Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: Evidence from a restriction-refeeding regimen

Male rats maintained their body weight at approximately 85% that of sham-lesioned controls following lesions of the lateral hypothalamus (LH). One month following surgery, the food intake of half the LH-lesioned animals was restricted until their body weight had declined to 80% that of nonrestricted LH animals. Half the sham-lesioned animals were similarly restricted until their body weight fell to 80% that of nonrestricted control animals. When returned to an ad lib feeding schedule, both restricted groups were initially hyperphagic and quickly restored their body weights to the level of the nonrestricted group from which they were originally selected. In doing so, the LH animals increased their food intake by the same amount and took the same number of days to restore their weight to control levels as the sham-lesioned animals. These observations provide further evidence of the vigor and effectiveness with which LH animals defend their reduced level of maintained body weight.     

Growth hormone, insulin-like growth factor-1, and the insulin-like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus

Rats with lesions of the lateral hypothalamus (LH) maintain a reduced body protein mass that they effectively defend when challenged by under- or over-nutrition. The two studies reported here evaluate the potential contributions of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the insulin-like growth factor-binding (IGFBP) to this persistent maintenance of a reduced body protein mass by LH rats. At 18 weeks postlesion, it was found that the serum levels of GH, IGF-1, total IGFBP, and IGFBP-3 of LH rats maintaining reduced body protein were not different from those of age-matched controls. However, closer to the time of surgery, at which time the lesion-induced body protein adjustments are known to occur, altered hormone and binding protein levels were observed. Specifically, at 3 weeks after lesioning, the IGF-binding proteins of LH rats were significantly elevated, whereas their GH levels were lower than those of controls. Because the GH, IGF-1, and IGF-binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning, none apparently underlie the chronically reduced body protein mass that LH rats display. Closer to the time of lesioning, however, altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level.     

Food intake and utilization in lateral hypothalamically lesioned rats

The daily food intake of rats with lateral hypothalamic (LH) lesions was monitored in two experiments. Confirming earlier reports, LH-lesioned animals were found to ingest nearly the same amount of food per day as nonlesioned controls even though their body weights remained substantially below those of the controls. In view of this result, an experiment was conducted to compare the efficiency of food utilization of LH-lesioned and control animals at different body weights. First, the daily food intakes of seven LH-lesioned rats and seven nonlesioned controls were determined. The body weights of these animals were then lowered by restricting food intake in four successive weekly periods to 85%, 70%, 55% and 40% of their ad lib level. Finally, all animals were refed for one week at their prerestriction levels of food intake reduced in proportion to the intervening loss in metabolic mass (body weight_kg^0.75). At each level of caloric restriction, the weight losses observed in the LH-lesioned and control animals were equivalent. Likewise, though given only prerestriction amounts (indexed to their reduced metabolic mass), LH-lesioned and nonlesioned animals both gained weight rapidly and at equivalent rates during refeeding. Thus, LH-lesioned animals appear to utilize food in a normal fashion and, as do controls, adapt to weight loss by increasing their efficiency of food utilizazion. In the case of LH-lesioned animals, however, such adjustments occur around a reduced level of maintained body weight, or set-point.     

Body weight and body composition of male rats following hypothalamic lesions.

Carcass analyses were performed on 160 male rats maintaining reduced, normal, or elevated levels of body weight following lateral hypothalamic (LH), sham (control), or ventromedial hypothalamic (VMH) lesions, respectively. Extracted body lipid (ranging from 26 to 738% of the control mean) correlated highly (r = +0.95) with the level of maintained body weight (which ranged from 67 to 191% of control). Neither the nonfat solids (which ranged from 60 to 123% of control) contributed significantly to the variance in body weight (r = +0.01 and +0.06, respectively). Fat thus accounted for approximately 90% of the overall variance in body weight among LH, control, and VMH animals. Consideration of only the LH data, however, revealed a breakdown of this close covariance of body fat and weight. Fat mass correlated significantly with body weight in LH rats maintaining weight 0-12% below normal; but, at maintained body weights below 88%, the correlation between weight and fat in LH rats was only +0.07. Variation in lean body mass then better accounted for differences in body weight. The implications of these observations for existing lipostatic theories of weight regulation are discussed.     

