Search

Leptin administered intracerebroventricularly (ICV) or intrahypothalamically inhibits food intake (FI), however, to our knowledge the effects of leptin administration have only been examined in one extrahypothalamic site (dorsal raphe nucleus). Our objectives were t. (1) determine the FI effects of leptin administration into the anterior piriform cortex (APC), an area linked to the control of FI in amino acid (AA) deficiency, (2) examine leptin action during short term anorexia that develops in response to AA deficiency. Bilateral injections of leptin (0.25 μ) into the APC suppressed FI of a balanced diet between 6 and 12 h by 36% (p < 0.01) and over the first 12 and 24 h by 15% (p < 0.05). Bilateral administration of leptin (0.1 μg) inhibited FI between 12 and 24 h by approximately 48% (p < 0.05) on a threonine-imbalanced diet without significantly affecting FI on a threonine-corrected diet. The increase of plasma leptin concentrations in response to feeding a threonine-basal diet was greater than that following an AA imbalanced diet, suggesting that suppression of FI by an AA imbalanced diet is not mediated by an increase of leptin. Our results suggest that (1) administration of leptin into a brain area outside the hypothalamus suppresses FI, and (2) leptin is unlikely to play a selective role in the short term anorectic response to AA deficiency. These data are consistent with the hypothesis that endogenous leptin can act within the APC to modulate FI.

Fuel management is undertaken to mitigate the adverse consequences of wildfire. Finite mitigation budgets demand selective prioritization of forest stands for targeted fuel reduction treatments. A range of modeling methods have been used to identifiy optimal fuel treatment plans at various spatial and temporal scales of investigation; however, strategic analysis of fuel management alternatives can involve a range of limitations and challenges, including the prevalence of one-time solutions, static models lacking dynamic adaptability, and challenges in accounting for the stochastic nature of fire behaviour. To navigate these complexities, our study combines remote sensing-based analysis with a random search optimization algorithm to inform strategic fuel management and wildfire mitigation planning. For two communities in Alberta, Whitecourt and Hinton, we assessed landscape fire exposure within and around the built environment and rated hazardous fuels by the number of buildings they exposed (i.e., Building Exposure load, BEL). Through the assessment of BEL and the outcomes of the optimization algorithm, our model identified key areas for intervention, enabling a more informed allocation of mitigation resources. We found good alignment between expert-derived fuel treatment areas and our model-derived fuel reduction areas, PFRs, confirming the utility and relevance of our findings. The methodology is adaptable to diverse regional fuel characteristics and it also offers a phased implementation to assisting communities with financial constraints. The suggested systematic approach aids communities that lack local expertise in developing proactive fuel treatment strategies. Additionally, this study emphasizes the need to combine fuel treatment prioritization with community involvement, acknowledgment of potential local limitations, and financial planning to enhance its effectiveness and adaptability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: High- protein diets have become increasingly popular with various touted benefits. However, the extent to which protein quantity and source affects cognitive functioning through altering postprandial amino acid profiles has not been investigated. Further, whether all protein sources are similarly anorexigenic is uncertain. The objective of this study was to determine the influence of protein level and source on Barnes maze performance, satiety and plasma amino acid levels in male Sprague-Dawley rats., Methods: Rats were entrained to a meal-feeding schedule consisting of a 30 minutes meal, equivalent to 20% of average daily intake, one hour into the dark phase then ad libitum access to food for 5 h. On test days, rats received one of three isocaloric diets as their first meal, hereafter referred to as Egg White (EW), Wheat Gluten (WG), or Basal, and then were measured for cognitive performance, feeding behavior, or plasma amino acid levels via jugular catheter. Percentage energy from protein was 35% for both EW and WG and 20% for Basal with equal amounts provided by EW and WG proteins., Results: Rats provided EW performed similarly to Basal on the Barnes maze, whereas WG performed worse. EW increased satiety, whereas WG reduced satiety relative to Basal. Both EW and WG increased postprandial concentrations of large neutral and branched chain amino acids relative to Basal, but in EW, concentrations were slower to peak, and peaked to a higher level than WG., Discussion: Results demonstrate the importance of protein source for cognition and satiety enhancing effects of a high-protein meal.

Noradrenergic activity in the ventromedial hypothalamus (VMH) is increased and activates a sympathoadrenal response during hypoglycemia. How the rate at which hypoglycemia develops affects local glucose concentrations and norepinephrine (NE) release was evaluated by placing microdialysis probes into the VMH of male Sprague-Dawley rats receiving insulin (20 mU·kg(-1)·min(-1)) and variable glucose infusions. During a first episode of hypoglycemia, interstitial glucose concentrations in the VMH generally declined at the same rate as plasma glucose; however, the faster hypoglycemia developed, the greater the magnitude of the initial NE release in the VMH (r(2) = 0.72, P < 0.001). Following recurrent episodes of hypoglycemia, VMH glucose decreased at a slower rate than plasma glucose, and the initial NE release was attenuated at the same rates of blood glucose decline. The plasma glucose threshold for the initial NE release in VMH was similar for all groups (∼3.23 mM); however, the VMH glucose threshold was stimulated and was lower when blood glucose declined more slowly (0.86 ± 0.06 vs. 1.06 ± 0.04 mmol/l, P < 0.01). The timing of the initial increase in NE release in VMH corresponded with an increase in plasma epinephrine during the first episode of hypoglycemia but not following recurrent hypoglycemia. Although a decrease in VMH glucose concentration is required for noradrenergic activation in VMH, there does not appear to be a set glucose threshold within the VMH for activation of this response.

Some studies suggest that increased consumption of soy protein hydrolysates may cause body weight loss but the mechanism of action is unknown. The objective of this investigation was to determine whether intracerebroventricular (i.c.v.) infusion of soy protein hydrolysates decrease food intake and body weight. Adult male Sprague Dawley rats (n = 24) received i.c.v. injections of soy hydrolysate I (SH I) or soy hydrolysate II (SH II) three times weekly for 2 weeks. Krebs solution and leptin were used as negative and positive controls respectively. SH I (6.5-20 kDa with a strong band at 14 kDa) was produced by hydrolysis with alcalase, and SH II (approximately 2 kDa) was obtained by hydrolysis and ultrafiltration. Leptin successfully reduced body weight (-1.60 g) 24 h (p = 0.0093) after the third injection. SH I caused significant (p = 0.0009) decreases in body weight (-1.70 g) 24 h after the third injection but not after 48 h. SH II showed a tendency to prevent body weight gain but this effect was short of statistical significance (p < 0.40). Food intake was not affected by any of the soy hydrolysate treatments but leptin injection did cause significant decreases in food intake (p < 0.05). Data suggest that soy alcalase hydrolysate can decrease, in the short term, the rate of body weight gain independently of food consumption. This preliminary data show that soy peptides may play a role on body weight regulation, possibly by increasing energy utilization.

