Hyperphagia and obesity following ventromedial hypothalamic lesions in rats with subdiaphragmatic vagotomy

Bilateral subdiaphragmatic vagotomy chronically reduced body weight to 85–90% of sham vagotomy weight levels in female rats maintained on a standard pellet diet (observed for 114 days). Ventromedial hypothalamic lesions 70 days after vagotomy resulted in marked hyperphagia and obesity, although the increases were not as great as those following lesions in nonvagotomized animals. When the order of surgery was reversed, vagotomy reduced the body weight of obese VMH-lesioned rats to vagotomized control levels, with no evidence of recovery after 90 days. These results suggest that while enhanced vagal activity and/or vagally mediated hyperinsulinemia contribute to VMH lesion-induced overeating and weight gains, they are not necessary for the manifestation of either the hyperphagia or obesity. The importance of adaptation to the effects of vagal transections for the appearance of hypothalamic hyperphagia and obesity is discussed.     

Effects of dopamine-depleting brain lesions on experimental hyperphagia in rats

Dopamine (DA)-depleting brain lesions of various sizes were produced in rats either by intracerebroventricular injections of 6-hydroxydopamine (6-HDA) or by electrolytic lesions of the lateral hypothalamic (LH) area. Among 30 animals that became aphagic and adipsic for at least four days after large LH or 6-HDA-induced brain lesions, only three developed hyperphagia after electrolytic lesions of the ventromedial hypothalamus (VMH) or daily injections of long-acting protamine-zinc insulin (PZI). In 20 rats with smaller LH or 6-HDA-induced lesions, which had not shown marked initial behavioral dysfunctions, only three gained as much weight after VMH lesions as the control animals. Similarly, 6 of 10 rats with smaller LH lesions could not tolerate a 15-day series of PZI treatments, although 14 of 17 rats with smaller 6-HDA-induced lesions increased their food intake and gained weight during the PZI treatments as did control animals. These results indicate that hypothalamic hyperphagia can be blocked by DA-depleting brain lesions that neither produce an initial period of aphagia and adipsia nor involve hypothalamic tissue. They further indicate that even small LH lesions may prevent the development of hyperphagia elicited by PZI, whereas only very large 6-HDA-induced lesions consistently have this effect.     

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.     

Differential effects of cuts through the posterior hypothalamus on food intake and body weight in male and female rats

Large knife cuts in the coronal plane through the posterior hypothalamus which transected the caudal connections of the medial hypothalamus without producing significant direct damage to cellular components of the region resulted in a very marked increase in food intake and rate of weight gain in female rats, but had little or no effect in male rats of the same strain. Water intake was equally elevated in both sexes. A detailed analysis of the effects of smaller cuts in the same region indicated that the pathways that are responsible for the effectiveness of the larger cuts do not course through the region immediately behind the ventromedial nuclei (VMN) but, instead, through the perifornical region lateral and posterior to the VMN. In the female, hyperphagia is not seen after cuts behind the VMH or lateral to the fornix but all cuts that invade the perifornical region to a significant extent result in overeating and obesity. In the male, a very mild hyperphagia (but no obesity) is seen after cuts that are restricted to this perifornical region but larger cuts that involve even minor aspects of the lateral hypothaalmus (LH) are entirely ineffective. Analysis of the effects of cuts that involve the medial, perifornical, and lateral hypothalamus to varying extent suggested that the disinhibitory effects of perifornical transections may be counteracted by relatively strong inhibitory effects due to damage to fibers in the lateral hypothalamus in the male, where the influence of the perifornical system appears to be weak, but not in the female, where the influence of the perifornical system appears to be very strong. The marked sex differences which characterize the effects of all cuts on body weight indicate that the perifornical system may be concerned specifically with metabolic functions that contribute to the development and/or maintenance of the organism's setpoint for body weight.     

