Early streptozotocin diabetes and hunger

The initial effect of streptozotocin diabetes is not hyperphagia, but reduced food intake. Diabetic hyperphagia reaches maximum only after many days. Utilization of body fat may account for the delayed appearance of diabetic hyperphagia; this effect may be mediated by plasma fat metabolites. Plasma levels of free fatty acids (FFAs), ketone bodies, and glycerol are greatly elevated following STZ treatment, but return nearly to normal as diabetic hyperphagia appears.     

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.     

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。     

Paraventricular hypothalamic clonidine increases rather than decreases susceptibility to activity-based anorexia in the rat.

Anorexia has been related to reduced activity of the paraventricular hypothalamic (PVN) noradrenergic-feeding system. In this study we determined whether clonidine (an alpha 2-adrenergic agonist) infused into the PVN reduced susceptibility to activity-based anorexia (ABA) in the rat. In Experiment 1, clonidine (6 doses) was chronically infused into the PVN of male Sprague-Dawley rats. All animals were exposed to ABA (1.5 hr/day food access; 22.5 hr/day running wheel access) until a 25% body weight loss was reached. Dose-related increases in susceptibility to ABA and decreases in food intake were observed. In Experiment 2, for which heavier animals and 3 doses of clonidine were used, we found no difference in food intake and wheel activity but increased susceptibility to ABA. Chronic clonidine infused into the PVN does not produce hyperphagia and exacerbates rather than attenuates susceptibility to ABA.     

Hypothalamic implants of dilute estradiol fail to reduce feeding in ovariectomized rats

To investigate further the site where estradiol (E(2)) inhibits food intake, we tested the effects on feeding of subcutaneous and intrahypothalamic implants of 10% E(2) benzoate in cholesterol (CHOL) or CHOL alone. E(2) was implanted subcutaneously in Silastic tubes, and intrahypothalamically via bilateral 29-gauge cannulas into the paraventricular nucleus (PVN) or the medial preoptic area (MPA) of ovariectomized (OVX) Sprague-Dawley and Long-Evans rats. Three-day implant periods followed 3-day baseline periods. Rats were allowed ad libitum access to chow and tap water, and food intake and body weight were measured each day. Subcutaneous 10% E(2) implants in Sprague-Dawley rats reduced food intake 21% on Day 2 and 34% on Day 3 (P's<.01) and decreased 3-day body weight gain 11 g (P<.05). In contrast, 10% E(2) implants in the PVN of Sprague-Dawley rats did not change food intake or body weight. Implants of 10% or 20% E(2) in the MPA also failed to decrease food intake. MPA implants of 10% E(2) decreased body weight gain 8 g (P<.05), but MPA implants of 20% E(2) decreased weight gain only 4 g (P>.05). To determine whether the strain of rat affected our negative results on food intake, we implanted 10% E(2) into the PVN of Long-Evans rats. Again, PVN E(2) did not decrease food intake significantly in comparison to the pretest baseline. PVN E(2) did, however, decrease body weight gain 5 g and decreased food intake 6% compared to rats with implants of CHOL (both P<.05), but these effects appeared to be due to an increase in feeding in the CHOL group in comparison to their baseline. Finally, CHOL and E(2) implants did not impair the responsivity of the PVN because acute implants of norepinephrine (NE) into the PVN of E(2)- or CHOL-treated Long-Evans rats significantly increased food intake. Our results do not support the hypothesis that E(2)'s actions in either the PVN or the MPA are sufficient to account for its inhibitory effects on feeding.     

Sleep deprivation of rats: the hyperphagic response is real

STUDY OBJECTIVES: Chronic sleep deprivation of rats causes hyperphagia without body weight gain. Sleep deprivation hyperphagia is prompted by changes in pathways governing food intake; hyperphagia may be adaptive to sleep deprivation hypermetabolism. A recent paper suggested that sleep deprivation might inhibit ability of rats to increase food intake and that hyperphagia may be an artifact of uncorrected chow spillage. To resolve this, a palatable liquid diet (Ensure) was used where spillage is insignificant. DESIGN: Sleep deprivation of male Sprague Dawley rats was enforced for 10 days by the flowerpot/platform paradigm. Daily food intake and body weight were measured. On day 10, rats were transcardially perfused for analysis of hypothalamic mRNA expression of the orexigen, neuropeptide Y (NPY). SETTING: Morgan State University, sleep deprivation and transcardial perfusion; University of Maryland, NPY in situ hybridization and analysis. MEASUREMENTS AND RESULTS: Using a liquid diet for accurate daily measurements, there was no change in food intake in the first 5 days of sleep deprivation. Importantly, from days 6-10 it increased significantly, peaking at 29% above baseline. Control rats steadily gained weight but sleep-deprived rats did not. Hypothalamic NPY mRNA levels were positively correlated to stimulation of food intake and negatively correlated with changes in body weight. CONCLUSION: Sleep deprivation hyperphagia may not be apparent over the short term (i.e., < or = 5 days), but when extended beyond 6 days, it is readily observed. The timing of changes in body weight and food intake suggests that the negative energy balance induced by sleep deprivation prompts the neural changes that evoke hyperphagia.     