Food intake is stimulated following administration of orexin-A into the perifornical region of the lateral hypothalamus (LH/PFA). Orexin neurons originating in the LH/PFA interact with a number of hypothalamic systems known to influence food intake, including glutamatergic neurons. Glutamatergic systems in the LH/PFA were demonstrated to initiate feeding through N-methyl-d-aspartic acid (NMDA) receptors. Male Sprague-Dawley rats fitted with brain guide cannulas to the LH/PFA were used in two experiments. In the first experiment, a combination microdialysis/microinjection probe was used to deliver artificial cerebrospinal fluid (aCSF) or 500 pmol of orexin-A into the LH/PFA. Orexin-A increased interstitial glutamate to 143 +/- 12% of baseline (P < 0.05), which remained elevated over the 120-min collection period. In the second experiment, the NMDA receptor antagonist d-2-amino-5-phosphonopentanoic acid (d-AP5; 10 nmol) was administered before orexin-A. The orexin-induced increase in food intake (from 1.1 +/- 0.4 to 3.2 +/- 0.5 g, P < 0.05) during the first hour was absent in rats receiving d-AP5 + orexin-A (1.2 +/- 0.5 g). There was no effect of d-AP5 alone on food intake. These data support glutamatergic systems in the LH/PFA mediating the feeding response to orexin-A through NMDA receptors.

OBJECTIVE-To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K(+) channels (K(ATP) channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K(ATP) channels in the VMH alter local GABA levels and whether the effects of modulating K(ATP) channel activity within the VMH can be reversed by local modulation of GABA receptors. RESEARCH DESIGN AND METHODS-Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the K(ATP) channel opener diazoxide, 3) the K(ATP) channel closer glybenclamide, 4) diazoxide plus the GABA(A) receptor agonist muscimol, or 5) glybenclamide plus the GABA(A) receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis. RESULTS-As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of K(ATP) modulators were reversed by GABA(A) receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%. CONCLUSIONS-Our data suggests that K(ATP) channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.

The neuromodulatory peptides orexin A and B are important central nervous system regulators of appetite. We previously identified the rostral lateral portion of the hypothalamus as an area important to orexin A feeding regulation. As gamma-aminobutyric-acid (GABA) within the lateral hypothalamus also mediates feeding, we sought to determine the relationship between orexin and GABA signaling within this site. Adult male Sprague-Dawley rats were implanted with cannulae directed to the rostral lateral hypothalamus and saclofen (GABA-B receptor antagonist), biccuculine (GABA-A receptor antagonist) or muscimol (GABA-A receptor agonist) were injected prior to orexin A. Both GABA antagonists failed to significantly affect orexin A-induced feeding, but muscimol significantly and dose dependently inhibited orexin A-induced feeding. Using in vivo microdialysis GABA release within this region significantly dropped during the first hour following orexin A administration, coinciding with orexin A-induced feeding. Together, these data indicate that orexin A may influence food intake by decreasing GABAergic tone within the rostral lateral hypothalamus.

Proinflammatory cytokines inhibit learning and memory but the significance of interleukin-6 (IL-6) in acute cognitive deficits induced by the peripheral innate immune system is not known. To examine the functional role of IL-6 in hippocampus-mediated cognitive impairments associated with peripheral infections, C57BL6/J (IL-6(+/+)) and IL-6 knock-out (IL-6(-/-)) mice were trained in a matching-to-place version of the water maze. After an acquisition phase, IL-6(+/+) mice injected intraperitoneally with lipopolysaccharide (LPS) exhibited deficits in working memory. However, IL-6(-/-) mice were refractory to the LPS-induced impairment in working memory. To determine the mechanism by which IL-6 deficiency conferred protection from disruption in working memory, plasma IL-1beta and tumor necrosis factor alpha (TNFalpha), c-Fos immunoreactivity in the nucleus of the solitary tract (NTS), and steady-state levels of IL-1beta and TNFalpha mRNA in neuronal layers of the hippocampus were determined in IL-6(+/+) and IL-6(-/-) mice after injection of LPS. Plasma IL-1beta and TNFalpha and c-Fos immunoreactivity in the NTS were increased similarly in IL-6(+/+) and IL-6(-/-) mice after LPS, indicating high circulating levels of IL-1beta and TNFalpha and activation of vagal afferent pathways were not sufficient to disrupt working memory in the absence of IL-6. However, the LPS-induced upregulation of IL-1beta and TNFalpha mRNA that was evident in hippocampal tissue of IL-6(+/+) mice was greatly attenuated or entirely absent in IL-6(-/-) mice. Collectively, these data suggest that humoral and neural immune-to-brain communication pathways are intact in IL-6-deficient mice but that, in the absence of IL-6, the central cytokine compartment is hyporesponsive.

Carbohydrate is a preferred macronutrient of rats during the early dark phase and associated with an increase in norepinephrine (NE) and neuropeptide Y (NPY) in the paraventricular nucleus (PVN). Macronutrient choice is altered during zinc deficiency (ZD). The relationship between NE activity in the PVN and macronutrient choice during early dark was evaluated in rats fed zinc adequate (ZA) or ZD diet for 14 days. Total caloric intake was similar for ZA and ZD groups (-20 kJ) but ZA rats selected 63 +/- 5% of calories as carbohydrate while ZD rats selected 53 +/- 5% of their calories from protein (p < 0.01). Pair-fed (PF) rats selected 62 +/- 5% of calories as carbohydrate. Noradrenergic activity was lower (p < 0.01) in ZD and PF compared to ZA. The association between increased NE in the PVN at dark onset and selection of carbohydrate is not supported by the present results.

