Relationship between plasma corticosterone and insulin levels in rats with ventromedial hypothalamic lesions

The effects of ventromedial hypothalamic (VMH) lesions on plasma corticosterone, insulin, and glucose levels were studied in food-restricted and ad lib fed female rats. VMH lesions resulted in significant elevations of corticosterone and insulin levels compared to control values during the first 25 days after surgery. However, unlike insulin values which were generally greater in VMH rats fed ad lib than in food-restricted animals, plasma corticosterone levels were unaffected by level of food intake. Corticosterone and insulin levels were unrelated preoperatively and in sham-operated animals, but were positively correlated (r = .82) by Day 25 in ad lib fed VMH rats. It is concluded that the elevation in plasma glucocorticoids observed in VMH rats is a primary effect of the lesion that is independent of food intake or initial weight gain.     

Effects of food restriction and adrenalectomy in rats with VMH or PVH lesions

The effects of adrenalectomy in rats with ventromedial or paraventricular hypothalamic lesions have been studied in two experiments. Rats with ventromedial hypothalamic lesions or lesions in the paraventricular nucleus were allowed to gain weight for fourteen days at which time they were adrenalectomized. Before adrenalectomy, animals with VMH lesions ate more, gained significantly more weight than animals with lesions in the paraventricular nucleus, and both were significantly heavier and consumed more food than sham-operated controls. Following adrenalectomy, food intake decreased and both groups of lesioned animals lost weight. The animals with VMH lesions stabilized at weights above the control animals. Implantation of corticosterone enhanced weight gain and food intake in animals with lesions in either the paraventricular nucleus or the ventromedial hypothalamus. In the second experiment, one subgroup of rats with VMH lesions was adrenalectomized, and allowed to eat ad lib. Two other groups of sham-operated rats with VMH lesions served as controls. One group ate ad lib and one group was pair fed to the food intake of the adrenalectomized VMH-lesioned rats. Weight gain in the adrenalectomized VMH-lesioned rats and the pair-fed VMH-lesioned controls was similar and less than the VMH-lesioned rats eating ad lib. GDP binding to interscapular brown adipose tissue was related to the degree of weight gain, not to the presence of the VMH lesion. These data show that corticosterone is essential for the expression of obesity in both PVH- and VMH-lesioned rats. They also argue that the reduction in the activity of the sympathetic nervous system of VMH-lesioned rats as estimated by the GDP binding to mitochondria from brown adipose tissue is associated with hyperphagia.     

Transplantation of pancreatic beta-cells prevents development of hypothalamic obesity in rats.

The present experiments have tested the hypothesis that ventromedial hypothalamic (VMH) lesions enhance insulin secretion by neural mechanisms. Rats were made diabetic by injecting streptozotocin to destroy their own pancreatic beta-cells. Subsequently, transplants of fetal pancreatic tissue were placed under the renal capsule. VMH lesions were placed in rats whose diabetes was cured with transplants as well as sham-transplanted animals. The animals were followed for 4 wk. The lesioned rats with pancreatic transplants gained no more weight than the sham-operated controls. There was no significant rise in insulin in the transplanted rats after VMH lesioning, but the VMH lesioned rats with intact pancreatic tissue showed the expected rise in insulin. Food intake rose 71% in the VMH lesioned rats with intact beta-cells, but only 23% in the VMH lesioned rats with transplants. Hypertrophy of the pancreatic islets was also observed in the VMH lesioned rats with an intact pancreas, but was not found in the VMH lesioned rats with a transplanted pancreas. Thus, transplantation of pancreatic tissue beneath the renal capsule of diabetic rats prevented the characteristic hyperphagia, hyperinsulinemia, and obesity in VMH lesioned rats whose pancreas was free from intact innervation. The results support the hypothesis that neural mediation of the rise in insulin is the primary factor in the development of hypothalamic obesity.     

