats, a second experiment measured the food intake of unoperated rats when given a choice between a control high-fat diet and one adulterated with various concentrations of DHEA. Even at a concentration of 0.05%, rats clearly identified and avoided the DHEA-adulterated diet. While these results do not rule out effects of DHEA on metabolic rate or lipogenesis, they do indicate that the unpalatability of DHEA-adulterated diets may be a contributing factor in the observed effects on food intake and body weight.     

Diet composition alters the satiety effect of cholecystokinin in lean and obese Zucker rats

Although exogenous administration of the peptide cholecystokinin (CCK) has been shown to reduce food intake in a variety of experimental situations, few studies have examined the influence of dietary content upon CCK's effectiveness, particularly in obese states. To evaluate the effectiveness of CCK administration in animals consuming high fat diets, groups of obese and lean Zucker rats were maintained on laboratory chow (CH), a high fat diet isocaloric to chow (IF), or a hypercaloric fat diet (HF). After a 17 hr fast, rats were given intraperitoneal injections of saline or ascending doses of 0.06 to 2.0 micrograms/kg of the synthetic octapeptide of CCK. On all diets, obese rats required higher doses of CCK to significantly reduce feeding and showed smaller intake reductions than lean rats (p less than 0.001). Despite higher baseline caloric intakes (p less than 0.001), rats of both genotypes maintained on HF displayed larger reductions of intake than those fed IF or CH (p less than 0.001). Intake reductions by either genotype maintained on IF or CH were not reliably different. The manner in which the satiety effect of CCK was enhanced in rats consuming the calorically dense, palatable HF diet is unclear but may be related to orosensory and/or postingestive attributes of the diet.     

Effect of food deprivation and maintenance diet composition on fat preference and acceptance in rats

High-fat diets typically elicit greater kcal intake and/or weight gain than low-fat diets. Palatability, caloric density, and the unique postingestive effects of fat have each been shown to contribute to high-fat diet hyperphagia. Because long-term intake reflects the sum of many individual eating episodes (meals), it is important to investigate factors that may modulate fat intake at a meal. The present studies used high-fat (hi-fat) and high-carbohydrate (hi-carb) liquid diets (both 2.3 kcal/mL) to assess the effect of hunger level (0 versus 24-h food deprivation) and fat content of the maintenance diet (12 versus 48%) on fat preference (when a choice among foods is offered in a two-bottle test), and acceptance (only one food offered) in male rats. Preference for hi-fat relative to hi-carb (two-bottle test) was enhanced by 24-h food deprivation, and by a high-fat maintenance diet. In contrast, neither deprivation nor maintenance diet composition influenced relative meal size (one-bottle test) of hi-fat and hi-carb: irrespective of test conditions, meal size of hi-fat was bigger than meal size of hi-carb.     

Opiates and medial hypothalamic knife cuts cause hyperphagia through different mechanisms

Several experiments were performed to determine whether the hyperphagia caused by medial hypothalamic knife cuts and that induced by opiate agonists are mediated by a common mechanism. In the first set of experiments, male Sprague-Dawley rats were given bilateral parasagittal medial hypothalamic knife cuts or a sham procedure and fed a high-fat Crisco-chow diet. Knife-cut and sham-operated rats were approximately equally sensitive to the suppressive effects of naloxone on food intake. The kappa opiate receptor agonist ketocyclazocine generally increased daytime food intake in sham-operated rats; in contrast, the normal hyperphagia of knife-cut rats was in most cases either unchanged or decreased by ketocyclazocine. In a second set of experiments, neither diet composition nor hypothalamic knife cuts significantly affected the feeding responses to naloxone or the stimulatory effects of the kappa agonist butorphanol tartrate. It was hypothesized that the differential effects of ketocyclazocine in knife-cut and sham-operated rats are a consequence of the sedative effects of the drug combined with the elevated baseline of the knife-cut subjects. This hypothesis was supported by a third experiment, in which ketocyclazocine also reduced nocturnal intake in unoperated rats and butorphanol increased intake. That feeding responses to naloxone and butorphanol were essentially unchanged by hypothalamic knife cuts suggests that the opioid feeding system is independent of the longitudinal feeding inhibitory pathway believed to be involved in knife-cut-induced hyperphagia.     

Caloric compensation in hypothalamic obese rats

The present study explored the influence of pelleted diets on adjustment to caloric dilution in hypothalamic obese rats. Medial hypothalamic lesioned and normal rats were maintained on a high fat diet until the static stage of hyperphagia was reached. They were given three pelleted diets which consisted of undiluted Noyes pellets and Noyes pellets diluted 25 or 50 percent with kaolin. In contrast to previous reports that hypothalamic obese rats do not compensate for caloric dilution of their diet, the obese animals showed as large an increase in food intake on the dilute pelleted diets as did the control animals. These results were interpreted by viewing texture as a dimension of palatability which influences food intake in hypothalamic obese rats.     