Unraveling the obesity of OLETF rats

Cholecystokinin (CCK) is a brain gut peptide that plays an important role in satiety. CCK inhibits food intake by reducing meal size. CCK's satiety actions are mediating through its interaction with CCK1 receptors. Otsuka Long Evans Tokushima Fatty (OLETF) rats are a CCK1 receptor knockout model that allows the study of multiple CCK functions. OLETF rats are hyperphagic with the hyperphagia expressed as a significant increase in the size of meals. OLETF rat obesity is secondary to the hyperphagia and has been proposed to derive from two regulatory deficits. One is secondary to the loss of a feedback satiety signal. The other results from increased dorsomedial hypothalamic NPY expression. Recent studies have examined developmental aspects of altered feeding, body weight and orexigenic signaling in OLETF rats. OLETF rats demonstrate increases in meal size in independent ingestion tests as early as two days of age. OLETF pups are also more efficient in suckling situations. Consistent with such developmental differences, examinations of patterns of hypothalamic gene expression in OLETF pups indicate significant increases in DMH NPY expression as early as postnatal day 15. Access to a running wheel and the resulting exercise have age dependent effects on OLETF food intake and obesity. With running wheel access shortly after weaning, food intake decreases to the levels of LETO controls. When running wheel access is discontinued, food intake temporarily increases resulting in an intermediate phenotype and the absence of diabetes. Together these data demonstrate roles for peripheral CCK and CCK in feeding and body weight control and support the use of the OLETF rat as a model for examining obesity development and for investigating how interventions at critical developmental time points can alter genetic influences on food intake and body weight.     

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.     

Food intake and blood fuels after oil consumption: differential effects in normal and diabetic rats

The mechanisms by which fat feeding suppresses the hyperphagia of diabetic rats were examined. Rats that were allowed to consume a small amount (1.5 ml) of corn oil decreased subsequent food intake within 6 hr after ingesting. Diabetic rats decreased food intake much more than normal rats. Similar results were obtained when oil was given intragastrically. Analysis of blood samples revealed that diabetic rats showed greater increases in plasma ketones and triglycerides and smaller increases in plasma glycerol than normal rats following consumption of 1.5 ml corn oil. This difference between diabetic and normal rats appeared when rats were allowed to eat after oil ingestion as well as when they were fasted. Brief periods of food deprivation (2.5-4.5 hr) substantially increased plasma ketones and glycerol and decreased plasma triglycerides in both diabetic and normal rats. The results indicate that diabetic rats decrease food intake more than normal rats after fat feeding because they oxidize more of the ingested fat.     

Hyperketonemia (ketosis), oxidative stress and type 1 diabetes.

The long-term complications of diabetes are the leading causes of morbidity and mortality in the type 1 diabetic population and remain a major public health issue. Hyperglycemia is one of the major risk factors in the development of vascular complications. A growing body of evidence indicates that hyperglycemia leads to increased oxidative stress and monocyte and endothelial cell dysfunction. In addition to hyperglycemia, type 1 diabetic patients frequently experience ketosis (hyperketonemia). The blood concentration of ketone bodies reaches higher than 25mM in diabetics with severe ketosis. Traditionally, clinical practice has considered hypertketonemia to be present only in type 1 diabetic patients. Newer data indicate that diabetic ketoaciosis or hyperketonemia co-exists with hyperglycemia among older type 2 diabetic patients and in African Americans and other minority groups with type 2 diabetes. This review will focus on the role of hyperketonemia in the etiology of oxidative stress in diabetic patients. The data presented here illustrate that the ketone body acetoacetate (AA) can generate superoxide radicals and cause increases in oxidative stress and cellular dysfunction. The data included in this review demonstrate that blood levels of markers of oxidative stress are elevated in hyperketonemic patients compared with those of normoketonemic diabetic patients. Thus, both in vitro and in vivo research indicate that ketosis can generate oxygen radicals and result in excess cellular oxidative stress in type 1 diabetic patients. Elevated oxidative stress levels in ketotic patients can play a significant role in the development of vascular inflammation and contribute to the increased incidence of vascular disease and complications associated with type 1 diabetes.     