Influence of sympathectomy on the lateral hypothalamic lesion syndrome

Sympathetic involvement in the lateral hypothalamic (LH) lesion syndrome was examined. Male rats were surgically or chemically sympathectomized and then given LH lesions. At 24 hr postlesion, lesion-induced hyperglycemia but not hyperthermia was attenuated by splanchnicectomy and celiac ganglionectomy. Hyperthermia but not hyperglycemia was attenuated by adrenal demedullation, adrenalectomy, and neonatal guanethidine treatment. Guanethidine-sympathectomized rats also displayed lower basal temperatures, more perilesion chromatolysis, and severer external symptoms than their controls. No form of sympathectomy affected lesion-induced gastric pathology, plasma gastrin concentrations, or body weight loss. Nor did any sympathectomy influence the recovery of ingestive behavior, daily food intake, the feeding response to 2-deoxy-D-glucose, or body weight maintenance in recovered LH-lesion subjects. These results suggest that sympathetic hyperactivity contributes to some aspects of the acute LH syndrome: Hyperglycemia results from sympathetic outflow to the abdomen, whereas hyperthermia is determined by circulating catecholamines and extraabdominal sympathetic innervation. The results fail to support the hypothesis that chronic increases in sympathetic tone are responsible for the reduced food intake and body weight of the LH-lesion rat.     

Resting oxygen consumption in over- and underfed rats with lateral hypothalamic lesions

Rats maintaining stable, reduced body weights following lateral hypothalamic (LH) lesions were given either ad lib amounts of a palatable liquid diet or restricted amounts of a hydrated chow diet. The palatable diet produced weight gains while the diet restriction led to weight reductions in both LH- and sham-lesioned rats. Body composition analysis indicated that these changes in body mass were accounted for largely by changes in carcass fat. Resting oxygen consumption (expressed relative to body weight raised to the 3/4 power) was altered by both dietary regimens. Resting oxygen consumption in sham-lesioned rats increased by 5% following overfeeding and decreased by 13% following food restriction. LH-lesioned rats made similar responses to these dietary challenges. Overfed LH-lesioned rats increased their rate of resting oxygen consumption by 11%. Underfed LH-lesioned rats decreased oxygen consumption by 11%. These findings provide further evidence that rats with LH lesions defend a reduced level of body weight. The changes in energy expenditure that mitigate weight change in sham-lesioned animals are also present in LH-lesioned rats. In the latter, however, these adjustments serve to stabilize body weight at a lower level.     

Hyperinsulinemia and its role in maintaining the hypothalamic hyperphagia in chickens

Body weights and skeletal growth of female rats treated neonatally with low doses of testosterone propionate (TP) or estradiol benzoate (FB) were greater than oil-treated controls. After ovariectomy at 75 days of age EB-treated animals gained less weight than did the oil-treated controls and TP-treated rats which were comparable in weight gain. Neonatal treatment with TP or EB produced decreased sensitivity to the anorexic and weight-limiting effects of estrogen treatment after ovariectomy. However, all groups were equally sensitive to the anorexic effects of a single dose of CI-628. The possible mechanisms by which neonatal treatments with gonadal hormones influence food intake and body weight regulation are discussed.     

Involvement of a humoral factor in regulation of body weight in parabiotic rats.

