Serotonin-depleting midbrain lesions do not prevent ovariectomy-induced weight gain.

Past research has shown that subdiaphragmatic vagotomy and midbrain raphe lesions are each effective in impeding the development of hypothalamic obesity while neither affects the development of genetic obesity in Zucker rats. To further test the parallels that may exist between these two manipulations on another putative obesity model, we studied the effects of midbrain raphe lesions on the development of ovariectomy-induced weight gain, previously shown to be unaffected by vagotomy. Ten adult female rats received thermal lesions of the dorsal and median raphe nuclei (RAPHE) while 7 served as sham controls (SHAM). Following a 26-day recovery period during which body weight, food intake and water intake were periodically monitored, bilateral ovariectomy (OVX) was performed on 7 RAPHEs and 4 SHAMs, with laparotomy (LAP) being performed on 3 RAPHEs and 3 SHAMs. Body weights and intake variables were monitored for an additional 58 days, then animals were sacrificed for brain histological and biochemical assessments. RAPHEs weighed less despite eating and drinking more than SHAMs throughout this study. Nevertheless, OVX rats gained more weight regardless of lesion (mean +/- SEM weight gain = 73.9 +/- 5.5 g for RAPHE + OVX and 67.0 +/- 6.6 g for SHAM + OVX vs. 30.7 +/- 3.0 g for RAPHE + LAP and 39.7 +/- 5.5 g for SHAM + LAP). This occurred without reliable changes in the food or water intakes of either OVX subgroup. Histology confirmed that RAPHE lesions were largely localized to the dorsal and median raphe nuclei, as planned.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in body weight and food-related behaviour induced by destruction of the ventral or dorsal noradrenergic bundle in the rat

Three experiments contrasted the effects of 6-hydroxydopamine-induced lesions of the ventral noradrenergic and dorsal noradrenergic projections, predominantly to hypothalamus and cortex, respectively, upon body weight changes and food-related behaviour in the rat. In general, ventral noradrenergic bundle lesions enhanced weight gain and these effects were exaggerated by the provision of palatable cheese to the standard chow diet. In contrast, lesions of the dorsal noradrenergic bundle produced minor changes in body weight. Associated with the effects of ventral noradrenergic bundle lesions were hyperphagia, enhanced suppression of intake of food adulterated with quinine, (at high concentration), a small attenuation of food neophobia, and enhanced acquisition, but not performance, of the eating response to tail-pinch stimulation. These ventral noradrenergic bundle lesions failed to alter basal activity levels, amphetamine anorexia or the diurnal pattern of eating or activity. In contrast, lesions of the dorsal noradrenergic bundle did not produce either hyperphagia or enhanced rejection of food adulterated with quinine. However, there was a strong attenuation of food neophobia and a retarded acquisition (but unimpaired performance) of eating in response to tail-pinch stimulation.

The results are discussed in connection with previous studies of ventral and dorsal noradrenergic bundle lesions, with the effects of ventromedial hypothalamic lesions and with the underlying behavioural and physiological processes that mediate these contrasting effects of different neuroanatomical patterns of central noradrenaline depletion.     

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.     

Locomotor activity and ingestive behavior after damage to ascending serotonergic systems

The effects of electrolytic midbrain raphe lesions on ingestive behavior and locomotor activity of rats were compared to those produced by intracerebral injections of 5,7 dihydroxytryptamine (5,7 DHT) at various points along the ascending serotonergic pathways. Only electrolytic lesions of the median and/or dorsal raphe nuclei produced significant changes in food intake, water intake, body weight gain, and wheel running activity. Intracerebral injections of 5,7 DHT, a selective serotonergic neurotoxin, had no effect on any of these variables. However, 5,7 DHT induced lesions produced decreases in forebrain synaptosomal uptake of serotonin which were equivalent to, or greater than, those resulting from electrolytic lesions of the midbrain raphe nuclei. Failure of 5,7 DHT injections to replicate the behavioral changes resulting from electrolytic lesions of the midbrain raphe nuclei suggests that loss of ascending serotonergic projections was not responsible for the behavioral effects that followed the electrolytic lesions.     