During insulin-induced hypoglycemia, there is an increase in extracellular norepinephrine (NE) in the ventromedial hypothalamus (VMH). This brain area is known to play an important role in integrated hormonal and behavioral responses to systemic hypoglycemia. Selective glucoprivation restricted to the VMH is both necessary and sufficient to initiate secretion of counterregulatory hormones. The present study was designed to investigate whether increased release of NE in the VMH depends on detection of glucoprivation localized in this area. In awake, chronically catheterized male Sprague-Dawley rats, extracellular NE in the VMH was monitored using 1-mm microdialysis probes perfused with Krebs Ringer buffer (KRB) or KRB + 100 mM d-glucose (d-Glc). During insulin-induced hypoglycemia (glycemic nadir approximately 2.4 mM) extracellular NE was increased to >160% of baseline (P < 0.01) only in the KRB + insulin group. There was no increase in NE from baseline when glucose was added to the perfusate to maintain euglycemia at the periprobe environment. The sympathoadrenal response to hypoglycemia, present in the KRB + insulin group, was attenuated in the d-Glc + insulin group. The present results confirm that noradrenergic activation in the VMH during systemic hypoglycemia depends on detection of glucoprivation locally in this area. These data provide additional support for the importance of increased noradrenergic activity in the VMH in the counterregulatory hormonal responses to hypoglycemia.

The literature on the effects of ovarian hormones on rodent learning and memory is mixed. In this study, the authors examined the role of task stressfulness. Female hooded rats were tested during proestrus or estrus on the hidden-platform water maze in warm (33 degrees C) or cold (19 degrees C) water. There were no effects of cycle or temperature, but estrous phase interacted with temperature such that proestrous rats performed better overall under the warm condition and estrous rats performed better under the cold condition. Plasma corticosterone, measured after 4 trials, varied significantly with estrous phase. Water temperature, perhaps through stress, influences the effect of estrous phase on water maze performance.

This study evaluated whether attenuation of sympathoadrenal responses to recurrent hypoglycemia is mediated by diminished noradrenergic activity in the hypothalamus. Male Sprague-Dawley rats received either once daily insulin (1.0 units/kg) injections or an equal administration of saline for 3 days. Both groups received an administration of insulin on the fourth day, during which blood glucose and plasma catecholamines were determined, and extracellular norepinephrine (NE) in the ventromedial hypothalamus (VMH) or paraventricular hypothalamic nucleus (PVN) was monitored with microdialysis. The peak response of plasma epinephrine to insulin-induced hypoglycemia (nadir approximately 3.2 mmol/l) was significantly reduced during the fourth hypoglycemic episode (774 +/- 134 pg/ml) compared with the first episode (2,561 +/- 410 pg/ml, P < 0.001). Baseline levels of extracellular NE were elevated approximately 25% (P = 0.07) in the VMH and approximately 46% (P = 0.03) in the PVN after multiple hypoglycemic episodes. There was no difference in noradrenergic activity during the first or fourth hypoglycemic episode in either brain area. The reduced sympathoadrenal output after recurrent hypoglycemia is likely postsynaptic from hypothalamic NE release or is mediated via a collateral pathway.

The activity of neurons in the ventromedial hypothalamus (VMH) important for initiating compensatory responses to hypoglycemia is influenced by ambient glucose concentration. In the present study, we used in vivo microdialysis to evaluate interstitial glucose concentrations in rat VMH under various glycemic conditions. Using the zero-net-flux method, steady-state glucose concentration in the VMH was approximately 20% of blood glucose (approximately 1.4 mmol/l) in fed rats but approximately 14% of blood glucose (approximately 0.7 mmol/l) in overnight-fasted rats. During moderate hypoglycemia VMH glucose declined in parallel with blood glucose; however, VMH glucose decreased to a greater degree than blood glucose during a more severe hypoglycemic episode, falling to 10 +/- 1.2% of blood levels (P < 0.01). To determine whether VMH glucose concentrations were influenced by recurrent episodes of hypoglycemia a second zero-net-flux study was conducted. Steady-state glucose concentrations in the VMH were approximately 20% lower after three episodes of recurrent hypoglycemia, a value 17.8 +/- 0.8% of blood glucose, although the relative change in VMH glucose levels during the first and fourth hypoglycemic episodes were similar. From these results, we conclude that interstitial glucose concentrations in the VMH are not maintained at a constant level and are more dynamic than previously proposed.

Three-choice macronutrient intake studies indicate that zinc-deficient (Zn-) rats selectively decrease intake of carbohydrate. Because glucoprivic stimuli increase food intake and selection for carbohydrate, the ability of Zn- rats to respond to glucoprivation induced by 2-deoxy-D-glucose (2-DG) was tested. Rats were fed a Zn-adequate (Zn+) or Zn- diet. In part 1, rats were challenged with 0, 250, or 400 mg 2-DG/kg BW (i.p.) after zinc deficiency was established. In part 2, rats received saline or 2-DG while zinc deficiency was being induced and then after deficiency was established. Food intake was increased after injection of 2-DG to Zn+ rats; however, food intake was not higher after 2-DG administration to Zn- rats. A dose-response test for 2-DG further confirmed these results. In part 2, it was found that Zn- rats lose the response to 2-DG administration when zinc deficiency-induced anorexia begins, after 3 days of consuming a zinc-deficient diet. It appears that the ability to sense blood glucose concentrations may be impaired during zinc deficiency, and this impairment could be a part of the anorexia that develops during zinc deficiency in the rat.

Alterations in neurochemical activity in the paraventricular nucleus (PVN) of the hypothalamus may account for decreased intake of zinc-deficient diets. Male Sprague-Dawley rats were fed zinc-deficient (ZD) or zinc-adequate (ZA) diet for 14 d before samples of extracellular fluid in the PVN were collected by microdialysis or push-pull perfusion. A third set of rats was pair-fed (PF) an amount of ZA diet equal to the intake of ZD rats. Samples were collected over a 2-h period spanning the transition from light to dark. All rats then consumed the zinc adequate diet ad libitum for 3 d before a second set of samples was collected. The increase in extracellular norepineprhrine (NE) during h 1 of the dark period to 147 +/- 13% of baseline (P < 0.05) was apparent only in ZA rats at d 14. After the 3-d repletion period, the increase in NE at dark onset occurred in all three groups. An increase in extracellular neuropeptide Y (NPY) at dark onset to 174 +/- 32% of baseline in rats fed ZA (P < 0.01) was measured in all three groups at both d 14 and 17. Basal NPY concentrations were significantly elevated in PF rats on d 14 (7.45 +/- 2.01 vs. 0.58 +/- 0.23 pmol/L, P = 0.01) and returned to ZA levels by d 17. The activities of the NE and NPY systems in the PVN were altered in rats fed a zinc-deficient diet; however, it is unclear whether the disruption in the NE and NPY neural systems in the PVN results in the altered feeding behavior accompanying zinc deficiency.