Excessive food intake and obesity was induced in one member of parabiotic pairs by electrical stimulation (three 30-min sessions/day for 2 wk) of the lateral hypothalamus (LH). The nonstimulated partners reduced spontaneous food intake the fatter the stimulated animals became. This reduced food intake resulted in a decreased body weight, fat content, and fat-free solid body mass. The decrease of food intake was not due to changed social behavior of the obese partner. It must be attributed to transmission of a humoral satiety factor. The very first stimulation of the LH in the stimulated partners resulted in a large increase in blood glucose and glucagon level without much change in the insulin level. These changes in blood parameters were probably due to strong sympathetic arousal. In the nonstimulated animals there were practically no changes in these parameters. One week of fattening resulted in increased basal glucose and insulin levels in the stimulated animals and decreased glucose levels in the nonstimulated partners, in which the basal insulin levels remained nearly normal. Basal glucagon levels were the same in both partners and did not differ from the prefattening situation. At that time during stimulation the obese animals showed a large increase in glucose and glucagon levels and a decrease in insulin level. On the other hand the nonstimulated animals showed a slow gradual increase in glucose and insulin level due to transmission from their fat partners because of the large gradient in these substances between the animals. These phenomena were still more pronounced after 2 wk of fattening. It is tentatively concluded that the humoral satiety factor is neither circulating insulin nor glucagon nor one of the major circulating nutrients.     

Effects of lateral hypothalamic lesions on schedule dependent and schedule induced behavior

Rats were reduced to 80 percent body weight and were exposed to an FI 1 min food reinforcement schedule for 30 min daily until lever presses, licks and water consumption stabilized for at least 10 days. Six animals were subjected to bilateral mid lateral hypothalamic (LH) lesions and 6 animals to bilateral posterior LH lesions. Animals were tested for 50 days following the lesions at 80 percent body weight, were permitted to recover body weight, and were tested for an additional 30 days under ad lib feeding and after body weight recovered. Animals were then subjected to the following four home cage tests: food consumption following food deprivation; drinking following water deprivation; insulin induced eating; and salt arousal of drinking. On the basis of the data collected in these tests and lesion locus and size, the 12 experimental animals were divided into 3 groups--asymmetrical, typical and posterior bilateral LH lesion and were compared to a sham lesion control group of 4 animals. The asymmetrical LH lesion group was similar to the sham lesion group except lever pressing was significantly depressed. Typical bilateral lesion animals displayed the usual LH syndrome with prolonged depression of both schedule dependent lever pressing and schedule induced licking and drinking. Posterior bilateral LH lesions produced the most drastic effects on both schedule dependent and schedule induced behavior. Results indicate that the neural mechanism which is involved in schedule induced polydipsia is destroyed by posterior bilateral LH lesions.     

Ventromedial hypothalamic lesions in rats: Gradual elevation of body weight set-point

Bilateral electrolytic (DC) or radiofrequency (RF) lesions of the ventromedial hypothalamic (VMH) area produced two abnormal stages of fattening in adult female rats. Following a negatively-accelerated, curvilinear phase of weight gain which lasted 10 weeks, a linear phase of fattening continued for an additional 30 weeks at a rate approximately double that of operated control rats of the same age. During this second phase of fattening, lesioned rats were food-restricted between the 20th and 26th weeks postlesion. Compared to the rate of weight gain in the linear phase prior to food restriction, the rate over the same weight range following release from food restriction was significantly greater for both DC and RF-lesioned rats. Furthermore, by the 40th postlesion week, the lesioned rats had approached the weight they would have been if not food restricted. These observations suggest that VMH area lesions induce a gradual climbing of the set-point for body weight which occurs independently of actual food intake or body weight, and which either follows or is superimposed on the immediate elevation of the set-point responsible for the initial, curvilinear phase of weight gain. As a model for human idiopathic obesity, the long-term effect of VMH area lesions may be more important than the immediate effect.     

Weight loss,slower growth and lower fasting heat production rates following LH lesions in female rats

Lesions in the lateral hypothalamus (LH) can result in a permanent loss of body weight and slower growth in female rats, but do not do so invariably. Weight and growth rate changes were always accompanied by lower rates of fasting heat production (FHP) independent of changes in activity. The thyroids of these animals were significantly below normal in size. None of the traditional deficits of the “LH syndrome” were present: the animals ate when deprived of water: drank when deprived of food (although less than the control animals) and increased their food intakes when injected systemically with insulin, at least on the initial test. With repeated tests the food intake following insulin-induced hypoglycemia declined both in the animals with lesions and in the animals whose body compositions and weights had been lowered to the same levels.     

Capacity to produce cytokines during weight restoration in patients with anorexia nervosa.

