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.     

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.     

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.     

Role of vagal nerve activity during suckling. Effects on plasma levels of oxytocin,prolactin, VIP,somatostatin, insulin,glucagon, glucose and of milk secretion in lactating rats

The aim of this study was to investigate the role of vagal nerve activity for the release of oxytocin, prolactin and gastrointestinal (GI) hormones during suckling as well as for the secretion of milk in lactating rats. We have therefore performed experiments on vagotomized lactating rats. The animals were decapitated and trunk blood was collected from nonsuckling rats and from suckling rats in connection with milk ejection. Oxytocin, prolactin, vasoactive intestinal polypeptide (VIP), somatostatin, insulin, glucagon and glucose levels in plasma were measured by RIA-technique. In addition, maternal weight as well as the weight of the litters were recorded 7 d after vagotomy. As expected, oxytocin and prolactin levels rose in response to suckling in sham-operated controls. In vagotomized animals the suckling-induced increase of oxytocin was blocked and prolactin levels were significantly decreased. VIP levels in plasma increased following suckling in sham-operated animals and failed to respond after vagotomy. In contrast, somatostatin levels that rose significantly in sham-operated rats were even more significantly raised in vagotomized animals. In addition, insulin but not glucagon levels were increased by suckling. The insulin response, however, persisted after vagotomy. Interestingly, suckling was followed by a lowering of blood-glucose levels in vagotomized, but not in sham-operated animals. The vagotomized rats ate as much and increased in weight as sham-operated rats during the 7 d of vagotomy. The litters of vagotomized rats, however, gained significantly less weight in comparison with control litters. In conclusion, this study shows that vagal nerve activity is of importance for the release of oxytocin, prolactin, vasoactive intestinal polypeptide and somatostatin during suckling. In addition, vagal nerve activity was found to be of fundamental importance for adequate milk secretion, since litters of vagotomized rats increased in weight less than litters of sham-operated operated animals.     

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.     

Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia

The relation of hyperinsulinemia to hyperphagia was examined in rats with lesions of the ventromedial hypothalamus (VMH). Plasma insulin and glucose levels were assayed after a 4-hr fast and 17 min after the initiation of a meal (6 ml of sweetened milk in 7 min) in animals with sham lesions, VMH animals maintained at preoperative body weight by food restriction, and VMH animals fed ad lib. Both VMH groups displayed basal and postabsorptive hyperinsulinemia, compared with the sham-operated control group, but insulin levels were greatest under the ad lib feeding condition. It is suggested that VMH hyperinsulinemia is due both to a primary effect of the lesion and to hyperphagia and that marked obesity can result in the absence of basal hyperinsulinemia as a result of hyperphagia with consequent postabsorptive hyperinsulinemia.     

Effects of guanethidine sympathectomy on ventromedial hypothalamic obesity

Since ventromedial hypothalamic (VMH) lesions apparently produce chronic increases in parasympathetic activity and decreases in sympathetic responses, two experiments were performed to determine whether decreases in sympathetic tone alone are sufficient either to produce elements of the VMH syndrome or to potentiate the expression of the syndrome in animals with lesions. In experiment 1, rats that had been injected with guanethidine sulfate for 5 wk (40 mg X kg-1 X day-1) to produce a permanent sympathectomy (SympX) were maintained on a high-fat diet and subsequently subjected to VMH lesions. In experiment 2, adrenal-demedullated animals were treated with guanethidine for 6 wk and then subsequently underwent VMH lesions. SympX in the studies (81 and 85% depletion of superior cervical ganglia neurons, respectively) did duplicate the effects of VMH lesions on salivary gland weights. In neither experiment, however, did SympX alone or in combination with demedullation mimic the effects of VMH lesions on food intake, body weight, or body fat. Determinations of free fatty acids (FFAs) in the experiments confirmed that VMH lesions elevate basal FFA levels, but they also indicated that effective VMH lesions need not impair the FFA mobilization to 2-deoxyglucose challenges as some basomedial hypothalamic lesions do. In addition, experiment 2, which employed a prolonged period of high-fat feeding, revealed that SympX plus adrenal demedullation could potentiate (a 13% increase) the effects of VMH lesions on body weight. The results taken together do not support the conclusion that a preponderance of the VMH syndrome can be accounted for by the type of reduction in sympathetic tone produced by guanethidine.     

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.     

Medial hypothalamic lesions in Syrian hamsters: characterization of hyperphagia and weight gain

Syrian golden hamsters (Mesocricetus auratus) received bilateral lesions aimed at the ventromedial hypothalamus (VMH) or a sham lesion. In the first study, some of the animals in each surgical group were housed in standard sedentary conditions while others had free access to running wheels. The lesions produced a 30% increase in the daily intake of chow, and this was accomplished exclusively by increased meal sizes. As a result, lesioned hamsters gained body weight relative to controls both on the chow diet and in a subsequent high fat diet phase. The effects were comparable in both sedentary and exercising groups. The lesions produced increases in body length and fat content. In the second study, lesions were made in the VMH or in adjacent nuclei and, after an initial period on chow, the hamsters were then given a choice between chow and high fat diet. The lesioned hamsters showed no unusual preference for the high fat diet but, as before, those with damage to the VMH or paraventricular nucleus (PVN) showed exaggerated body weight gain. Hamsters with these lesions were hyperinsulinemic in both fed and fasted conditions at the end of the study.     