Anti-diabetic effect of ginsenoside Rb(3) in alloxan-induced diabetic mice

As one of the main active component of protopanaxdiol type ginsenosides, ginsenoside Rb(3) is rarely reported in the treatment of diabetes. The anti-diabetic activity of ginsenoside Rb(3) was investigated in a model of alloxan-induced diabetic mice in the present study. The physiological parameter such as fasting blood glucose level, oral glucose tolerance, body weight, food intake and water intake were measured. Glucose consumption in C2C12 myotubes was also determined in order to investigate the molecular mechanism of ginsenoside Rb(3) in anti-diabetes. The alloxan-induced diabetic mice were treated with ginsenoside Rb(3) for 2 weeks at doses of 5 mg/kg, 15 mg/kg and 25 mg/kg. After 2 weeks treatment of ginsenoside Rb(3), the fasting blood glucose levels of DG 15 and DG 25 were respectively reduced by 36.70% and 37.50% compared to control group. At a dose of 25 mg/kg, oral glucose tolerance was significantly improved compared to control group (P < 0.05). The AUC decreased by 34.47% (from 2442 ± 291 mmol·min/L to 1600 ± 109 mmol·min/L). Both food intake and water intake were remarkably lowered. The injury of pancreas tissues was repaired, which was observed by using HE staining and optic microscope. In vitro, at concentrations of 100 and 200 μM, ginsenoside Rb(3) increased glucose consumption in C2C12 myotubes by 76.83% and 97.20%, respectively, as compared to the control group. However, the body weight of diabetic mice was not significantly altered. In conclusion, our results showed that ginsenoside Rb(3) reduced fasting blood glucose level, food intake, water intake, improved oral glucose tolerance, and repaired injured pancreas tissues of alloxan-induced diabetic mice. Therefore, it was suggested that ginsenoside possesses the potential of the clinical use in preventing and treating diabetes.     

Hypothalamic neuropeptide Y (NPY) in obese Zucker rats: implications in feeding and sexual behaviors

Neuropeptide Y (NPY), a peptide of the pancreatic polypeptide family, is actually considered to be the most potent stimulator of food intake in rats when centrally injected. It has also suppressive effects on several components of sexual behavior. It was measured in discrete microdissected brain nuclei in obese hyperphagic Zucker fa/fa rats also characterized by a deficient reproductive function, as well as in their lean homozygous (Fa/Fa) and heterozygous (Fa/fa) counterparts. When compared with the lean (Fa/Fa) rats, NPY concentrations were significantly increased in the obese rats in the arcuate nucleus-median eminence (ARCME, +300%), in the paraventricular (PVN, +60%), suprachiasmatic (SCH, +90%), accumbens (+100%) and supraoptic (+40%) nuclei, as well as in the median preoptic area (MPOA, +70%). As PVN is one of the most important nuclei involved in the control of food intake and one site of NPY action, the high levels found in this nucleus might be a major component at the origin of hyperphagia in the obese animals. Food intake might be overstimulated by a sustained production of NPY as shown by the high concentrations found in the ARCME. NPY might also intervene in the pattern of food intake, for NPY contents were also largely modified in the SCH, the nucleus regulating feeding periodicity and in the MPOA, which is possibly involved in the regulation of energy balance. Finally, as the MPOA is the only site of action of NPY on sexual behavior, the higher levels measured in this area might contribute to the defective reproductive function of the obese Zucker fa/fa rat.     

Corticotropin-releasing factor as well as opioid and dopamine are involved in tail-pinch-induced food intake of rats

Several kinds of stress such as psychological stress, restraint, and foot shock inhibit feeding behavior through corticotropin-releasing factor (CRF). In contrast, a mild tail pinch increases food intake in rats. Although dopamine and opioid are thought to be involved in tail-pinch-induced food intake, it is unknown whether CRF participates in this phenomenon. Therefore, we attempted to clarify this issue using rats. A 30-s tail pinch increased food intake in 30 min after the tail pinch, and this increase was blocked by intraperitoneal injection of CRF receptor type 1 selective antagonist. CRF increased food intake in 30 min after intracerebroventricular injection at a dose of 2 or 10 ng, and this increase was also blocked by CRF receptor type 1 antagonist. Tail-pinch- or CRF-induced food intake was blocked by naloxone, pimozide, and spiperone. These results suggest that CRF, through CRF receptor type 1 as well as opioid and dopaminergic systems, are involved in the mechanism of tail-pinch-induced food intake. The results also suggest that brain CRF has dual effects on food intake, hyperphagia and anorexia, in a stress-dependent manner.     