Effects of quinine adulterated diets on the food intake and body weight of obese and non-obese hypothalamic hyperphagic rats

Female rats given knife cuts between the medial and lateral hypothalamus overate and became obese on a high fat diet. When switched to a quinine diet the knife cut rats initially underate and lost weight, but their body weights did not fall significantly below that of controls maintained on the same diet. Knife cut rats also maintained weights at control levels when given a moderately bitter quinine diet immediately after surgery, but displayed subnormal weights when switched to a very bitter diet. Cuts lateral to the fornix produced a greater weight suppression on the quinine diet, but a smaller weight gain on a high fat diet than did cuts medial to the fornix. The results indicate that the hypothalamic knife cuts elevate the upper limit of body weight with little or no change in the lower body weight limit, and that obesity rather than hypothalamic damage per se is the major cause of the hyperphagic rat's finickiness to unpalatable quinine diets. A dual lipostatic model of the hypothalamic hyperphagia syndrome is discussed.     

Ghrelin、melanotan-Ⅱ以及胆囊收缩素对下丘脑双侧室旁核损伤大鼠摄食的影响

目的探讨大鼠下丘脑双侧室旁核(PVN)损伤引起的过食和肥胖的产生机制。方法 Wistar雄性大鼠36只,通过电损伤下丘脑双侧PVN使大鼠产生过食和肥胖,检测ghrelin、melanotan-II(MT-II,一种合成的α-黑色素细胞刺激素——α-MSH的结构同源体)以及胆囊收缩素-8(CCK-8)摄食作用的改变。结果双侧PVN损伤后大鼠的体重和摄食量明显增加,显示出过食和肥胖,手术后1周,外周给与Ghrelin,3～4h后PVN损伤组比伪损伤组的摄食量增加明显,Ghrelin显示出更强的刺激摄食的作用;中枢给予MT-Ⅱ可明显抑制24h节食大鼠的食物摄取,然而PVN损伤后MT-II对24h节食大鼠摄食的抑制作用减弱甚至消失;外周给予CCK-8可明显抑制大鼠各时间段的摄食作用,PVN损伤组和伪损伤组之间未见明显差异。结论大鼠下丘脑双侧PVN损伤引起的过食和肥胖可能与增强的ghrelin对摄食的刺激作用和(或)α-MSH受体的破坏有关。     

Dipsogenic potentiation by sodium chloride but not by sucrose or polyethylene glycol in tuberomammillary-mediated polydipsia

The aim of this study was to examine the dipsogenic mechanisms involved in the recently discovered tuberomammillary (TM)-mediated polydipsia. Rats with bilateral electrolytic lesions of each TM subnucleus underwent several dipsogenic treatments, both osmotic and volemic. Animals with ventral (E2) or medial TM lesions (E3 or E4) showed a potentiated hyperdipsic response to hypertonic sodium chloride administration but not to sucrose or polyethylene glycol treatments. The increase in response to sodium chloride was significantly greater in groups E3/E4 and E2 than in the non-lesioned group and in animals with polydipsia induced by lesion of the median eminence. As previously reported, hyperphagia was induced by lesion to ventral TM nuclei (E1 or E2), confirming a possible role for the TM complex in food intake. However, lesions in medial nuclei (E3 or E4) did not produce this increase in food intake. These results are interpreted in relation to the hypothalamic systems involved in food and water intake.     