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.     

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.     

Comparison of DNA contents of visceral organs in rats with ventromedial hypothalamic lesions and fed a high fat diet

Bilateral lesions of ventromedial hypothalamus are followed by a number of changes including vagal hyperactivity and hyperinsulinemia. To investigate if cell proliferation occurs in visceral organs in rats with ventromedial hypothalamic (VMH) lesions and fed a high fat diet, we determined DNA contents of visceral organs (liver, pancreas, small and large intestines, spleen, kidney and heart) 1 and 4 week after VMH lesions or start of high fat diet. In rats with VMH lesions, DNA contents increased significantly in liver, pancreas, and small and large intestines at 1 week, and maintained the same levels until the 4th week. DNA contents increased most in the pancreas, followed by small and large intestines, and liver. DNA content did not change in spleen, kidney, or heart. In rats fed a high fat diet, there was no increase in the DNA content of these organs, except in the small intestine at 4 weeks. The results suggest that VMH lesions produce excessive DNA synthesis in visceral organs, whereas a high fat diet does not. VMH lesions may induce cell proliferation in visceral organs through vagal hyperactivity and/or changes of humoral growth factors.     

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.     

Liver of ovariectomized rats is resistant to resorption of lipids

Ovarian hormones have been shown to regulate liver lipid accumulation in rats. The present study was designed to evaluate liver lipid resorption in ovariectomized (Ovx) rats. Ovx and sham-operated (Sham) rats were submitted to a high-fat (HF; 43% kcal fat as energy) diet for 5 weeks and then either maintained on this diet or switched to a standard (SD; 12.5% kcal fat as energy) diet till weeks 8 and 13 (n=8 rats/group). Body weight, energy intake, liver and intra-abdominal fat accumulation and plasma metabolic profile were determined. Body weight was significantly (P<0.01) higher in Ovx than in Sham groups at all times and switching diet did not alter the body weight pattern. The weight of the intra-abdominal fat depots and plasma leptin levels, along with liver triacylglycerol (TAG) concentrations, were significantly higher (P<0.01) in Ovx than in Sham rats. Switching diet reduced intra-abdominal fat depot weight and plasma leptin in all groups. Switching diet also resulted in a decrease in liver fat accumulation in Sham rats at all times. However, 8 weeks after the diet switch (week 13) liver fat accumulation was as high in Ovx rats as those maintained on the HF diet. When liver TAG values measured at week 13 were compared to initial pre-switching values (week 5), liver TAG levels in Ovx animals were maintained at the same level independently of the diet switch, while in Sham rats switching to a SD diet reduced liver TAG accumulation (P<0.05). The same comparisons with plasma TAG levels revealed an opposite relationship. These data suggest that liver lipid resorption in Ovx animals is more related to the ovarian hormone status than to the type of ingested diet.     

Diet selection following area postrema/nucleus of the solitary tract lesions

Ten adult Long-Evans male rats were offered access to fat, protein and carbohydrate from separate sources. After adaptation to this diet, 5 animals received thermal lesions of the area postrema and adjacent caudal-medial portion of the nucleus of the solitary tract (AP/cmNTS). The remainder were sham-operated. AP/cmNTS lesioned rats ate significantly less and lost more weight than controls during the first postsurgery measurement period (Days 4–13 after lesioning). The decrease of food intake of AP/cmNTS lesioned rats was due to reduced fat consumption. Carbohydrate and protein intakes of lesioned animals did not differ from those of controls. Food intakes and weight changes of lesioned rats did not differ from those of controls during days 14–23 after lesioning. Intake of fat by lesioned animals remained low but was no longer significantly different from that of controls. Carbohydrate and protein intakes of lesioned rats increased slightly but did not differ significantly from those of nonlesioned controls.     