Noradrenergic and GABAergic systems in the medial hypothalamus influence plasma glucose and may be activated during glucoprivation. Microdialysis probes were placed into the ventromedial nucleus (VMH), lateral hypothalamus (LHA), and paraventricular nucleus (PVH) of male Sprague-Dawley rats to monitor extracellular concentrations of norepinephrine (NE) and GABA. During systemic hypoglycemia, induced by insulin (1.0 U/kg), NE concentrations increased in the VMH (P < 0.05) and PVH (P = 0.06) in a bimodal fashion during the first 10 min and 20-30 min after insulin administration. In the VMH, GABA concentrations increased (P < 0.05) in a similar manner as NE. Extracellular NE concentrations in the LHA were slightly lower (P = 0.13), and GABA levels remained at baseline. The increases in NE and GABA in the VMH were absent during euglycemic clamp; however, NE in the PVH still increased, reflecting a direct response to hyperinsulinemia. On the basis of these data, we propose that the activity of noradrenergic afferents to the medial hypothalamus is increased during hypoglycemia and influences the activity of local GABAergic systems to activate appropriate physiological compensatory mechanisms.

Growth hormone-releasing factor (GRF) is thought to perform two distinct functions within the brain. GRF synthesized in the median eminence (ME) stimulates the release of growth hormone (GH) from the pituitary, while GRF in the suprachiasmatic nucleus and median preoptic area (SCN/MPOA) may stimulate selection of dietary protein. These two functions may be coupled to regulate and enhance growth. During zinc repletion, a period characterized by increased protein intake and accelerated growth, we examined this coupling by measuring GRF peptide content in hypothalamic sites and neutralizing GRF function by infusing anti-GRF antibody into the hypothalamus during zinc repletion. Total GRF content and GRF content in the ME and SCN/MPOA were decreased in zinc-deficient (Zn-) rats compared to zinc-adequate (Zn+) rats (P < 0.05). There were no differences in GRF content during zinc repletion in either nuclei. Subsequently, we investigated the macronutrient feeding patterns of rats chronically infused with anti-GRF IgG into the lateral ventricle of the brain during zinc repletion. All Zn- and Zn+ rats administered anti-GRF IgG exhibited a reduction in protein intake during zinc repletion. The Zn- rats receiving anti-GRF-IgG consumed equal amounts of total diet compared to those receiving vehicle during the repletion period however they consumed less carbohydrate (P < 0.05) and considerably more fat (P < 0.02). There were no significant differences in carbohydrate or fat intake in Zn+ rats receiving anti-GRF antibody. These results suggest that GRF likely directs protein intake during normal growth, but may interact with additional appetite-controlling neuropeptides during zinc repletion.

Noradrenergic mechanisms in the hypothalamus may be involved in counterregulatory responses to glucoprivic episodes. After 2-deoxy-D-glucose (2-DG; 1.2 mmol/kg iv), extracellular norepinephrine (NE) concentration in the ventromedial hypothalamus (VMN) increased in a bimodal fashion to 251 +/- 39% (P < 0.001) and 150 +/- 17% (P < 0.001) of baseline during the first 30 min. In the lateral hypothalamus (LHA), NE decreased by 30 min (61 +/- 4%, P < 0.001) and no consistent changes were measured in the paraventricular nucleus (PVN). Because the NE response in the VMN after 2-DG followed the same pattern as GABA, the interaction between NE and GABA was evaluated. In the VMN, GABA had little effect on extracellular NE concentrations but NE increased GABA concentrations 166 +/- 13%, (P < 0.01). In the presence of yohimbine (alpha(2)-adrenoceptor antagonist) the first GABA peak after 2-DG was absent, and the second GABA peak was absent in the presence of timolol (beta-adrenoceptor antagonist). These results support an interaction among noradrenergic and GABAergic systems in the VMN during glucoprivation and that increased NE mediates the increase in extracellular GABA after 2-DG.

The anterior piriform cortex (APC) is essential for the anorectic reactions to an amino acid-imbalanced diet, and it also responds to repletion of the limiting amino acid. In the present study, we examine the dynamic changes of the interstitial dopamine metabolites in the APC following feeding of either an amino acid-corrected or -imbalanced diet. Microdialysates, collected from the APC, were analyzed using HPLC with electrochemical detection. The concentrations were 19.7 +/- 4.8 microg/L for 3, 4-dyhydroxyphenylacetic acid and 25.1 +/- 4.4 microg/L for homovanillic acid, respectively, in the baseline dialysates. After diet treatments, no significant changes occurred in 3, 4-dyhydroxyphenylacetic acid in the corrected (n = 7) or imbalanced (n = 9) groups vs. the basal group (n = 7). However, after feeding the threonine-corrected diet, the concentration of homovanillic acid was significantly less (P < 0.01) than after the basal and imbalanced diets. The homovanillic acid level in the corrected group was already significantly lower than in the basal group by 20 min (P < 0.05), and reached its lowest level at 70 min (P < 0.05). The concentrations of homovanillic acid in the corrected group remained at this low level until the end of the experiment. The present results introduce the idea that the dopaminergic system is involved in the feeding responses to essential amino acid repletion.

Zinc deficiency reduces intake and produces an unusual approximately 3.5-d cycle of intake in rats. The mechanism underlying the anorexia and cycling has not yet been defined; current hypotheses suggest that alterations in amino acid metabolism and neurotransmitter concentrations may be a part of this anorexia. Recent reports indicate that appetite-stimulating neuropeptide Y (NPY) may be elevated during zinc deficiency. This suggests that a resistance to NPY may exist during zinc deficiency because NPY levels are high, yet appetite is low. The purpose of this study was to measure NPY peptide and mRNA concentrations during zinc deficiency in specific nuclei of the hypothalamus in which peptide and mRNA for NPY are known to be associated with appetite, and also to determine whether zinc-deficient rats are responsive to central infusions of NPY. Both NPY peptide levels in the paraventricular nucleus and NPY mRNA levels in the arcuate nucleus were higher (P < 0.05) in zinc-deficient rats than in zinc-adequate rats. When rats were administered exogenous NPY to the paraventricular nucleus, both zinc-deficient and zinc-adequate rats responded similarly by increasing food intake. These results suggest that NPY is elevated during zinc deficiency in an attempt to restore normal food intake levels, rather than being reduced and thereby contributing to the anorexia associated with zinc deficiency. During zinc deficiency, NPY receptors are able to bind NPY and initiate an orexigenic response.