OBJECTIVE: Anorexic patients are surprisingly free of infectious complications despite their seriously undernourished state. To study this phenomenon, we longitudinally measured the capacity to produce cytokines in restricting-type anorexic patients. METHODS: Lymphoproliferative responses with phytohemagglutinin (PHA) and the capacity of whole blood to produce cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and granulocyte-colony stimulating factor (G-CSF), were longitudinally measured before and after weight gain, that is, at admission and at less than 60, 65, and 75% of standard body weight (SBW), in 17 patients with restricting-type anorexia nervosa and in 17 control subjects. RESULTS: Cytokine production of IL-1, IL-6, and TNF-alpha per monocyte in the anorexic patients recovered only with the start of refeeding, whereas IFN-gamma production per lymphocyte was similar to that in control subjects and did not change during weight restoration. Only G-CSF production, even at 75% SBW, did not improve during weight restoration. Between the weight at admission and 65% SBW, the increase in the percentage of SBW and improvement of the total protein level were significantly correlated with improvement of the lymphocyte proliferative response with PHA. CONCLUSIONS: The capacity to produce most cytokines recovered with the start of weight gain; however, recovery was not correlated with weight gain. The results suggest that the capacity to produce cytokines in these anorexic patients was dependent on something other than the absolute value of body weight, such as the start of refeeding, the neuroendocrine system, or the autonomic nervous system.     

Weight loss following LH lesions independent of changes in motor activity or metabolic rate

Lesions in the lateral hypothalamus (LH) which resulted in aphagia and a significant loss in body weight, did not reduce either the running wheel activity or the stabilimeter activity of the animals. Following recovery, the animals failed to regain the lost weight. They had normal food and water intakes under ad lib conditions, and ate food when water deprived. They did not drink when deprived of food. Both control and LH animals also had higher than normal oxygen consumption rates. However, the LH group was not higher than the controls postoperatively. These data argue against their being a unitary LH lesion syndrome and suggest that the chronic weight loss seen in animals with LH lesions is not a secondary consequence either of having disrupted the pituitary-thyroid axis, or of having changed the animals' spontaneous activity levels.     

Tolerance to amphetamine anorexia: role of learning versus body weight settling point

Three experiments were conducted to clarify the role of learning and body weight settling point in the development of tolerance to amphetamine anorexia. In the first experiment, rats that had become tolerant to the suppressant effect of amphetamine on milk intake were anorexic when subsequently offered other foods or water during a transfer test. These results appear to support a conditioning interpretation, which predicts a loss of tolerance when cues associated with drug administration are altered. Subsequent experiments examined the long-term effect of changing diets. In Experiments 2 and 3, rats made tolerant with milk as the diet showed prolonged anorexia when switched to Purina pellets or slightly bitter milk. However, when switched from pellets or adulterated milk to milk, tolerant rats were anorexic only 1 day and then ingested significantly more of the new diet. These results are inconsistent with a conditioning interpretation. Further analysis revealed that tolerant rats maintained their weight below the level of saline controls despite the recovery of food intake. Moreover, the level at which they maintained their weight varied with the palatability of the diet. These results suggest that amphetamine lowers the settling point for body weight and that tolerance does not develop to this effect (cf. Stunkard, 1981). From this perspective, the reinstatement of prolonged anorexia when apparently tolerant rats were switched to a less palatable diet can be understood as an attempt to attain a lower weight level.     

Long-term treatment of the MRL/lpr mouse with methotrexate and 10-deazaaminopterin

Female MRL/lpr mice were treated with I.P. doses of methotrexate (MTX) and 10-deazaaminopterin (DAAM) in the range of 1 to 100 mg/kg body weight/week, in two equally divided doses. Treatment began at 7 weeks of age and continued to 30 weeks of age. Joint histopathology scores were tightly correlated with skin lesion-proteinuria scores at 30 weeks of age. MTX at levels of 5, 25, and 100 mg/kg body weight/week and DAAM at a level of 25 mg/kg body weight/week significantly reduced skin lesion-proteinuria scores below controls in a dose dependent manner. Animals receiving MTX at 25 mg/kg body weight/week had a significantly longer median life span and animals receiving MTX at 100 mg/kg body weight/week had a greater than 15% suppression of growth when compared with cottrols. Longevity and skin lesion-proteinuria scores appeared to be good indicators of drug efficacy while growth suppression appeared to be a good indicator of drug toxicity.Supported in part by NIH grants CA-28103 and CA-32687, RR32-31S1, AR03555, AR20614, and the Veterans Administration Research Program.     