Postabsorptive hyperinsulinemia in rats with subdiaphragmatic vagotomy

The effects of bilateral subdiaphragmatic vagotomy and of lateral hypothalamic lesions on the acute plasma glucose and insulin responses to liquid and solid meals were studied in female rats. Following recovery of an initial postoperative weight loss, vagotomized rats exhibited an exaggeration of plasma glucose and insulin responses compared to sham-vagotomized animals 17 min after the initiation of a liquid meal (6 ml sweetened milk in 7 min). Vagotomy did not alter basal glucose and insulin levels. The exaggerated postabsorptive response to oral liquid glucose in vagotomized rats was not observed after the consumption of an isocaloric solid meal (1.86 g sucrose pellets in 7 min). Rats with lateral hypothalamic lesions had significantly lower basal glucose and insulin levels, but both the preabsorptive and postabsorptive responses to oral glucose were unaffected by the lesion. The results in vagotomized animals were attributed to enhanced gastric emptying of liquid loads leading to a more rapid absorption of glucose from the intestine, which in turn resulted in an increased insulin response. In humans this is followed by rapid-onset hypoglycemia, and it is hypothesized that the abnormal postabsorptive glucose and insulin responses account in part for the pattern of small, frequent meals observed with vagotomized animals on liquid diets.     

Comparison of radio-frequency and electrolytic lesions of the paraventricular hypothalamic nucleus

Radio-frequency and anodal electrolytic lesions of the paraventricular nucleus (PVN) were found to produce equal and dramatic increases in body weight in female rats. Neither of the groups with lesions had significantly elevated plasma insulin levels during a period of food restriction, but individual values varied greatly. Both groups displayed marked basal hyperinsulinemia after 30 days of food ad lib. It is concluded that radio-frequency and electrolytic PVN lesions produce similar obesity syndromes.     

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.     

Hypothalamic hyperphagia prevented by prior subdiaphragmatic vagotomy: Insulin hyperphagia is unaffected

Male rats were given bilateral subdiaphragmatic vagotomy or a sham operation. Both groups of animals showed equivalent hyperphagia and weight gain during a ten day treatment with long-acting insulin. Despite this ability to increase feeding, the vagotomized rats did not overeat and become obese after VMH lesions.     

Reciprocal changes in gluconeogenic enzyme activity in liver and kidney by VMH lesion

The effects of bilateral lesions of the ventromedial hypothalamus (VMH) on daily rhythms of the activity of a gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), in the liver and kidney of rats were examined. PEPCK activity in the liver was considerably lowered by VMH lesions, but its rhythm remained similar to that of control liver. In contrast, PEPCK activity in the kidney was markedly elevated by the lesions. From these findings, it is suggested that the VMH is not the site of the master biological clock of the rhythm of PEPCK activity. Although these results do not exclude the possibility that hyperphagia and hyperinsulinemia associated with VMH lesions induce changes in the levels of PEPCK activities, they support the hypothesis that suppression of the sympathetic nervous system causes the changes in PEPCK activity through direct or indirect mechanisms. These findings also suggest that the reciprocal change in PEPCK activities in the liver and kidney after VMH lesions is related to complementary functions of the two organs in maintenance of homeostasis of blood glucose.     

Influence of type of reinforcement on operant responding by rats with ventromedial lesions

Bar-pressing on FR schedules for sucrose rewards was studied in rats with ventromedial hypothalamic (VMH) lesions. When both VMH and control rats were maintained on ad lib feeding, their bar-pressing performance for sucrose did not differ, but if the VMH group was maintained at control body weight levels, they responded more frequently for sucrose than controls. In a subsequent experiment performance for Noyes pellets and 32% sucrose was directly compared in VMH and control animals maintained at 85% of their respective postoperative body weight levels. Under these conditions controls responded more frequently than lesioned rats for either type of reinforcement, but the magnitude of the difference was greater with the Noyes pellet reward.     