Serotonin-depleting midbrain lesions fail to mitigate hyperphagia and obesity in the Zucker fatty rat

Previous research has shown that damage to the dorsal and median raphe nuclei of rats can impede the subsequent development of hypothalamic hyperphagia and obesity as well as impair the defense of established hypothalamic obesity in response to food deprivation. The present study sought to determine if raphe injury might alter the development of another form of obesity, namely that which occurs spontaneously in the Zucker fatty rat. Subjects were 20 obese females (fafa; mean weight of 200 g) and 20 lean littermate controls (FaFa females; mean weight of 150 g). Following 10 days of baseline intake and weight recordings, half of each group received radio-frequency heat lesions of the dorsal and median raphe nuclei while the other half received sham surgery. Except for a mild suppression of food intake and weight gain during the first few days after lesioning, raphe injury did not alter the hyperphagia or obesity shown by fatties over the 7 week ad lib feeding period studied. Additional 24-hr intake tests of varying sucrose and quinine solutions revealed reduced sucrose acceptance and enhanced quinine rejection by fatties much as has been seen in previous studies of hypothalamic obese rats. Terminal assays of forebrain monoamine levels confirmed that raphe lesions were effective in depleting serotonin (-71% compared to controls) without producing major changes in norepinephrine or dopamine (-14% and +2%, respectively). The inability of raphe lesions to mitigate this form of hyperphagia and obesity suggests that earlier observations of their attenuating effects on hypothalamic obesity were not due to non-specific impairments of behavioral or metabolic factors necessary to permit overeating and weight gain.     

Nocturnal feeding pattern in the prepubertal rat: influence of the ventromedial hypothalamus (VMH)

Daily feeding patterns, food intake and changes in body weight of male and female prepubertal rats were observed across a period from 21 to 50 days of age. Light/dark differences in feeding were found for both males and females throughout the recorded period, with feeding occurring predominantly during the dark period. The light/dark difference in feeding behavior gradually increased as the animals developed. Bilateral lesions placed in the VMH of female rats at 21 days of age disrupted the light/dark differences in feeding behavior primarily by decreasing dark period feeding. These lesions further resulted in a period of hypophagia and retarded body weight gain as well as a delay in pubertal onset. These data indicate that prepubertal rats regulate their feeding behavior so that food intake occurs principally during the dark period and that the integrity of the VMH is necessary for this regulation.     

The effects of pretraining on the bar-pressing performance of VMH-lesioned rats

Ventromedial hypothalamic lesioned rats preoperatively trained on an FR-128 schedule displayed postoperative improvements in performance which were a direct function of the degree of hyperphagia. The postoperative performance by the pretrained VMH-lesioned animals did not significantly differ from that of control animals during short test sessions following periods of deprivation, but substantially exceeded that of controls with continuous opportunity to respond. The increase in the number of pellets obtained was achieved by increases in both the meal size and the rate of bar-pressing. Previous attempts to account for the deficit in performance by nonpretrained VMH-lesioned animals in terms of decreased motivation or lowered activity are rejected in favor of an explanation based on a modification of affective response following such lesions.     

Reinforcement frequency and body weight as determinants of motivated performance in hypothalamic hyperphagic rats

Non-Obese and Obese VMH lesioned rats were tested on a series of increasing VI schedules (from 0.25 to 4.0 min). Response rates decreased as a function of increases in interreinforcement interval for all groups, and the functions did not differ in form or in slope between the groups. Respone rates for the Non-Obese VMH, Lesion Control, and Normal Control groups were similar, while response rates for the Obese VMH group were significantly less than those of the other groups. This reduction in work output by the Obese VMH rats was attributed solely to their increased weight at the time of testing.     