Effect of maternal exercise on fetal and placental glycogen storage in the mature rat.

The purpose was to determine the effects of exercise on fetal and placental glycogen storage patterns at 20 days gestation (term 21 days) in mature (approximately 12 months of age) Sprague-Dawley rats. The exercise protocol consisted of treadmill running at 30 m min-1, on a 10 incline, for 60 min, 5 days per week, for 4 weeks prior to conception, which continued until day 19 of pregnancy. Exercise produced a significant reduction in fetal body weight, placental weight, and fetal organ weights (heart, kidney, brain, and liver) compared to sedentary control animals (p <.05). However, when fetal body size was taken into account, these differences disappeared, except for the fetal brain:body weight ratio, which was larger in the exercised animals compared to controls (p <.05). Fetal liver glycogen concentrations were significantly lower in exercised animals compared to nonrunning control animals (p <.05). These results demonstrate that exercise of mature rats may compromise fetal development and hepatic glycogen storage in the fetus.     

Body image disturbance in anorexia nervosa during the acute and recuperative phase.

Perception of body size, subjective experience of body image distortions and differentiation of body concept in the human figure drawing were assessed in adolescent anorexia nervosa patients and controls shortly after hospital admission, and again 6 months later during the recuperative phase. Size estimation was not found to be a distinguishing variable, as both groups exhibited overestimation tendencies of comparable magnitude at both time periods. By contrast, experiences denoting estrangement from the body, insensitivity to body sensations, and weakness of body boundaries were more prevalent in anorexics, and persisted at high levels after frank symptoms of weight and eating disorder had subsided. Anorexics were also shown to depict the human figure with less differentiation relative to controls. Within the anorexic sample the presence of vomiting was linked to greater subjective experience of body image distortion, and such phenomena appear to be a more enduring feature in this subgroup. Overall, the results were viewed as lending support to the argument that defects in body image formation render the anorexic vulnerable to their manifest pathology, which is itself activated by maturational conflicts unique to adolescence.     

Ovarian influences on body weight regulation in rats with lateral hypothalamic lesions

The effect of lateral hypothalamic lesions upon the level of maintained body weight was studied in gonadally intact and ovariectomized female rats. The body weight of both the gonadally intact and ovariectomized animals declined after lesioning; but, while the weight level of the ovariectomized animals remained approximately 10% below normal, the body weight of the intact group steadily approached that of nonlesioned controls. This result suggests that ovarian factors contribute to the smaller effect on body weight as reported by others for females with lateral hypothalamic lesions. Further support for this hypothesis was found in the observations that (1) the reduced effect of lateral hypothalamic lesions on body weight of gonadally intact females was associated with prolonged periods of diestrus and (2) the normal weight suppressing effects of estrogen were attenuated by lateral hypothalamic lesions in the ovariectomized animals.     

The role of body size in climbing and locomotor behavior of protein-malnourished and well-nourished rats

Behavioral comparisons of malnourished and well-nourished rats often involve animals of different sizes--even after rehabilitation of malnourished animals. The role of body size in two kinds of behavior affected by early malnutrition was investigated. Rats subjected to protein restriction during the preweaning period (LH) or during the pre- and postweaning periods (LL) climbed more than well-nourished rats (HH) at the ages of 35-225 days. This difference reflected differences in body weight; at comparable body weights LH and LL rats climbed no more than HH rats. Females climbed more than males, which also reflected differences in size, but decreases with age did not depend entirely on growth. LH rats were more active in running wheels than HH rats. For both LH and LL rats, the overall changes with diet and age resembled those in climbing, except that the effects of sex, but not age, were partly independent of size.