Hepatic metabolism of glucose and other nutrients influences feeding behavior. The present study was conducted to confirm prandial decreases in hepatic glycogen concentrations following a short-term fast. Male Sprague-Dawley rats were fasted 6-12 h during the light phase before having access to chow for one or two 20-min meals at the beginning of the dark phase. Plasma glucose and insulin concentrations in hepatic and portal venous blood and hepatic glycogen concentrations prior to and at the end of each meal were compared. Glucose concentration in the hepatic vein was greater than that in the portal vein prior to the meals but not at the end of the meal. Insulin levels were higher in the portal vein than the hepatic vein pre- and postprandially. Hepatic glycogen concentrations increased after each meal in younger (2-month-old) rats but not older (6-month-old) rats. Fasting levels of hepatic glycogen were lower in the younger rats than the older rats; however, the increase in hepatic glycogen was not due to differences in baseline glycogen concentrations at the start of the meal. The reported prandial decreases in hepatic glycogen of fasted rats were not apparent in this study. Because of the difference between 2- and 6-month-old rats in periprandial hepatic glycogen metabolism after a short-term fast, the age of the animal needs to be considered if the dynamics of liver glycogen metabolism are to be incorporated into a model of food intake regulation.

The diminished sensitivity of genetically obese (fa/ fa) Zucker rats to the glucoprivic agent 2-deoxy-D-glucose (2-DG) may involve impaired release of the neurotransmitter gamma-aminobutyric acid (GABA) in discrete regions of the hypothalamus. Extracellular GABA concentrations in the medial (MH) and lateral (LH) hypothalamus of lean (Fa/Fa) and age-matched obese (fa/fa) male Zucker rats before and after 2-DG (1.2 mmol/kg i.v.). Basal GABA concentrations were higher (P < 0.05) in the MH of obese vs. lean rats. No differences were noted in LH GABA levels between lean and obese rats or in baseline extracellular GABA levels between brain regions in lean rats. In lean rats, a characteristic bimodal increase in GABA concentrations was apparent in the MH, whereas GABA concentrations decreased in the LH during the 60 min after 2-DG. No changes in GABA concentrations in dialysate from the MH or LH of obese rats were observed after 2-DG. The alterations in basal activity and responsiveness to glucoprivic stimuli by GABAergic system in the MH of obese rats may reflect a defect in central glucostatic control of food intake and, ultimately, in the hypothesized autonomic imbalance in fa/fa Zucker rat.

When total parenteral nutrition (TPN; containing glucose, fat, and amino acids; caloric ratio 50:30:20) providing 100% of the rat's daily caloric intake is given for 3-4 days, food intake rapidly decreases by approximately 85%. After stopping TPN, there is a lag period of 3-4 days before food intake returns to previous level, which appears to be related to fatty acid oxidation and fat deposition. Carnitine plays a key role in the oxidation of fatty acids, and was demonstrated to reduce fat deposition in rats receiving TPN, by increasing beta oxidation. We therefore investigated whether rats receiving TPN supplemented with carnitine may prevent either the decrease or speed up the resumption or normalization of food intake, after TPN is stopped. Fourteen adult Fischer-344 rats had a central venous catheter inserted. After 10 recovery days, controls (n = 7) were infused with TPN providing 100% of rat's daily caloric intake for 3 consecutive days, followed by 4 more days of normal saline. The carnitine group (n = 7) received the same solution, but which provided 100 mg/kg/day carnitine. Daily food intake was measured and data were analyzed using ANOVA and Student's t-test. Both parenteral solutions depressed food intake maximally by almost 90% by day 3. Carnitine accelerated the normalization of food intake by decreasing the lag period by 1 day. We conclude that the addition of carnitine enhanced the normalization of post-TPN food intake and argue that this may be on the basis of enhanced fatty acid oxidation, a substrate known to play a significant role in the anorexia induced by TPN.

Whether in tumor-bearing rats a temporal relationship exists between an increase in plasma free tryptophan (FTRP), an increase in brain serotonin (5-HT), and onset of anorexia was studied. Rats were assigned to three groups: tumor-bearing (TB), pair fed (PF), and controls. Food intake was recorded daily. In TB rats anorexia developed on Day 18 and thereafter food intake decreased progressively until end of study. After tumor inoculation, tumor became palpable on Day 10 and continued to grow exponentially until end of study. Rats were killed on Days 6, 10, 16, 18, 22, and 26 to determine plasma FTRP, FTRP/LNAA, and brain 5HT and compared to PF and controls. On Day 6, before tumors became detectable, FTRP and FTRP/LNAA were increased (P < 0.05) in TB rats vs controls. Both continued to increase so that by Day 18 when food intake had started to decrease (P < 0.05), brain 5-HT increased and correlated with the onset of anorexia (R2 = 0.6, P < 0.05). Increases in plasma FTRP the precursor to brain 5-HT occurred in TB rats before physical appearance of tumor and increased until an increase in brain 5-HT occurred, leading to anorexia.

To determine if endogenous gamma-aminobutyric acid (GABA) is secreted by a pancreatic beta-cell-derived cell line and to determine the effects of glucose on GABA release, beta TC6 cultures were incubated in the presence of 1 or 10 mmol/l glucose for 12 h and then subjected to a 2-h secretion test in Krebs-Ringer buffer containing 1 or 10 mmol/l glucose. beta TC6-conditioned medium was collected at 15, 30, 60, and 120 min after glucose stimulation for GABA analysis by high pressure liquid chromatography-electrochemical detection. After 30 min, medium GABA concentrations were significantly higher (p < 0.05) in cultures that were exposed to high glucose during both the 12-h incubation period and the 2-h secretion test than in the remaining three glucose combinations. To address possible roles of beta-cell-derived GABA, the effect of GABA on glucagon secretion from pancreatic alpha TC6 cells was tested at concentrations released from beta TC6 cells. Inhibition of glucagon secretion by alpha TC6 cells was observed in the presence of GABA at concentrations equivalent to concentrations secreted by beta TC6 cells. The inhibitory effects of GABA on glucagon secretion by alpha TC6 cells were blocked by the GABAA receptor antagonist bicuculline and were dissociated from the inhibitory effects of glucose. Together, these results provide the first documentation that endogenous GABA is released from a highly differentiated beta-cell line and that glucose and GABA independently attenuate glucagon secretion by a pancreatic alpha-cell line.

