An analysis of temporal changes in meal number and meal size at onset of anorexia in male tumor-bearing rats.
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Animals↗
Biomedical subjects
A Laviano
Publications and source records attributed to A Laviano.
Hypothalamic dopamine and serotonin in the regulation of food intake.
Because daily food intake is the product of the size of a meal and the frequency of meals ingested, the characteristic of meal size to meal number during a 24-h light-dark cycle constitutes an identifiable pattern specific to normal states and obesity and that occurs during early cancer anorexia. An understanding of simultaneous changes in meal size and meal number (constituting a change in feeding patterns) as opposed to an understanding of only food intake provides a more insightful dynamic picture reflecting integrated behavior. We have correlated this to simultaneous changes in dopamine and serotonin concentrations and to their postsynaptic receptors, focusing simultaneously on two discrete hypothalamic food-intake-related nuclei, in response to the ingestion of food. The relation between concentrations of dopamine and serotonin limited to the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) as they relate to the influence of meal size and meal number during the hyperphagia of obesity and anorexia of cancer as measured in our experiments are discussed. Based on these data, conceptual models are proposed concerning: 1) an "afferent-efferent neurotransmitter unit," with facilitatory or inhibitory neuropeptide properties to generate an appropriate neuroendocrine and neuronal response that ultimately modifies food intake; 2) initiation and termination of a meal, thereby determining the number and size of a meal under normal conditions; and 3) a schema integrating the onset mechanism of cancer anorexia. Nicotine is used as a tool to further explore the relation of meal size to meal number, with a focus on simultaneous changes in dopamine and serotonin concentrations in the LHA and VMN with the onset of acute anorexia of nicotine infusion and acute hyperphagia of nicotine cessation. Data concerning the role of sex-related hormones on dopamine and serotonin with regard to the LHA and VMN in relation to the modulation of food intake are also presented.
Animals↗
Effects of intra-VMN mianserin and IL-1ra on meal number in anorectic tumor-bearing rats.
BACKGROUND: Tumor growth in animals and humans is associated with the onset of anorexia and reduced food intake. We previously demonstrated that the ventromedial nucleus of hypothalamus (VMN) plays a contributory role in mediating cancer anorexia. Because serotonin and interleukin-1 (IL-1) are putative mediators of cancer anorexia, we hypothesized that their influence on food intake during tumor growth might occur via their action within the VMN. METHODS: To test this hypothesis, 12 Fischer rats injected subcutaneously with 10(6) viable MCA sarcoma cells (TB rats) and their nontumor-bearing controls (NTB, n = 13) were studied. When anorexia developed, TB and NTB rats received bilateral intra-VMN microinjections of the serotonin antagonist mianserin (200 nmol) or the IL-1 receptor antagonist (IL-1ra, 25 ng). Food intake and its determinants of meal number and size were continuously recorded via a computerized device. RESULTS: In NTB rats, intra-VMN mianserin did not affect food intake, whereas after IL-1ra or vehicle a momentary decrease in food intake due to a predominant reduction of meal size occurred. In TB rats, intra-VMN mianserin or IL-1ra selectively increased meal number, leading to improved food intake. CONCLUSIONS: Data suggest that intra-VMN serotonin and IL-1 are involved in influencing cancer related anorexia.
Animals↗
Comparison of early feeding pattern dynamics in female and male rats after reversible ventromedial nucleus of hypothalamus block.
BACKGROUND: In the hypothalamus, a number of interconnected foci, including the ventromedial nucleus of hypothalamus (VMN), interact to control food intake (FI). FI is a function of meal number (MN) and meal size (MZ). Because gender differences exist in feeding patterns, we aimed at investigating the role of the VMN in determining the relationship of MZ and MN in female and male rats. METHODS: FI and feeding patterns of 10 female and 12 male Fischer-344 rats were studied after VMN block, achieved via stereotaxically located intra-VMN microinjection of the neuronal blocker, colchicine (0.32 microgram dissolved in 50 nL of isotonic injectate and instilled on each side into the VMN). RESULTS: After colchicine injection in normal female rats, an immediate and significant increase in FI occurs as a result of the following: 1) increased MZ in dark and light phases and 2) increased light phase MN with consequent loss of the normal diurnal cycle in FI. Recovery of feeding cycle and normal vaginal smear pattern occurred by study's end. In normal male rats, VMN block resulted in the following: 1) an increase in FI resulting from increased MN occurring predominantly during the light phase, thereby 2) disrupting the usual light/dark feeding cycle. CONCLUSIONS: Sexual differences in regulation of FI occur after temporary reversible VMN block: in female rats, MZ is more sensitive to experimental modulation, whereas in male rats it is MN.
Animals↗
Potential strategies for ameliorating early cancer anorexia.
