Obesity-inducing lesions of the central nervous system alter leptin uptake by the blood-brain barrier.

Leptin regulates body adiposity by decreasing feeding and increasing thermogenesis. Obese humans and some obese rodents are resistant to peripherally administered leptin, suggesting a defect in the transport of leptin across the blood-brain barrier (BBB). Defective transport of exogenous leptin occurs in some models of obesity, but in other models transport is normal. This shows that factors other than obesity are associated with impairment of leptin transport across the BBB. In order to further investigate these factors, we determined leptin transport in rats made obese by lesioning of the ventromedial hypothalamus (VMH), paraventricular nucleus (PVN), or posterodorsal amygdala (PDA). These regions all contain leptin receptors and lesions there induce obesity and hyperleptinemia and alter the levels of many feeding hormones which might participate in leptin transporter regulation. We measured the uptake of radioactively labeled leptin by the BBB by multiple-time regression analysis which divides uptake into a reversible phase (Vi, e.g., receptor/transporter binding to the brain endothelial cell) and an irreversible phase (Ki, complete transport across the BBB). Leptin uptake was not affected in rats with VMH lesions. No significant change occurred in the entry rate (Ki) for any group, although Ki declined by over 35% in rats with PVN lesions. Decreased uptake was observed in rats with PVN lesions and with PDA lesions. This was primarily due to a reduced Vi (about 21% for the PDA). This decreased uptake is most likely explained by decreased binding of leptin to the brain endothelial cell, which could be because of decreased binding by either receptors or transporters. This suggests that some of the feeding hormones controlled by the PVN and PDA may participate in regulating leptin uptake by the BBB.

Factors affecting the perception of naturalness and flavor strength in citrus drinks.

In two profiling experiments and one grouping experiment, panelists evaluated orange drinks in order to measure the effects of design variables, especially color, on basic tastes as well as on more consumer-like attributes such as flavor strength and naturalness. Naturalness was increased in one experiment by lowering degrees Brix or increasing quinine HCl. Low sweet-sour ratios were generally perceived as more natural. Pectin had no effect on naturalness. Flavor strength was increased consistently by augmenting levels of quinine HCl, sucrose, citric acid or degrees Brix. Addition of Cochineal Red increased sweetness and flavor strength but decreased the perception of naturalness for the aromas studied.

Level of corticosterone replacement determines body weight gain in adrenalectomized rats with VMH lesions.

Adrenalectomized female rats with lesions of the ventromedial hypothalamus or sham lesions were given SC implants of wax pellets or a fused mixture of corticosterone-cholesterol (40, 75, or 130% by weight). In animals with sham lesions, high dosages of corticosterone proved to be catabolic (r = -0.61 between plasma corticosterone and weight change). In marked contrast, animals with VMH lesions displayed substantial weight gains at all circulating levels of corticosterone, with a significant positive correlation (r = +0.48) between these two variables. It is concluded that: a) damage to the basomedial hypothalamus alters an organism's response to corticosterone at both ends of the dose-response curve, and b) both Type I and Type II corticosterone receptors in the brain play a role in hypothalamic obesity.

Hyperphagia and obesity in female rats with temporal lobe lesions.

Damage to the temporal lobes in cats, dogs, and primates has long been known to result in hyperphagia and obesity, but research into the role of this area of the brain in feeding behavior has largely been neglected because of an inability to produce similar results in rats. The present study reports hyperphagia and obesity in female rats with small electrolytic lesions centered in the posterodorsal amygdala. Daily food intake more than doubled in the first few days after surgery and mean weight gain was more than four times that observed in animals with sham lesions during the first 26 days. The rats with lesions were not hyperresponsive to a switch in diets (lab chow to high-fat, and back). In all animals that gained abnormal amounts of weight, the posterior extent of the lesions extended through the amygdalohippocampal area into the ventral hippocampal formation. The results suggest that the temporal lobe is an important extrahypothalamic site for the regulation of food intake in rodents.