Changes in ingestive behaviors and body weight following intracranial application of 17 alpha-estradiol

The present experiment was conducted to determine if central implants of 17 alpha-estradiol could influence food intake, water intake, and body weight in ovariectomized rats. A total of fifteen animals were fitted with bilateral guide cannulae in the paraventricular nucleus (PVN) and stimulated unilaterally with cholesterol and 17 alpha-estradiol in each side of the brain. Compared with cholesterol treatment, 17 alpha-estradiol implants in the PVN significantly lowered food intake and body weight but did not affect water intake. These findings indicate that the PVN is a brain region responsive to the effects of 17 alpha-estradiol on feeding behavior, and support the hypothesis that the effects of estrogens on ingestive and reproductive behaviors are organized separately within the brain.     

Role of the ventromedial hypothalamus in prolactin-induced hyperphagia in ring doves.

Prolactin (PRL) strongly stimulates feeding activity and body weight gain in ring doves, and of the brain loci tested to date, the ventromedial hypothalamus (VMH) is the most effective site of PRL action in promoting these changes. To determine if the VMH is essential for this response, we examined the effects of VMN destruction on spontaneous feeding and on changes in food intake induced by intracerebroventricular (i.c.v.) injections of PRL. Male birds were selectively destroyed by radiofrequency lesions (n = 6). A group of sham-lesioned males (n = 6) served as controls. Lesioned birds exhibited a transient increase in food intake that peaked around the seventh postoperative day and declined to baseline levels by day 12. In contrast to this pattern, body weights of lesioned birds increased in parallel with food intake, but remained elevated throughout the 3-week postoperative period. During the peak period of hyperphagia in the lesioned group, food intake and body weight increases were two to three times greater in lesioned birds than in controls. After postoperative feed intake had stabilized, each bird received 5 daily i.c.v. injections of ovine PRL. Food intake and body weight increased dramatically in both groups in response to PRL treatment, and no group differences were observed in response to magnitude. We conclude that VMH destruction strongly perturbs feeding and body weight regulation in doves. However, VMH integrity is not essential for the expression of PRL-induced hyperphagia.     

Insulin infusion during a nocturnal fast suppresses the subsequent day-time intake

Much recent evidence suggests a dual and opposite action of insulin on food intake and body weight. Peripherally administered, long acting insulin stimulates weight gain and food intake. On the contrary intracerebroventricularly infused insulin decreases food intake and body weight. It has been suggested that the shift from the nocturnal hyperinsulinism and hyperphagia to the day-time hypoinsulinism and hypophagia depended on the action of insulin on the brain during the night. It has also been hypothesized that the absence of nocturnal hyperinsulinism due to fasting was partly responsible for the hyperphagia observed during the subsequent day-time. In the present experiment, insulin was infused intravenously at various low doses (0.01, 0.025, 0.05 U/hr) during a nocturnal fast. Its effects on the following diurnal free food intake were investigated. It was shown that the experimentally elevated plasma insulin induced a dose-dependent reduction in the day-time feeding response. It was concluded that this reduction is due to the chronic action on the brain of the high plasma insulin level induced by the infusion during the nocturnal fast.     

Induction of ventrolateral hypothalamic fatty acid oxidation in diabetic rats

Diabetic rats were used to test a previous hypothesis that alterations in ventrolateral hypothalamic (VLH) fatty acid oxidation observed in over- and underfed rats were a function of the animals' peripheral energy balance and not merely a function of their energy intake. Standard adaptations to the diabetic condition were exhibited in streptozotocin diabetic rats such as depressed body weights, hyperphagia and hyperglycemia, elevated serum free fatty acids, depressed insulin concentrations, depressed hepatic glucose oxidation and elevated hepatic fatty acid oxidation. Rates of VLH fatty acid oxidation to CO2 and to an acid, water-soluble fraction in diabetic rats were elevated relative to non-diabetic rats. The alterations in VLH fatty acid oxidation in diabetic rats were similar to changes previously observed in animals exhibiting a negative energy balance. The results were discussed with respect to the concept that VLH fatty acid oxidation was a component in the recognition of peripheral energy balance and, in part, served to alter the regulators of energy balance and food intake.     