Ventromedial hypothalamic lesions and stomach ulcers: reduction by non-nutritive bulk ingested in the post lesion period

The effects of some dietary properties on stomach ulceration resulting from ventromedial hypothalamic (VMH) brain lesions, were investigated in two experiments. In the first experiment two groups of rats received VMH lesions and one group received sham lesions. One of the lesioned groups was deprived of food and water during the 24 hr post lesion period, as was the sham lesioned group. The other lesioned group was given access to a highly palatable diet and water during the post lesion period. No stomach ulcers were found in the sham lesioned rats. The VMH lesioned group with access to food and water had less glandular stomach ulceration 24 hr after the lesion procedure than the VMH lesioned deprived group (p<0.01). In the second experiment four groups of rats received VMH lesions and were then given access to one of the following diets during the post lesion period: water, 16.7% sucrose solution, non-nutritive bulk (silica and methylcellulose), or bulk containing 16.7% sucrose. A multivariate analysis of variance was applied to five measures obtained in this experiment. The two groups receiving the bulk diets had significantly less stomach ulceration than the two groups given the liquid diets. Addition of the surcose to the liquid or bulk diet had no significant effect on gastric pathology. These experiments demonstrate that the ingestion of bulk diet in the post lesion period results in a reduction in gastric ulceration in the rat. And thus, similar to previous demonstrations that bulk diet has antiulcerogenic effects in other experimental procedures for gastric ulcer production (e.g., starvation, pylorus ligation, or electric shock), the present experiments demonstrate an antiulcerogenic property for bulk diet on stomach ulcers induced by VMH lesions.     

Reappearance of dynamic hyperphagia during the static phase in medial hypothalamic lesioned rats

Female rats overate and became obese following electrolytic lesions of the medial hypothalamus. While every animal displayed the characteristic dynamic-static hyperphagic syndrome, not all of them maintained a permanent static phase. After many weeks or months of maintaining body weight at an elevated obese plateau with near-normal food consumption, several of the rats which had at least doubled their preoperative body weight displayed a spontaneous renewal of hyperphagia that was longer lasting and nearly equal in amplitude to the initial dynamic phase. Only one of the less obese animals displayed the phenomenon. The sudden increases in food intake and body weight were not due to a change in diet or any of the other variables which are known to influence the eating habits of obese lesioned rats.     

Role of the stria terminalis in food intake and body weight in rats

Previous studies have shown that lesions of the posterodorsal amygdala result in hyperphagia and obesity in female rats. In the present study, lesions of the stria terminalis at its most dorsal point (before it separates into dorsal and ventral components) also resulted in hyperphagia and excessive weight gains in female rats compared to female rats with sham lesions, as did coronal knife cuts anterior to the ventromedial hypothalamus. Identical lesions and knife cuts did not elevate food intake or weight gains in male rats compared to male control animals. Examination of the anterograde degeneration with the amino-cupric-silver method in the brains of two female rats with hypothalamic knife cuts revealed degenerating terminals in the capsule of the ventromedial hypothalamus and in the premammillary nuclei, two classic indicators of damage to the dorsal component of the stria terminalis. No degenerating axon terminals were observed in the paraventricular nucleus. Differences from previous studies that used male rats were attributed to a sex difference for the effects of amygdaloid and ventromedial hypothalamic lesions. It is proposed that the posterodorsal amygdala, dorsal component of the stria terminalis, and ventromedial hypothalamus are part of an inhibitory pathway in the regulation of feeding behavior.     

Suppression of food intake in diabetic rats by voluntary consumption and intrahypothalamic injection of glucose

When given a choice between 2 concentrations of glucose (5 and 35%) normal rats prefer to consume most of their glucose from the concentrated source while diabetics prefer the dilute source. Although both consume approximately the same total amount of glucose, on a caloric basis the glucose depressed chow intake more in diabetics than in normal rats, indicating that diabetics can experience the satiating effects of glucose. Also, since the diabetics excreted more glucose in urine during the glucose access, the overall retention of calories appeared to be less than of controls, indicating the diabetics are effectively hypophagic as compared to controls when they ingested large quantities of glucose. Direct injection of glucose into the ventromedial hypothalamus suppressed feeding as effectively in diabetics as in controls, indicating that normal titers of insulin are probably not necessary for suppression of feeding by ingested glucose in diabetic animals.     