VMH lesions in vagotomized rats: a note of caution

Transections of the vagus nerve immediately below the diaphragm in female rats resulted in a high percentage of deaths by starvation and/or dehydration. Those that did survive had to be chronically maintained on a high fat diet. Transections midway between the stomach and diaphragm usually allowed recovery of normal food intake with a pellet diet, although body weight remained below that of sham-vagotomized animals. VMH lesions in these recovered (90 days) midlevel vagotomized rats caused either marked weight gains, marked weight losses, or wide fluctuations in body weight, results which would not be predicted by hypotheses which attribute VMH obesity to increased vagally mediated insulin secretion. We previously found that VMH lesions in rats with vagal transections just above the stomach resulted in a high percentage of rats that displayed hyperphagia and obesity, and conclude that the level of transection is of critical importance to the manifestation of VMH obesity. Autopsies revealed that midlevel vagally transected rats which failed to gain weight after VMH lesions suffered a loss of esophageal tonus or obstruction at the pyloric sphincter. We believe that the failure to observe hyperphagia in vagotomized rats following VMH lesions is at least partially due to overloading the capacity of the stomach and/or the accumulation of food in the esophagus (resulting in choking) with attempts at overeating.     

Hypothalamic obesity: comparison of radio-frequency and electrolytic lesions in weanling rats

Female rats were subjected to radio-frequency or anodal electrolytic lesions of the ventromedial hypothalamus (VMH) when 28 days old. Blood samples for determination of basal plasma insulin and glucose levels were taken on postoperative day 30 (Experiment 1) and on day 10 (Experiment 2). Body weight and daily food intake of rats with either type of lesion did not differ from unoperated animals during the first 10 days, but rats with electrolytic lesions, unlike radio-frequency lesioned animals, displayed excess food intake and weight gain starting in the third postoperative week. Both types of lesions produced stunted linear growth and a higher than normal Lee Obesity Index. Only the rats with electrolytic VMH lesions were significantly hyperinsulinemic on postoperative day 30, with a mean plasma insulin level that was at least double that observed in unoperated or radio-frequency lesioned animals. On day 10, however, the animals with electrolytic lesions had markedly lower plasma insulin and glucose levels compared to the other two groups, which did not differ from one another. There was no apparent difference in the size of the lesions produced by the two techniques, and it is therefore concluded that some of the endocrine dysfunctions resulting from electrolytic VMH lesions are due to metallic ion deposits (stimulating adjacent tissue) rather than to tissue ablation.     

Significance of hyperinsulinemia in ventromedial hypothalamus-lesioned rats

The significance of the hyperinsulinemia on the altered metabolism in ventromedial hypothalamus (VMH)-lesioned rats was tested. VMH lesions induced increases in fatty acid synthesis, lipoprotein lipase (LPL) activity, and plasma urea levels, and a decrease in plasma triglyceride concentrations. Similarly, in normal rats treated with pharmacological doses of insulin (14 U X rat-1 X day-1), fatty acid synthesis and LPL activity in fat tissue and the plasma urea were considerably elevated and plasma triglyceride was lowered compared with untreated controls. When endogenous insulin production was abolished by streptozotocin treatment, the four metabolic variables in the VMH-lesioned rats did not differ from those in diabetic controls. Substitution with 2 U of insulin X rat-1 X day-1, however, restored the differences in metabolism between VMH-lesioned diabetic and control diabetic rats. Substitution with 3 or 4 U insulin X rat-1 X day-1 showed the same differences. In VMH-lesioned rats the insulin level increased significantly from the 10th to the 70th day postoperatively; however, the rate of fatty acid synthesis, LPL activity, and plasma urea levels decreased, whereas plasma triglyceride concentrations increased. The results strongly suggest that the metabolic changes occurring after VMH lesions are only in part explained by the hyperinsulinemia associated with the VMH syndrome and indicate that other hormonal and/or nervous factors are involved.     