Glucocorticoids and hypothalamic obesity.

Recent studies have demonstrated a role for adrenal glucocorticoid hormones in the hyperphagia and obesity which follow lesions of the ventromedial hypothalamus (VMH). Although VMH lesions elevate morning plasma corticosterone levels, it is concluded that this contributes little to the development of obesity. More importantly, animals with VMH lesions appear to be hyperresponsive to very low levels of circulating glucocorticoids. The overeating and obesity are both prevented and reversed by either complete adrenalectomy or complete hypophysectomy (i.e., resulting in plasma corticosterone levels of less than 1.0 microgram/dl) and restored by dosages of glucocorticoids that have no effect on feeding behavior and weight gain in nonlesioned adrenalectomized animals. Mineralocorticoid hormones have no effect on hypothalamic obesity. Judging by the time course of effects on feeding behavior in VMH-damaged mice of a single intracerebroventricular injection of a low dose of glucocorticoid, which has no effect when administered intraperitoneally, it is concluded that glucocorticoids exert their effect centrally in a permissive, rather than a regulatory, manner. Stimulation of the neighboring paraventricular nuclei (PVN) with norepinephrine or neuropeptide Y produces a rapid feeding response which is also abolished by adrenalectomy and restored with administration of glucocorticoids. However, it is unlikely that the PVN is the site at which glucocorticoids exert their effect in animals with VMH lesions, for PVN lesions or knife-cuts, or combination VMH-PVN lesions, also result in hyperphagia and obesity. It is concluded that adrenal glucocorticoid hormones exert their permissive effects on feeding behavior at brain sites other than the medial hypothalamus. The septo-hippocampal complex is suggested as a possible site.

Effects of adrenalectomy and corticosterone administration on hypothalamic obesity in rats.

The present experiment was designed to assess the role of adrenal hormones in hypothalamic hyperphagia and obesity. Ventromedial hypothalamic (VMH) or sham lesions were produced either 15 days before or after adrenalectomy (ADX) or sham adrenalectomy in rats in a completely counterbalanced design (experiment 1). Body weight and food intake were recorded for 30 days after the second surgery. Adrenalectomy in obese VMH animals eliminated all excess weight gain and decreased food intake to below the level of all control groups. VMH lesions in ADX animals did not produce the characteristic weight gain associated with ventromedial hypothalamic damage, and this group was not significantly different from animals with sham lesions in body weight or food intake. In experiment 2, the administration of corticosterone resulted in a marked increase in the rate of weight gain in ADX-VMH animals, and the withdrawal of the hormones was followed by weight loss. It is concluded that adrenal glucocorticoid hormones are necessary for the development and maintenance of VMH hyperphagia and obesity.

The role of vagally-medicated hyperinsulinemia in hypothalamic obesity.

Evidence that the obesity syndrome which follows ventromedial hypothalamic (VMH) lesions is at least partially the result of a primary metabolic dysfunction is reviewed, as are proposals that the altered metabolism is due to enhanced vagally-mediated insulin release. This hypothesis was based largely on experiments demonstrating the complete reversal of hypothalamic obesity by subdiaphragmatic vagotomy, but subsequent studies have revealed that hypothalamic obesity is not always prevented by prior vagal transections. Interpretation of these discrepant results has been made difficult because of the frequent use of gastric secretion, behavioral, or other indirect tests for completeness of vagotomy. A review of more recent studies which have employed either direct assessment of vagotomy effects on insulin levels, pharmacological blockade of vagal efferent activity, or selective vagotomies indicates that vagally-mediated hyperinsulinemia can account for no more than 40% of the weight gain observed in animals with VMH lesions fed ad libitum, and may not be involved in the obesity that results from some parasagittal VMH knife cuts. It is concluded that vagally-mediated hyperinsulinemia does make a substantial, although not exclusive, contribution to the increased carcass lipid content observed in VMH animals that are food-restricted or pair-fed with control animals.