gamma-Aminobutyric acidergic (GABA) mechanisms in the ventral hypothalamus may be involved in counterregulatory responses to glucoprivic episodes. Microdialysis probes (1 mm) were placed into the ventromedial hypothalamus (VMH) or lateral hypothalamus (LHA) of male Sprague-Dawley rats 3.5 h before 2-deoxy-D-glucose (2-DG) administration (200 mg/kg i.v.). Probes were perfused (2 ml/min) with Ringer solution, and samples were collected every 10 min from 30 min before to 60 min after 2-DG. By 30 min after 2-DG, GABA concentration in VMH dialysate increased in a bimodal fashion to 204 +/- 36% (P < 0.01) of baseline, and GABA concentration in LHA dialysate decreased to 77 +/- 4% (P < 0.01) of baseline. The changes in dialysate GABA concentrations occurred concurrently with the animals eating and returned to baseline by 60 min. When animals were denied access to food after 2-DG, the decrease in LHA GABA was not apparent and VMH GABA remained approximately 15% above baseline at the end of the sample period. The results of the present study provide evidence that GABAergic systems in the ventral hypothalamus are responsive to alterations in glucose status.

Peripherally infused interleukin-alpha (IL-1 alpha) reduces food intake. Since the innervated liver modulates eating activity via the vagus, we investigated the role of the hepatic vagus in the etiology of IL-1 alpha induced anorexia. Ten male Fischer 344 rats were randomly assigned to hepatic vagotomy (HX-IL-1 group) or sham operation (Sham-IL-1 group), and an internal jugular catheter was inserted in all rats. Another six sham operated rats receiving normal saline i.v. throughout the study period served as general controls. After a 10-day recovery period, HX-IL-1 and Sham-ILI-1 rats were infused with 3 micrograms day-1 of IL-1 alpha for 3 days, followed by a 4 day infusion of saline. During the IL-1 alpha infusion, food intake was reduced at a similar rate and by a similar amount in both vagotomized and sham-operated rats. When IL-1 alpha infusion was stopped, food intake normalized at a similar rate in both HX-ILI-1 and Sham-IL-1 groups. These data indicate that the hepatic vagus is not involved in the etiology of IL-1 alpha induced anorexia.

The relationship between surfeit caloric consumption during intravenous infusion of a parenteral nutrition solution providing 100% daily caloric needs (PN-100; glucose:fat:amino acid = 50:30:20), carcass adiposity, and postinfusion food intake was evaluated. Rats received saline (control) or PN-100 for 4 days via jugular vein. PN-100 rats were either allowed or denied access to chow during the infusion period. When food was available during the 4 days of PN-100, total cumulative caloric intake, eaten and infused, was 40% higher than controls (p < 0.01). Percent carcass adiposity was increased from 8.8% to 11.6% (p = 0.04), and there was a 3-day delay before food intake returned to baseline. When caloric intake was limited to that provided by PN-100, carcass adiposity was not increased and food intake was 86% of baseline during the first 24 h after stopping PN-100. Delayed return of normal food intake following PN-100 is the likely consequence of excess caloric ingestion during the PN-100 infusion period. The surfeit caloric intake resulted in increased carcass adiposity.

During parenteral nutrition (PN) there is an incomplete compensatory decrease in oral caloric intake. The effects of two factors influencing nutrient utilization, diurnal timing of PN infusion and composition of available diet, on compensatory feeding were investigated in male rats receiving 100% of daily caloric need as PN (PN-100). Compensation for infused calories increased from 70 to 80% (P < 0.05) when the timing of infused kilocalories more closely matched diurnal pattern of oral kilocalories intake (e.g., 75% kcal daily during the dark phase, 25% during the light phase). There was a similar degree of compensation when the diet and PN-100 had the same caloric distribution (50% kcal from carbohydrate, 30% from fat, and 20% from protein). Adjusting the diurnal timing of infused calories and diet composition concurrently further increased compensation for infused calories from 70 to 90% (P < 0.05). In the rat PN-100 model, compensation for infused calories is improved by adjusting the temporal pattern of infusions and diet composition.

Food intake is reduced during parenteral nutrition (PN) proportionally to the amount of calories or composition of the solution infused. The relative importance of infused glucose and lipid, 50 and 30% of PN kilocalories, respectively, in reducing food intake during PN was examined. Glycolysis, fatty acid oxidation, or both were acutely disrupted with 2-deoxy-D-glucose (2-DG) and mercaptoacetate (MA). Rats receiving intravenous infusions of saline or a PN solution providing 100% of total daily calories (PN-100) received a single intraperitoneal injection of saline, 2-DG, and/or MA during the early light phase. 2-DG (1.4 or 2.2 mmol/kg) did not initiate feeding in PN-100 rats, although hyperglycemia was evident in all rats 1 h after 2-DG. Food intake of PN-100 rats after MA (0.4 mmol/kg) was approximately 50% that of control rats. When 2-DG (1.4 mmol/kg) and MA (0.4 mmol/kg) were administered concomitantly, PN-100 and control rats consumed the same amount of food. During PN-100, rats appeared to be more sensitive to losing metabolic energy derived from lipid than from glucose.

During parenteral nutrition (PN) glucoprivic-induced feeding appeared to be neutralized by the oxidation of infused fatty acids. With the use of a latin-square design, the feeding response to 2-deoxy-D-glucose (2-DG) and/or 2-mercaptoacetate (MA) was evaluated in male Sprague-Dawley rats with hepatic branch vagotomy (HV) or sham operations (SO). Rats received continuous infusions of 0.9% saline or PN providing 100% of daily caloric needs (PN-100) for four consecutive days. During PN-100, food intake was stimulated by 2-DG in HV rats and when fatty acid oxidation was simultaneously inhibited by MA. 2-DG-induced hyperglycemia was apparent under all conditions. Lipoprivic-induced feeding and increased plasma free fatty acid concentrations were absent in HV rats, whether MA was administered alone or with 2-DG. The feeding response to glucoprivic challenges is influenced by the relative availability of alternate energy sources. The lack of feeding response to 2-DG during PN-100 is mediated by vagal input of hepatic fatty acid oxidation status.