Infant rats: VMH damage and the ontogeny of obesity and neuroendocrine dysfunction

The VMH was bilaterally destroyed in preweanling (Day 10) or postweanling (Day 40) male and female rats. Growth parameters (body weight, body length, Lee indices) were measured until 200 days of age, nutrient intake was measured during maturity, and an analysis of endocrine gland weights and adenohypophyseal morphology was performed on preweanling rats. When compared with controls, growth was abnormal for VMH rats after 50–80 days of age. Bilateral preweanling females displayed elevated body weights, normal body lengths, and elevated Lee indices, while bilateral preweanling males had normal body weights, stunted linear growth, and elevated Lee indices. Postweanling VMH rats exhibited elevated body weights and elevated Lee indices; however, postweanling VMH males displayed augmented linear growth. VMH rats were normophagic and demonstrated finickiness to taste-aversive fluids. Endocrine gland analysis revealed that preweanling VMH males had neuroendocrine deficits related to somatotrophic hormone (low pituitary weight, decreased adenohypophyseal acidophils), while female VMH rats had neuroendocrine pathology related to metabolic dysfunction (all gland weights were low, decreased adenohypophyseal basophil size).     

Overeating and obesity produced by interruption of the caudal connections of the hypothalamus: evidence of hormonal and metabolic disruption.

Surgical transection of the posterior connections of the medial basal hypothalamus is much more effective in producing hyperphagia and obesity in female than in male rats. The hyperphagia of female rats can be attenuated by daily injections of estradiol. When starved to the weight of control animals, previously obese female rats with cuts through the posterior hypothalamus showed only mild hyperphagia but quickly returned to their elevated body weights. The results indicated that hormonal and metabolic disturbance are important factors in determining food intake and body weight following damage to the ventromedial hypothalamus.     

Palatability and caloric density as determinants of food intake in hyperphagic and normal rats

Female albino rats with lesions of the ventromedial hypothalamus and without any lesions were presented with powdered diets, the caloric density and palatability of which were varied independently by adding kaolin and sodium saccharin or confectioner's sugar. As the dilution of the unsweetened diet increased above 20% the lesioned rats decreased food consumption more than did the controls, and they increased consumption less than did the controls over successive days of exposure to the diluted diets. Sweetening the dilute diets usually produced a larger increase in food consumption among the hyperphagic rats, especially those in the dynamic phase, than among their controls. The data are interpreted in terms of the hypothesis that lesions of the ventromedial hypothalamus remove or attenuate the long term influence of nutritional balance, leaving body weight to be adjusted to a set point defined by the interaction of prevailing values of other stimuli such as diet palatability that are known to influence initiation and termination of eating.     

Feed efficiency in growth-retarded rats with ventromedial and dorsomedial hypothalamic lesions produced shortly after weaning

Weanling male rats received electrolytic lesions (L) in the ventromedial (VMN) and dorsomedial (DMN) hypothalamic nuclei; sham-operated rats served as controls. The animals were maintained for various periods up to 50 postoperative days on lab chow under standard conditions. In a short-term study, food intake and body weights were measured daily and body weight gain was divided by the food eaten to obtain the efficiency of food utilization. Also, gains in metabolic size ($\text{kg}\text{3}\text{4}$) were divided by food eaten. Both manipulations showed that DMNL rats, except for the first two postoperative days, utilized food normally. The same changes were obtained for weanling VMNL rats, except that they did not show a decline in utilization during the first two postoperative days. Computation of efficiency of food utilization for both VMNL and DMNL rats over postoperative durations ranging from 7 to 50 days showed that among 12 out of 14 experiments DMNL rats utilized food as well as controls. Out of 8 experiments, rats with VMNL utilized food better for weight gained than controls in one and poorer than controls also in one experiment; in reference to metabolic size they utilized food normally. The foregoing data, gathered from 225 DMNL, 64 VMNL and 181 control rats show quite convincingly that food utilization in both types of experimental animals is unimpaired despite profound reductions in ponderal and linear growth and food intake in the DMNL rat and reduced circulating growth hormone levels in the VMNL rat.     