Effects of VMH lesions on schedule induced and schedule dependent behaviors

Ten male hooded rats were exposed to an FI 1 min food reinforcement generator schedule at 80% body weight and schedule dependent lever pressing and schedule induced licking and drinking were recorded. When lever pressing, licking, and drinking stabilized the 10 rats were divided into two groups. One group was composed of 4 animals subjected to sham lesion procedures plus one animal with asymmetrical ventromedial hypothalamic (VMH) lesions. The other group was composed of 5 animals with bilateral symmetrical VMH destruction. Results demonstrate that VMH destruction produces a slight transient decrease only in water intake when on schedule at 80% body weight. When animals are returned to ad lib eating and body weight increased and they are returned to the test chamber, the VMH lesion animals display increased licking and drinking. Although VMH lesion animals ate and drank more than controls, they did not eat more in response to food deprivation and did not drink more in response to water deprivation and the intraperitoneal administration of hypertonic saline. The presence or absence of food or water was the determining factor in the overeating or excessive drinking of the VMH lesion animals. Results are discussed in terms of gastrointestinal influences on the hypothalamic mechanisms involved in the production of schedule induced behaviors.     

Seasonal weight gain is attenuated in food-restricted ground squirrels with lesions of the suprachiasmatic nuclei

The role of seasonal hyperphagia in the genesis of prehibernation fattening was assessed in golden-mantled ground squirrels. One group of animals was fed ad lib throughout the weight gain phase of the annual body weight cycle (June-October); a group of neurologically intact animals and one of squirrels with brain lesions incorporating the suprachiasmatic nuclei (SCN) were fed amounts of food equivalent to quantities consumed prior to the body weight trough (May). Part of the seasonal increase of body mass is independent of increases in food consumption; intact animals fed ad lib or restricted to prefattening food intakes underwent similar increases in body mass and possessed equivalent amounts of abdominal white adipose tissue. Food restriction combined with SCN lesions attenuated seasonal weight gain and reduced abdominal fat mass. However, some of the brain-damaged squirrels still evidenced weight gain, a result supporting a previous conclusion that the SCN are involved in circannual body weight rhythm generation but their contribution to this process is not essential for continued rhythmicity in most individuals.     

Comparison of metabolic alterations in hypothalamic and high fat diet-induced obesity.

The heterogeneous nature of the experimental obesities induced by ventromedial hypothalamic (VMH) lesion and high fat diet (HFD) have been demonstrated by comparing VMH-lesioned and sham-operated rats fed a HFD or low fat diet (LFD). VMH rats had increased fat mass serum insulin and serum triglycerides but lower serum glucagon and smaller salivary glands than sham-operated animals. The body weight of HFD obese rats was intermediate between VMH and sham-operated animals on the LDF. Liver and fat pad weights showed effects of lesions and diet. Diet did not affect plasma glucagon or insulin. Pair-feeding VMH rats with sham-operated rats prevented weight gain but did not prevent the increase in insulin and fall in glucagon. Studies of insulin secretion from isolated perifused islets showed that basal and both phases of stimulated secretion were significantly increased in VMH groups. The changes in plasma insulin, plasma glucagon, and salivary gland weight in VMH groups are interpreted as showing decreased activity of the sympathetic nervous system following VMH lesions.     

The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight

Early researchers found that lesions of the ventromedial hypothalamus (VMH) resulted in hyperphagia and obesity in a variety of species including humans, which led them to designate the VMH as the brain's "satiety center." Many researchers later dismissed a role for the VMH in feeding behavior when Gold claimed that lesions restricted to the VMH did not result in overeating and that obesity was observed only with lesions or knife cuts that extended beyond the borders of the VMH and damaged or severed the ventral noradrenergic bundle (VNAB) or paraventricular nucleus (PVN). However, anatomical studies done both before and after Gold's study did not replicate his results with lesions, and in nearly every published direct comparison of VMH lesions vs. PVN or VNAB lesions, the group with VMH lesions ate substantially more food and gained twice as much weight. Several other important differences have also been found between VMH and both PVN and VNAB lesion-induced obesity. Concerns regarding (a) motivation to work for food and (b) the effects of nonirritative lesions have also been addressed and answered in many studies. Lesion studies with weanling rats and adult pair-tube-fed rats, as well as recent studies of knockout mice deficient in the orphan nuclear receptor steroidogenic factor 1, indicate that VMH lesion-induced obesity is in large part a metabolic obesity (due to autonomic nervous system disorders) independent of hyperphagia. However, there is ample evidence that the VMH also plays a primary role in feeding behavior. Neuroimaging studies in humans have shown a marked increase in activity in the area of the VMH during feeding. The VMH has a large population of glucoresponsive neurons that dynamically respond to blood glucose levels and numerous histamine, dopamine, serotonin, and GABA neurons that respond to feeding-related stimuli. Recent studies have implicated melanocortins in the VMH regulation of feeding behavior: food intake decreases when arcuate nucleus pro-opiomelanocortin (POMC) neurons activate VMH brain-derived neurotrophic factor (BDNF) neurons. Moderate hyperphagia and obesity have also been observed in female rats with damage to the efferent projections from the posterodorsal amygdala to the VMH. Hypothalamic obesity can result from damage to either the POMC or BDNF neurons. The concept of hypothalamic feeding and satiety centers is outdated and unnecessary, and progress in understanding hypothalamic mechanisms of feeding behavior will be achieved only by appreciating the different types of neural and blood-borne information received by the various nuclei, and then attempting to determine how this information is integrated to obtain a balance between energy intake and energy output.     