Intermittent feeding and fasting reduces diabetes incidence in BB rats.

Food intake may be one of several factors which influence the risk of development of insulin dependent diabetes mellitus, but the influence of the pattern of food supply has not been studied previously. The aim of the present study was to investigate the effect of intermittent feeding and fasting upon diabetes in BB rats. This study included three groups. Group 1 served as control and included 77 animals, 79% became diabetic. In groups 2 and 3, after weaning, food but not water was withdrawn from the animals: 24 h twice a week in group 2; 24 h every second day in group 3. Group 2 included 40 BB rats, 50% (p < 0.004) became diabetic. Group 3 included 44 BB rats, 52% (p < 0.01) became diabetic. No differences were seen between sexes. Degree of insulitis was not influenced by changed food supply. Regarding blood glucose, no influence was seen among diabetic animals, among non-diabetic animals changed food supply reduced blood glucose values obtained at the end of the study. Intermittent feeding and fasting tended to reduce mean age at the time of diagnosis of diabetes, significance was reached only in female animals from group 3 compared to group 1. Body weight was obtained weekly. Intermittent feeding and fasting caused a reduced weight gain in group 2 as well as in group 3 compared to control animals; however, most pronounced in group 3 and also more pronounced among males compared to females. For pre-diabetic and non-diabetic animals comparable influence on body weight was seen. The main conclusion in the study is that intermittent feeding and fasting reduced diabetes incidence in BB rats.     

High-fat hyperphagia in neurotrophin-4 deficient mice reveals potential role of vagal intestinal sensory innervation in long-term controls of food intake

Neurotrophin-4 (NT-4) deficient mice exhibit substantial loss of intestinal vagal afferent innervation and short-term deficits in feeding behavior, suggesting reduced satiation. However, they do not show long-term changes in feeding or body weight because of compensatory behaviors. The present study examined whether high-fat hyperphagia induction would overcome compensation and reveal long-term effects associated with the reduced vagal sensory innervation of NT-4 mutants. First, modifications of a feeding schedule previously developed in rats were examined in wild-type mice to identify the regimen most effective at producing hyperphagia. The most successful schedule, which was run for 26 days, included access to a 43%-fat diet and pelleted chow every other day and access to only powdered chow on the alternate days. On high-fat access days mice consumed 25% more calories than mice with continuous daily access to the same high-fat diet and pelleted chow. This feeding regimen also induced hyperphagia in NT-4 deficient mice and their wild-type controls: on high-fat exposure days mutants consumed 35% more calories relative to continuous-access mutants, and wild types ate 25% more than continuous-access wild types. Moreover, on high-fat access days the alternating NT-4 mutants significantly increased caloric intake by 9% compared to alternating wild types. Thus, high-fat hyperphagia appeared to override compensation, permitting short-term changes in meal consumption by mutants that accrued into long-term changes in total daily food intake. This raises the possibility that intestinal vagal sensory innervation contributes to long-term, as well as to short-term regulation of food intake.     

Detection of neuronal activity and metabolism in a model of dehydration-induced anorexia in rats at 14.1 T using manganese-enhanced MRI and 1H MRS

In this study, hypothalamic activation was performed by dehydration-induced anorexia (DIA) and overnight food suppression (OFS) in female rats. The assessment of the hypothalamic response to these challenges by manganese-enhanced MRI showed increased neuronal activity in the paraventricular nuclei (PVN) and lateral hypothalamus (LH), both known to be areas involved in the regulation of food intake. The effects of DIA and OFS were compared by generating T-score maps. Increased neuronal activation was detected in the PVN and LH of DIA rats relative to OFS rats. In addition, the neurochemical profile of the PVN and LH were measured by (1) H MRS at 14.1T. Significant increases in metabolite levels were measured in DIA and OFS relative to control rats. Statistically significant increases in γ-aminobutyric acid were found in DIA (p=0.0007) and OFS (p<0.001) relative to control rats. Lactate increased significantly in DIA (p=0.03), but not in OFS, rats. This work shows that manganese-enhanced MRI coupled to (1) H MRS at high field is a promising noninvasive method for the investigation of the neural pathways and mechanisms involved in the control of food intake, in the autonomic and endocrine control of energy metabolism and in the regulation of body weight.