Diet composition determines course of hyperphagia in developing Zucker obese rats

Previous observations from this laboratory indicate that, during growth, the hyperphagia of the male genetically obese Zucker rat reaches a peak or "breakpoint" and then declines. To examine the effect of dietary macronutrient content on the course of hyperphagia, groups of male lean and obese rats were maintained from 5-28 weeks of age on powdered chow, or isocaloric diets (3.6 kcal/g) containing 72% of calories as corn oil, dextrose, or soy isolate protein (n = 5 lean and obese rats/diet). On chow, hyperphagia was maintained at a level of 7-8 g above lean control intake until a "breakpoint" was reached at 17 weeks, and obese intake declined to lean control level. On the fat diet, hyperphagia was increased to 10 g/day when a breakpoint was reached at 8 weeks. On the dextrose and protein diets, hyperphagia at a level of 3-4 g/day reached breakpoints at weeks 18 and 16, respectively. On all diets, the intakes of obese rats were precisely equal to the intakes of lean control rats by weeks 19-20. These data show that the magnitude and duration of hyperphagia in the developing obese rat are influenced by diet composition. Previously, we have proposed that the obese rat's hyperphagia arises from rapid adipocyte filling. Since high-fat diets facilitate adipocyte enlargement, the early "breakpoint" of hyperphagia seen with the high-fat diet may indicate that this feeding stimulation decreases as the fat cells of the obese rat approach maximal size.     

PVN-hindbrain pathway involved in the hypothalamic hyperphagia-obesity syndrome

This study examined the involvement of caudal brainstem projections of the hypothalamic paraventricular nucleus (PVN) in the medial hypothalamic (MH) hyperphagia-obesity syndrome. Experiment 1 demonstrated that a unilateral parasagittal knife cut in the MH combined with a contralateral coronal knife cut in either the ventrolateral pons (vP) or ventrolateral medulla (vM) significantly increased food intake and body weight in adult female rats. Overeating and overweight were also produced by a unilateral MH knife cut combined with a contralateral oblique cut under the nucleus of the solitary tract and dorsal motor nucleus of the vagus complex (NST/DX). In contrast, an MH cut x dorsolateral medullary cut combination did not increase food intake or body weight compared to a MH cut alone or sham surgery. Experiment 2 demonstrated that the hyperphagia/obesity effect of MH x vP knife cuts was comparable to that obtained with bilateral PVN lesions, but less than that produced by bilateral MH knife cuts. Bilateral vP cuts also increased body weight but the effect was less than that obtained with the other experimental treatments. Feeding the rats a high-fat diet rather than chow potentiated the hyperphagia and obesity syndromes produced by the various lesion conditions. Taken together, these findings suggest that the medial hypothalamic hyperphagia and obesity syndrome is due, in part, to damage to PVN projections to the caudal brainstem, the NST/DX complex in particular. The functional significance of this PVN-hindbrain "feeding" pathway and the identity of extra-PVN components of the hyperphagia-obesity syndrome remain to be established.     

Rats with hypothalamic knife cuts overeat an unpalatable diet

Female rats with bilateral parasagittal knife cuts between the ventromedial and lateral hypothalamus were fed a demonstrably unpalatable 0.4% quinine high-fat diet. These rats overate and maintained their body weights significantly above those of same-diet control animals. These results are similar to previous findings in this laboratory obtained from rats with ventromedial hypothalamic lesions.     

Decreased expression of CD36 in circumvallate taste buds of high-fat diet induced obese rats

Mammals spontaneously prefer lipid rich foods. Overconsumption of high-fat diet leads to obesity and related diseases. Recent findings indicate that taste may participate in the orosensory perception of dietary lipids and the fatty taste may contribute to a preference for and excessive consumption of dietary fat. CD36, a trans-membrane glycoprotein, which is located in the taste buds of circumvallate papillae of rodents, appears to be a plausible receptor for this fatty taste. Obese subjects present a stronger preference for fatty foods, though the mechanisms involved are complex and are not fully investigated. Our data from immunofluorescence and real-time RT-PCR showed that the expression levels of CD36 in circumvallate taste buds were significantly lower in high-fat diet induced obese rats as compared with that of control rats fed a normal diet. These results suggest that decreased expression of CD36 in circumvallate taste buds of high-fat diet induced obese rats may be associated with diminished fatty taste sensitivity and in order to compensate the preference for dietary fat, rats consume more fatty foods. Therapeutic strategies designed to alter or manipulate CD36 expression or function in taste buds may have important implications in treating obesity and related diseases.