To determine whether brain glycogen concentrations change during parenteral nutrition, Fischer 344 rats with jugular vein catheters received 0.9 N saline or parenteral nutrition providing 100% of daily calories (PN-100). Rats were killed after 4 days of PN-100 and serially after PN-100 was stopped. Food intake decreased during PN-100 to approximately 15% of control, but total kilocalories eaten and infused over the 4-day PN-100 period was approximately 130% of control. Food intake of PN-100 rats remained low for 3-4 days post-PN-100. At the end of the 4-day PN-100 period, plasma glucose and insulin (P = 0.01) and whole brain glycogen (P < 0.005) were higher than but similar to control within 24 h of PN-100 being stopped. When PN-100 rats were not allowed to eat during the infusion period, plasma glucose was lower, plasma insulin higher, and brain glycogen content the same as in control rats after 4 days of PN-100. The increased brain glycogen was the likely consequence of the hyperglycemia and hyperinsulinemia during PN-100 and was not causally associated with the reduced food intake either during or immediately after PN-100.

The effects of time before feeding and dose of dietary-limiting amino acids (DLAA) injected into the prepyriform cortex (PPC) on intake of amino acid-imbalanced diets were evaluated. Intake of imbalanced diet was increased from approximately 50% to approximately 75% of baseline when an optimal amount of DLAA (1 nmol L-isoleucine or 2 nmol L-threonine) was injected immediately prior to feeding. Injections made several hours prior to feeding were more effective, increasing intake of imbalanced diets to approximately 85% of baseline. Delivering two half-optimal doses of DLAA, several hours apart, increased intake of imbalanced diet only to the same level as a single injection of the optimal dose immediately prior to feeding. The increase in intake of a threonine-imbalanced diet after injecting 2 nmol threonine 6 h prior to feeding was abolished if an additional 2 nmol threonine was injected immediately prior to feeding. It appears that it is the sum of the changes in tissue DLAA concentrations in the PPC that are recognized and influence food intake when amino acid imbalanced diets are fed.

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.

Ingestion of imbalanced amino acid diets (IMB) has been associated with a decrease in norepinephrine (NE) concentration in the prepyriform cortex (PPC), an area essential for the anorectic response to IMB. Decreased NE could result from activity-induced release (and subsequent metabolism) of the transmitter. If activity of the NE system is important in the rat's anorectic response to IMB, reduced NE activity should result in increased IMB intake. Therefore, the feeding response to IMB was measured after injecting clonidine (Clon) into the PPC to inhibit NE release. At 3 and 6 h after Clon (1.0 and 1.5 micrograms/rat) injections, IMB intake was increased from 69 (the usual response to IMB in untreated animals) to > 100% of control intake. Effective injection sites did not include the gustatory neocortex, an area important for conditioned taste aversions. Thus activation of the NE system in the PPC may be associated with the initial reduced intake of IMB, suggesting that NE activity in the PPC has a role in the neural mechanisms that subserve recognition of amino acid deficiency.

The association among changes in glucose status, glutamate decarboxylase (GAD) activity, and food intake was evaluated in several hypothalamic areas of streptozotocin-diabetic rats fed a low- (12% of calories as fat) or high-fat diet (59% of calories as fat). Control rats consumed approximately 90 kcal/24 h of either diet, whereas diabetic rats consumed approximately 150 kcal/24 h of the low-fat diet and approximately 100 kcal/24 h of the high-fat diet. At the end of the study, diabetic rats fed the high-fat diet weighed more and had higher retroperitoneal fat depot weights (P less than 0.05) than diabetic rats fed the low-fat diet. In diabetic rats, GAD activity was 15-20% higher in the ventromedial nucleus (P less than 0.01) but similar to controls in the lateral hypothalamus, paraventricular nucleus, and area postrema. Diet did not affect GAD activity in the brain areas studied. The increase in ventromedial nucleus GAD activity was not associated with the level of food intake and was the likely result of altered glucose homeostasis in diabetic rats.

Serotonin3 (5-HT3) receptor antagonists (ICS 205-930 and MDL 72222) have been shown to block or ameliorate the anorectic response of the rat to amino acid imbalanced (IMB) diets. Two experiments were conducted to determine whether the effects of these antagonists are mediated through central or peripheral 5-HT3 receptors. In Experiment One, ICS 205-930 (ICS) was injected centrally, into either the lateral ventricle (doses: 0.3 pmol to 10 nmol), or the cisterna magna (62 nmol). The intake of rats fed an isoleucine IMB diet was not affected by these injections. In Experiment Two, rats received an IP injection of either saline, ICS, or a quaternized derivative of ICS (Q-ICS) that should not cross the blood-brain barrier. Both ICS- and Q-ICS-injected rats ate significantly more (p less than 0.05) IMB diet than saline-injected rats. Intake of IMB diet was not different (p greater than 0.4) between ICS and Q-ICS groups. From these results, it appears that ICS restores intake of IMB through a peripheral component.

Dietary selection and intake of a threonine-imbalanced diet were evaluated after increasing the concentration of the dietary limiting amino acid in the prepyriform cortex. Selection against the threonine-imbalanced diet in favor of a protein-free diet was reversed when 2 or 4 nmol threonine was injected bilaterally into the prepyriform cortex. However, intake of the threonine-imbalanced diet was significantly increased only after injection of 2 nmol threonine. The reduced intake of the threonine-imbalanced diet, compared to the basal diet, after injection of 4 nmol threonine was not the result of an excess in the concentration of amino acid (or nitrogen) injected into the PPC because intake of the threonine-basal diet was not reduced when 4 nmol threonine was administered. Intake of the threonine-imbalanced diet was also increased after injection of 2 nmol threonine plus 2 nmol isoleucine but not after injections of 2 nmol isoleucine. The changes in food intake when an imbalanced diet is fed appear to be the result of at least two separable responses: recognition of a diet as having an amino acid imbalance, as indicated by dietary choice, and reduction in food intake. The results of this study indicate that changing the concentration of the dietary limiting amino acid in the prepyriform cortex influenced dietary selection and food intake separately.

This study tested the concept that the level of fatty acid oxidation in the ventrolateral hypothalamus (VLH) reflects peripheral energy stores and elicits compensatory responses to changes in energy balance status. Fatty acid oxidation rates in the VLH were chronically altered over a 14-day period by infusing into the VLH either 0.1 mM 4-pentenoic acid (4-PA; 5 ng/h) or 1.0 mM L-carnitine (L-Carn; 98 ng/h). Fatty acid oxidation rates in the VLH were altered to a similar extent as by overfeeding (reduced 37% by 4-PA) and dietary restriction (increased 28% by L-Carn). Diffusion of infusates was limited, since there were normal rates of fatty acid oxidation in the ventromedial hypothalamus and cortex. There were no significant effects of altering fatty acid oxidation in the VLH on food intake, body weight, body composition, or serum levels of glucose, insulin, and free fatty acids. The results of this experiment indicate that the level of fatty acid oxidation in the VLH is unlikely to independently elicit changes in food intake or peripheral metabolism.