PVN-hindbrain pathway involved in the hypothalamic hyperphagia-obesity syndrome

This study examined the involvement of caudal brainstem projections of the hypothalamic paraventricular nucleus (PVN) in the medial hypothalamic (MH) hyperphagia-obesity syndrome. Experiment 1 demonstrated that a unilateral parasagittal knife cut in the MH combined with a contralateral coronal knife cut in either the ventrolateral pons (vP) or ventrolateral medulla (vM) significantly increased food intake and body weight in adult female rats. Overeating and overweight were also produced by a unilateral MH knife cut combined with a contralateral oblique cut under the nucleus of the solitary tract and dorsal motor nucleus of the vagus complex (NST/DX). In contrast, an MH cut x dorsolateral medullary cut combination did not increase food intake or body weight compared to a MH cut alone or sham surgery. Experiment 2 demonstrated that the hyperphagia/obesity effect of MH x vP knife cuts was comparable to that obtained with bilateral PVN lesions, but less than that produced by bilateral MH knife cuts. Bilateral vP cuts also increased body weight but the effect was less than that obtained with the other experimental treatments. Feeding the rats a high-fat diet rather than chow potentiated the hyperphagia and obesity syndromes produced by the various lesion conditions. Taken together, these findings suggest that the medial hypothalamic hyperphagia and obesity syndrome is due, in part, to damage to PVN projections to the caudal brainstem, the NST/DX complex in particular. The functional significance of this PVN-hindbrain "feeding" pathway and the identity of extra-PVN components of the hyperphagia-obesity syndrome remain to be established.     

Ingestive behaviors of rats with electrolytic median raphe lesions maintained on a food deprivation schedule

The current study examines the effects of electrolytic median raphe lesions on the feeding and drinking behaviors of rats maintained on a 23-hr food deprivation schedule. Measurement of food intake during the feeding period indicated no difference between the two groups but lesioned animals showed significantly more spillage than controls. Furthermore, measurement of water intakes indicated that median raphe lesioned rats consume significantly less water than controls in the absence of food and come to ingest virtually all of their daily fluid intake during the feeding period. Additionally, rats with lesions of this nucleus take significantly more drinks during the feeding period, often punctuating their meal with short draughts. Since similar behaviors are seen following the destruction of certain hypothalamic and limbic nuclei anatomically related to the median raphe, it is possible that these syndromes share an anatomical basis.     

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.     

Hypothalamic hyperphagia despite imposed diurnal or nocturnal feeding and drinking rhythms.

Rats normally do most of their eating at night. When ad lib fed rats are made hyperphagic with lesions or parasagittal hypothalamic knife cuts the increases in eating occur primarily during the day. This suggests that a disruption of circadian rhythms may mediate the overeating. However, when knife cut rats were food and water deprived all day excessive eating occurred at night. Similarly, when they were deprived all night overeating occurred during the day. Under both conditions od deprivation the food intakes and rapid weight gains of the ad lib fed knife cut group were defended. It was concluded that: (1) in hypothalamic hyperphagia either the excessive food intake or the excessive weight gain is defended when food and water are available only half of each day, and (2) disruption of nocturnal feeding and drinking rhythms is not the cause of hypothalamic hyperhagia.     

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.     

Sensitivity to satiating and taste qualities of glucose in obese Zucker rats

A general "glucoreceptor" defect, demonstrable in pancreatic islet and taste cells, may contribute to the metabolic and taste abnormalities of adult onset diabetes and possibly, if present at the level of the hypothalamus, could produce hyperphagia and the obesity seen in diabetics. To determine if a glucoreceptor defect generally accompanies obesity and glucose intolerance, behavioral responsiveness to glucose was examined in nine obese and nine lean female Zucker rats. Daily food and fluid intake were measured during three two-bottle preference tests, in which rats chose between water and one of several glucose solutions (1%, 3%, and 12%). Taste responsiveness to glucose of obese rats appeared normal; however, increased satiating effects of glucose were found in obese rats, possibly due to an enhanced delivery of glucose to neurons that inhibit feeding, caused by glucose intolerance. Also, obese rats had (a) increased brain weights, and (b) increased volumes of ventromedial and paraventricular hypothalamic nuclei. These findings, perhaps explainable by an increased delivery of nutrients to the developing brain, indicate that the hyperphagia of Zucker rats is due neither to an overt hypothalamic lesion nor to insensitivity to glucose.     

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.     