Development of food motivated behavior in free feeding and food restricted zucker fatty (fa/fa) rats

The food motivated behavior of ad lib fed or calorically restricted male Zucker fatty and lean rats was compared at 12, 16, 20 and 30 weeks of age. The groups were fasted for 0, 12 and 24 hr and required to lever press for food pellets on VI 40 sec. Responding by ad lib fatties was elevated over lean controls during the rapid growth period (12 and 16 weeks of age) but was significantly reduced following the completion of growth (20 weeks). Elevated responding accompanied hyperphagia by the ad lib fatties during growth but did not accompany a second, adult onset period of hyperphagia in these fatties. In contrast, fatties calorically restricted from birth responded at elevated rates at all ages compared to lean controls. At 20 weeks restricted fatties, which were as obese on a percentage body composition basis as ad lib fatties, responded significantly more than the latter group at all fasting levels. Metabolic measurements revealed elevated fat cell size, LPL activity/cell and insulin levels in both fatty groups at 15 weeks, and elevated fat cell number in these groups at 33 weeks. The possibility is discussed that enhanced lipogenic factors present during the rapid growth period combine with the metabolic demands of growth to produce a “compensatory hyperphagia” in the fatty rat.     

2-deoxy-D-glucose inhibits food intake in rats after ventromedial hypothalamic lesions

Changes in food induced by 2 deoxy-D-glucose (2 DG) have been investigated in newly lesioned rats during the two parts of the diurnal cycle. In a first experiment rats were injected with saline or 2 DG (250, 500, 750 mg/kg) at the beginning of the light or the dark period. In a second experiment rats were injected with saline or 2 DG (250 mg/kg) in the middle of the two periods after 0, 2, 4 or 6 hr of fasting. Results show that 2 DG exerts an inhibitory effect on food intake at night, as it does in intact rats, under ad lib conditions or after a short deprivation time. The stimulating effects of 2 DG on diurnal food intake observed in intact rats is not replicated in VMH rats. On the contrary an inhibition of intake follows a short food deprivation. The data suggest that 2 DG stimulates food intake only under metabolic and feeding conditions characteristic of the diurnal phase in intact rats. Since lipogenesis and hyperphagia are observed 24 hr a day in VMH animals, only inhibition could follow 2 DG.     

Development of VMH obesity in vagotomized rats.

In 3 different experiments, vagotomy failed to reverse or prevent the development of hyperphagia and obesity following VMH lesions. In the first experiment, previously vagotomized male rats were given bilateral VMH lesions after testing for completeness of vagotomy. In a second experiment on male rats, vagotomy preceded or followed VMH lesions, and testing for completeness of vagotomy was not carried out until the end of the experiment. In a third experiment obese VMH female rats were vagotomized before or after VMH lesions, and completeness of vagotomy was assessed histologically. In each experiment, vagotomized VMH rats displayed hyperphagia and became obese. Discrepancies between these results and those reported by others are discussed in terms of diet offered, surgical procedures, and the possibility of continuing malaise after vagotomy.