The effect of inhibiting protein synthesis within the prepyriform cortex (PPC) on intake of an amino acid imbalanced diet was evaluated in rats receiving bilateral injections of the dietary limiting amino acid (DLAA). Injection of the DLAA into the PPC increased intake of the imbalanced diet by 150% and incorporation of [3H]leucine into the trichloroacetic acid insoluble fraction of PPC homogenates by 248%. Coinjection of puromycin (100 mumol/L) or actinomycin D (10 mumol/L) blocked the increase in intake of the imbalanced diet but had no effect on intake of the basal diet. Puromycin blocked the increase in intake of the imbalanced diet whether injected with the DLAA or 6 h later. Selection of the imbalanced diet over a protein-free diet when the DLAA was administered was blocked by co-injecting puromycin or actinomycin D. The results indicated that the increased intake and the reversal of aversion to the imbalanced diet when the DLAA was injected into the PPC required de novo protein synthesis. The proteins necessary for the feeding response seemed to have a short half-life and seemed to require synthesis of new mRNA. We conclude that changes in concentration of the DLAA within the PPC influenced protein synthesis at the genomic level.

Diffusion or metabolism of the dietary limiting amino acid (DLAA) in the prepyriform cortex (PPC) may account for the time lag between injection of the DLAA into the PPC and the increase in intake of an amino acid-imbalanced diet. Results from the injection of [3H]Leu +/- [14C]Thr (DLAA) into the PPC indicated rapid (less than 15 min) and limited diffusion (85-90% of recovered label was less than or equal to 1 mm from the injection site). 3H and 14C decreased in the trichloroacetic acid (TCA)-soluble fraction and increased in the TCA-insoluble fraction during the first 1.5 h and remained constant in the TCA-insoluble fraction 1.5-6 h after injection. An increase (approximately 50%) in 3H in the TCA-insoluble fraction was found less than or equal to 30 min after injection of the DLAA. There was no affect of the DLAA on 3H in the TCA-soluble fraction. These results indicated that a change in metabolism within the PPC may be responsible for the delay in onset of the feeding response after injection of the DLAA into the PPC.

Activity of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD), was measured in brain areas involved in glucoregulation 60 min after a glucoprivie challenge. The rate of GAD activity in the ventromedial nucleus of the hypothalamus (VMN) increased in a dose-dependent manner in response to intraperitoneal injection of 2-deoxy-D-glucose (2-DG). The increase in VMN GAD activity was significantly correlated with an increase in food intake (r2 = .77, p less than 0.01). The increase in VMN GAD activity was not due to the higher food intake since rats receiving 2-DG and denied access to food also had elevated rates of VMN GAD activity. VMN GAD activity was increased 28% and 32% after intracerebroventricular injection of 2-DG or 5-thioglucose, respectively. The rates of GAD activity in the lateral hypothalamus and area postrema were not affected by either peripherally or centrally administered 2-DG. The increase in VMN GAD activity after glucoprivation may be involved in the regulation of blood glucose by influencing food intake.

The role of adrenal function in the anorectic response and adaptation of rats to a diet with an isoleucine (Ile) imbalance was investigated. In the first of four experiments, rats were fed a mildly Ile-imbalanced diet after treatment with metyrapone, and inhibitor of glucocorticoid synthesis. In two separate experiments, rats were presented with either a mildly or severely Ile-imbalanced diet (4.93 and 9.86% imbalanced amino acid mixture, respectively) after bilateral adrenalectomy. Finally, the effects of ICS 205-930, a serotonin-3 receptor antagonist, on the intake of mildly Ile-imbalanced diet were tested in adrenalectomized animals. In each experiment a 2 X 2 factorial design was used. Neither metyrapone nor adrenalectomy altered the initial depression in the intake of an imbalanced diet. The adaptation phase in the response of adrenalectomized rats fed a mildly Ile-imbalanced diet was not different from that of controls, but adrenalectomized rats fed severely Ile-imbalanced diets were unable to adapt. Adrenalectomy did not alter the anti-anoretic activity of ICS 205-930 in this model. These results suggest that adrenal hormones are not necessary for the initial anoretic response or adaptation of rats to an Ile-imbalanced diet, nor are they implicated in the anti-anorectic effect of serotonin-3 blockade.

Microinjection of the dietary limiting essential amino acid (DLAA) into the prepyriform cortex (PPC) increased intake of a diet having an imbalance among the essential amino acids (imbalanced diet) from 50-55% of baseline, when artificial cerebrospinal fluid (aCSF) was injected, to 70-75% of baseline. The increase in intake of the imbalanced diet by DLAA injection became apparent after 3-6 h and was maintained throughout the dark period. Meal size, meal duration, and the number of meals returned to normal after bilateral injections of the DLAA into the PPC of rats fed the imbalanced diet. Injection of the DLAA 30 min before the onset of the dark phase increased intake of imbalanced diet to 70% of baseline intake. When injections of threonine or isoleucine were made 6 and 3 h, respectively, prior to onset of the dark phase, intake of imbalanced diet increased to 85% of baseline intake. Results suggest that some form of processing of the injected DLAA within the PPC is necessary to increase the intake of imbalanced diets.

The mechanisms underlying the reduced intake of an amino acid-imbalanced diet (imbalanced diet) appears to involve a decrease in the content of the dietary limiting amino acid (DLAA) in the prepyriform cortex (PPC). Intake of imbalanced diet was increased from 45-50 to 70-75% of baseline after bilateral injection of the DLAA directly into the PPC, following an inverted U-shaped dose-response curve. Injections had no effect on intake of basal diets. Injection of the DLAA into the PPC reversed the aversion to imbalanced diet in choice studies, as rats selected an imbalanced diet over protein-free diet after such injections. Intake of imbalanced diet did not increase after a nonlimiting amino acid was injected into the PPC or after injections of the DLAA into other brain areas. Results were similar when either threonine or isoleucine was the DLAA. These results confirm that the decrease in the concentration of the DLAA in the PPC is involved in the reduction in intake of imbalanced diets.