Resistance of male Sprague-Dawley rats to sucrose-induced obesity: effects of 18-methoxycoronaridine

Evidence suggests that the development of obesity in males and females might be mediated by distinct mechanisms, warranting different treatment approaches. In previous studies from this laboratory, a high sucrose diet induced excessive weight gain in female Sprague-Dawley rats and administration of a selective antagonist of α3β4 nicotinic receptors, 18-methoxycoronaridine (18-MC), prevented this form of obesity. In the present study similar parameters were studied in male rats by using an identical experimental protocol. The effects of repeated administration of 18-MC on body weight gain, deposition of fat, consummatory behavior and biochemical markers of obesity in male rats were also assessed. In contrast to females, males consuming ad libitum quantities of sucrose solution (30%) in combination with normal chow did not become obese; they did not gain excessive weight nor show excessive fat deposition. Repeated administration of 18-MC (20 mg/kg, i.p.) attenuated weight gain in both sucrose-consuming and control animals without altering food or fluid intake. The present results indicate that males and females are differentially responsive to high carbohydrate-diet obesity. Such gender disparities could be secondary to sex-specific alterations in cholinergic mechanisms of feeding and body weight regulation.     

Excessive weight gains in female rats with transections of the stria terminalis

Recent studies have demonstrated hyperphagia and excessive weight gains in female rats with small lesions in the most posterodorsal aspects of the medial amygdala. In the present study, similar results were observed in female rats with bilateral transections of the stria terminalis just as it exits the amygdala to begin its dorsal ascent (mean weight gain of 35.9 g/20 days compared to 0.1 g/20 days for operated control animals). Cellular damage caused by the retractable wire knife was limited to the caudal globus pallidus. The results of previous studies that failed to observe weight gains after stria terminalis transections were attributed to the use of male animals. The present results, along with the pattern of anterograde degeneration that is observed after obesity-inducing amygdaloid lesions, suggest a medial amygdala-stria terminalis-medial hypothalamic pathway in the regulation of food intake and body weight, but other possibilities are considered.     

Stimulation of 5-hydroxytryptamine nerve cells in dorsal and median raphe nuclei elevates blood glucose in rats

The role played by dorsal or median raphe nuclei in glucoregulation was investigated by stimulating these nuclei in normal rats and in rats with chemical ablation of the hydroxytryptamine (5-HT) nerve cells in these nuclei. Electrical stimulation of either dorsal or median raphe nuclei increased blood glucose or the in vivo voltammetric signal of hypothalamic 5-OH-indole in normal rats; the increase in blood glucose level or the hypothalamic 5-OH-indole release was proportional to the intensity of stimulation. Microinjection of kainic acid or l-glutamate at the same sites also produced hyperglycemia or stimulated the hypothalamic 5-OH-indole release. This stimulation-induced hyperglycemia was significantly reduced by pretreatment of animals with spinal transection or adrenalectomy. In addition, selective destruction of the hypothalamic 5-HT nerve fibers, produced by administration of 5,7-di-hydroxytryptamine (a 5-HT nerve depletor) into both dorsal and median raphe regions, reduced the magnitude of the hyperglycemic responses to electrical stimulation of either dorsal or median raphe nuclei. The data indicate that stimulation of ascending 5-HT pathways in the rat's brain increases the adrenal-sympathetic efferent activity and leads to hyperglycemia.     

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.     

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.     

Inhibition by hypophysectomy of the hyperphagia and obesity following gold thioglucose

The effect of hypophysectomy in mice previously treated with gold thioglucose (GTG) was studied with respect to changes in food intake and development of obesity. As expected, all mice treated with GTG alone exhibited lesions in the ventromedial hypothalamus (VMH), hyperphagia and obesity. Hypophysectomy of GTG treated mice prevented the appearance of hyperphagia and obesity. Daily administration of the adrenal corticoid, cortisone, completely restored the hyperphagia and obesity in GTG treated hypophysectomized mice. The amounts of cortisone used did not appreciably affect food intake or body weights of normal, hypophysectomized or GTG treated mice. These findings indicate that the hypothalamic hyperphagia and obesity which normally follows the administration of GTG is dependent on a functional pituitary gland. Furthermore, the specific ability of an adrenal corticoid to completely restore the hyperphagia and obesity of GTG treated hypophysectomized mice in the absence of other pituitary factors, suggests that the pituitary adrenal axis serves as an important link in the regulatory mechanism for control of feeding behavior in the mouse.