高脂饲养致小鼠胰岛素抵抗对脂肪肝形成的影响

目的:探讨高脂饲养致小鼠脂肪肝形成的机制。方法:随机将8周雄性C57BL/6J小鼠分成高脂饲养组(给予含60%卡路里的高饱和脂肪酸饲养)和正常对照组,饲养12周。监测体重、肝重、血甘油三酯、血总胆固醇、血糖和血胰岛素水平,通过高胰岛素正葡萄糖钳夹实验反映胰岛素敏感性,HE染色、苏丹IV染色及肝脂含量反映肝组织脂质沉积情况,确定高脂饲养致小鼠脂肪肝的形成。通过Western blot法检测磷酸化胰岛素受体底物1(IRS1)和蛋白激酶B(Akt)水平反映胰岛素信号通路激活情况,检测固醇调节元件结合蛋白1(SREBP-1)和脂肪酸合成酶(FAS)蛋白水平反映肝内脂质合成的情况。结果:高脂饲养组小鼠体重及肝重较正常对照组小鼠明显增加。与正常对照组相比,高脂组血和肝组织内甘油三酯和总胆固醇含量显著升高,血清胰岛素水平升高,葡萄糖输注率减少,磷酸化IRS1和Akt水平降低。肝组织HE染色可见高脂组肝细胞胞浆内充满大量脂肪空泡,苏丹IV染色可见肝细胞内存在大量大小不一的红色脂滴;SREBP-1和FAS蛋白水平明显升高。给予外源性油酸干预原代正常肝细胞48 h,磷酸化IRS1和Akt水平呈浓度依赖性减低,而SREBP-1和FAS蛋白表达明显升高。结论:高脂饲养导致小鼠肝脏发生胰岛素抵抗,并通过激活SREBP-FAS脂肪合成途径,促进肝脏脂质沉积,从而诱发脂肪肝。     

Resveratrol prevents high-fat diet-induced obesity and oxidative stress in rabbits

The rapid epidemiological progression of obesity worldwide has been associated with increased consumption of diets, rich in fat and sugar. Mediterranean diets rich in resveratrol are associated with reduced risk of obesity and oxidative stress. The aim of the experiment was to investigate the protective effect of resveratrol on high fat diet (HFD) induced obesity and oxidative stress changes in rabbits. Thirty rabbits divided into six groups of five animals each were used for the experiment: Group 1?=?control (C), Group 2?=?high fat diet (HFD) only, Group 3?=?resveratrol 200?mg/kg (R200), Group 4?=?resveratrol 400?mg/kg (R400), Group 5?=?HFD?+?R200 and group 6?=?HFD?+?R400. After four weeks of treatment, the HFD group showed significant (P?<?0.05) increase in body weight of the animals, when compared with the groups co- administered with resveratrol and high-fat diet, and resveratrol alone groups. Activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) decreased significantly (P?<?0.05) in the HFD groups co-administered with resveratrol when compared with HFD group only. In conclusion, administration of HFD to rabbits increased body weight and decreased antioxidant enzyme activities which were mitigated by resveratrol administration.     

Sympathetic control of metabolic and hormonal responses to exercise in rats

The importance of the sympatho-adrenal system for the pancreatic hormonal response to exercise and, furthermore, the role of glucagon and catecholamines for the hepatic glycogen depletion during exercise were studied. Rats were either surgically adrenomedullectomized and chemically sympathectomized with 6-hydroxydopamine or shamtreated. Two weeks later the rats had either rabbit-antiglucagon serum or normal rabbit serum injected. Subsequently the rats either rested or swam with a tail weight for 75 min. Immediately afterwards cardiac blood was drawn and liver and muscle tissue collected. In control rats in spite of an increase in blood glucose concentrati4ns during exercise plasma insulin concentrations were unchanged, while glucagon concentrations increased. In sympathectomized rats, compared to control rats, glucagon concentrations increased less, and insulin concentrations were higher, although glucose concentrations were lower during exercise. Sympathectomy completely abolished the exercise-induced decrease in liver and muscle glycogen concentrations, whereas neither glycogen depletion nor plasma catecholamine concentrations were influenced by the administration of glucagon antibodies. These findings indicate that the sympatho-adrenal system enhances glucagon secretion as well as muscular and hepatic glycogen depletion but inhibits insulin secretion in exercising rats. The increase in glucagon concentrations, however, does not enhance hepatic glycogen depletion at the work load used.     

Role of gonadal hormones in diet selection and food utilization in female rats

Patterns of dietary self-selection were examined in ovariectomized and sham-operated female rats. Self-selection animals were offered separate dietary sources of protein, carbohydrate, and fat. Control animals were offered ground Purina Rodent Chow. Food intakes, water intakes, and body weights were measured daily for all animals. During a 19-day baseline period, selecting animals chose approximately one third of their daily caloric intake from each of the three diet sources. Following this baseline period, half of the self-selection animals and half of the control animals received bilateral ovariectomies, while the remaining animals in each diet group received sham-operations. Following ovariectomies, both self-selection and control animals significantly increased food intakes and rate of weight gains above baseline values. In contrast, sham-operated animals did not increase food intakes or rate of weight gain following surgery. When weight gain was calculated as a function of caloric intake, ovariectomized animals gained nearly twice as much weight per kilocalorie consumed as sham-operated animals. Ovariectomized animals showed no changes in diet selection after surgery, while sham-operated animals showed a slight decrease in the percentage protein selected. Differences between self-selection patterns in ovariectomized animals and in animals with other forms of experimentally-induced obesity suggest distinct metabolic patterns may underlie various forms of obesity.     

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.