Hypothalamic and midbrain control of sexual receptivity in the female rat

The ventromedial nucleus of the hypothalamus (VMN) appears to be one site of action for estrogen with respect to the induction of sexual receptivity. Lateral efferents from the VMN pass through a region capping the lateral part of the cerebral peduncle and constitute a “lateral pathway” connecting the VMN with midbrain structures. Bilateral lesions of this peripeduncular region markedly reduced the display of lordosis by estrogen or estrogen-progesterone primed female rats in sex behavior tests with males. Sexual receptivity was comparably reduced when a sagittal knife-cut lateral to the VMN on one side of the brain was combined with a lesion of the peripeduncular region on the other side of the brain. In other words, asymmetric brain damage which nevertheless bilaterally interrupts axons of the lateral pathway connecting the VMN and midbrain markedly reduces the occurrence of lordosis, and we conclude that the integrity of the lateral pathway is essential for the hormonal induction of sexual receptivity in female rats. This pathway may be one avenue through which the action of estrogen on cells of the VMN may bias activity in midbrain structures directly concerned with the elicitation and/or execution of the lordosis reflex, to bring about the occurrence of sexual receptivity in the female.     

Dietary obesity in adult rats: Similarities to hypothalamic and human obesity syndromes

Normal adult female rats fed a variety of supermarket foods in addition to lab chow rapidly gained weight and became obese compared to rats fed only lab chow. Group housing the animals in an enriched environment did not alter the development of dietary obesity, but housing the rats in activity wheels reduced, although did not prevent, the obesity. The dietary obese rats did not normally defend their excessive weights since they were less willing to eat quinine diets, worked less for food, failed to increase their activity when deprived, and regained their weight at a slower rate following a fast than did controls. The similarity between this behavioral pattern and that displayed by hypothalamic obese rats and overweight humans is discussed.     

The effects of estradiol on body weight and food intake in normal weight VMH-lesioned rats.

The effects of estradiol on food intake and body weight were examined in ovariectomized and VMH-lesioned, ovariectomized rats that were prevented from supranormal weight gain by food restriction. Estradiol injections that were effective in reducing weight in supranormal weight, ovariectomized rats had no effect on weight in normal weight, ovariectomized or VMH-lesioned, ovariectomized rats. Estradiol did not prevent hyperphagia and weight gain in VMH-lesioned, ovariectomized rats when they were provided with ad lib food.     

Visual identification of obesity by healthcare professionals: an experimental study of trainee and qualified GPs

Background

Guidelines suggest that GPs should intervene on patients’ weight, but to do so GPs must first recognise that a patient may have a weight problem and weigh them.

Aim

To examine whether GPs and trainee GPs can identify overweight and obese body weights by sight, and if this influences whether they would discuss weight with a potential patient.

Design and setting

Study of GPs and trainee GPs on the lists of the UK NHS Workforce West Midlands Deanery and NHS Sandwell and West Birmingham Clinical Commissioning Group.

Method

Participants viewed 15 standardised photographs of healthy-weight, overweight, and obese young males, and estimated their BMI, classified their weight status, and reported whether they would be likely to make a brief intervention for weight loss with that person.

Results

The sample of GPs and trainee GPs correctly classified a mean of 4.0/5.0 of the healthy weight males, a mean of 2.4/5.0 of the overweight, and a mean of 1.7/5.0 of the obese males. For each 1 kg/m² increase in actual BMI, participants underestimated BMI by −0.21 (95% CI = −0.22 to −0.18), meaning that participants would underestimate the BMI of a man of 30 kg/m² by approximately 2.5 kg/m², but were more accurate for lower body weights. Participants were more likely to intervene with those with a higher estimated BMI (OR 1.53, 95% CI = 1.49 to 1.58).

Conclusion

This sample of predominantly trainee GPs perceived overweight and obese weights as being of lower BMI and weight status than they actually are, and this was associated with a lower intention of discussing weight management with a potential patient. This was found to be true for trainee and fully qualified GPs who participated in the study. Healthcare professionals should not rely on visual judgements when identifying patients who may benefit from weight management treatment.