Hypothalamic obesity in female rats in absence of vagally mediated hyperinsulinemia.

In order to assess the role of vagally mediated hyperinsulinemia in hypothalamic obesity, plasma insulin and glucose levels were assayed in vagotomized and sham-vagotomized female rats after a 6-h fast and after a measured glucose meal both before and 10-14 days after ventromedial hypothalamic (VMH) lesions. Both groups displayed similar gains in body weight in the first 10 days after VMH lesions, but only the sham-vagotomized VMH-lesioned animals displayed elevated fasting insulin levels. Fasting glucose levels did not differ either before or after the lesion. The insulin response to oral glucose was increased in VMH rats, both in vagotomized and sham-vagotomized animals, and it is concluded that the hyperresponsiveness to oral glucose is independent of vagal mediation. Vagotomy markedly exaggerated the glucose and insulin response to oral glucose loading in both intact rats and rats with VMH lesions, probably as a result of more rapid absorption of glucose from the intestine. It is concluded that the fasting hyperinsulinemia that is characteristic of VMH animals is under vagal control and that its elimination does not prevent the development of obesity.

A re-examination of the ventromedial hypothalamic paradox.

Early studies of hypothalamic function found that damage to the ventromedial hypothalamus (VMH) resulted in marked overeating but inferior performance in food-motivated tasks, leading several investigators to conclude that hyperphagic VMH animals were actually less hungry than normal animals. However, numerous studies have since demonstrated that under certain conditions VMH-damaged animals will work as hard or harder for food, and consume as much or more of an unpalatable diet, than normal animals. A review of these experiments suggests that most of the deficits in food-motivated behavior are the result of two dysfunctions, one obesity induced, and the other a direct result of the lesion that can be greatly alleviated by preoperative adaptation. Explanations of the VMH paradox are also examined, and it is concluded that most are too narrow in scope, generally ignoring the fact that obesity and preoperative adaptation have similar effects on thirst- and some avoidance-motivated behaviors. It is proposed that the impaired performance of VMH-lesioned animals in food-reinforced tasks is largely the result of obesity- and lesion-induced dysfunctions that are not specific to either hunger- or thirst-motivated behaviors.

Naloxone-induced suppression of food intake in normal and hypothalamic obese rats.

Intraperitoneal injections of naloxone hydrochloride (1, 2, 4, and 8 mg/kg) suppressed food intake in both normal and hypothalamic obese rats maintained on a 4-hr per day feeding schedule. The decrease in feeding was more pronounced in the animals with ventromedial hypothalamic lesions. Appetitively motivated feeding, i.e., the consumption of sweetened milk under nondeprived conditions, was also suppressed by naloxone, but there was no reliable difference between groups. It is concluded that opiate receptors located in the ventromedial hypothalamus are not essential for the effects of opiate agonists and antagonists on feeding behavior.

Delayed response to 2-deoxy-D-glucose in hypothalamic obese rats.

A dose-response relationship for the effects of 2-deoxy-D-glucose (2-DG) (0-400 mg/kg) on food intake was established in normal and obese ventromedial hypothalamic lesioned rats. In normal animals the lowest dose that produced a statistically signififant increase over baseline food intake was 100 mg/kg 2-DG. Larger doses produced a progressively greater effect. Most of the increase in food intake occurred during the first hour after the injection of 2-DG, the latency of the first feeding bout being shorter for higher doses of the compound. Obese VMH rats significantly increased their 4-hr food intake after 150, 200, and 250, and 400 mg/kg 2-DG, but the increase in feeding was delayed compared to control animals. During the first hour after the injection, the food intake of obese rats was unaffected by doses of 2-DG up to 250 mg/kg, and inhibited by higher doses (300 and 400 mg/kg). The effects of VMH lesions on 2-DG-induced eating are attributed to the elimination of afferents from peripheral glucoreceptors.