BACKGROUND: Normally the lateral hypothalamic area (LHA) and the ventromedial nucleus (VMN) interact to regulate food intake (FI), the product of meal number (MN) and meal size (MZ), by changes in neurotransmitters, mainly dopamine and serotonin. Change in LHA dopamine influences meal size; while in VMN, decreasing dopamine and increasing serotonin levels influence meal number. Whether this situation exists in early cancer anorexia was tested in a series of studies to examine the role of the hypothalamus in the pathogenesis of early cancer anorexia. MATERIALS AND METHODS: In experiment 1, male Fischer tumor-bearing (TB) rats and weight-matched controls had FI, MN, and MZ measured continuously via a computerized rat eater meter. At onset of anorexia, feeding patterns were measured. In experiment 2, the VMN was temporarily blocked with 0.32 microgram of colchicine in TB rats, while TB controls had an equal volume of intra-VMN saline, and changes in feeding patterns were measured. In experiment 3, changes in VMN dopamine and serotonin were measured via microdialysis at anorexia and after tumor resection. RESULTS: In experiment 1, with the onset of anorexia, food intake decreased significantly in TB rats, initially by a decrease in MN and then by a decrease in both MN and MZ. No change occurred in controls, suggesting that VMN versus LHA played a more significant role in mediation of cancer anorexia. In experiment 2, following VMN block, FI increased significantly in anorectic TB rats, achieved by an almost exclusive increase in MN with minimal change in MZ, thus supporting the role of the VMN in anorexia. In experiment 3, at the onset of anorexia, FI decreased significantly in TB rats versus controls. TB rats had a significant increase in VMN serotonin and a significant decrease in VMN dopamine. After tumor resection, food intake improved and high levels of serotonin normalized with no change in dopamine. CONCLUSION: Serotoninergic and dopaminergic systems are involved in the etiology of cancer anorexia. The changes in food intake are mediated via the VMN by a decrease in meal number.
Animals↗
Peripherally injected IL-1 induces anorexia and increases brain tryptophan concentrations.
Interleukin-1 is an anorexigenic cytokine, and is involved in the pathogenesis of cancer anorexia. Interleukin-1 induced anorexia is mediated by direct action within the hypothalamus, and by peripheral mechanism(s) yet to be determined. Here we present evidence showing that in an animal model the peripheral injection of interleukin-1 is followed by a significant rise in brain tryptophan concentrations. Tryptophan is the precursor of the neurotransmitter serotonin, known to mediate the onset of satiety under normal and pathological conditions. By inference, we conclude that interleukin-1 induced anorexia is mediated by at least two different mechanism: i) interleukin-1 direct action within the hypothalamus; ii) increased brain serotonergic activity, secondary to interleukin-1 induced increased brain availability of the serotonin precursor, tryptophan.
Animals↗
Effect of kynurenine on tryptophan-albumin binding in human plasma.
Increased plasma free tryptophan levels have been reported in cancer patients and causally associated to the presence of anorexia. The pathogenesis of this occurrence is yet to be completely understood. Kynurenine is a metabolite of tryptophan, and has been reported increased in plasma during tumor growth. Because of the similarities between tryptophan and kynurenine we speculate that their rise in the presence of a tumor might be causally related. To test this hypothesis, we performed a series of in-vitro studies, showing that kynurenine supplementation reduces the amount of tryptophan bound to albumin, and thus, by competition, increases free tryptophan levels. The likely clinical consequences of these findings are discussed.
Humans↗
Interleukin-1alpha injection into ventromedial hypothalamic nucleus of normal rats depresses food intake and increases release of dopamine and serotonin.
A microdialysis injector probe administered IL-1alpha into ventromedial hypothalamus (VMN) and concurrently measured release of dopamine (DA), DOPAC, 5-HT, and 5-HIAA. After baseline dialyses, six rats received 2-ng IL-1alpha and six rats received vehicle (1 microl saline) into VMN. Sixty minutes later, food was provided for 40 min while VMN monoamines were measured every 20 min. Vehicle had no significant effect on monoamines, their metabolites, or food intake. Food intake was significantly lower in IL-1alpha rats vs. controls (p < 0.01). Baseline levels of VMN monoamines (pg/10 microl dialysate) in IL-1alpha and vehicle groups were similar. DA and 5-HT rose immediately on injecting IL-1alpha and remained higher (p < 0.05) than basal during the first 60 min and 40 min sampling period, respectively. Levels of 5-HIAA also increased (p < 0.01). Eating decreased VMN DA in controls, and decreased VMN DOPAC in IL-1alpha-treated rats. During eating, VMN 5-HT in control rats significantly increased while increasing VMN 5-HIAA occurred in IL-1alpha rats. Findings show that an IL-1alpha pathophysiological dose injected into the VMN was associated with anorexia and significantly increased dopaminergic and serotonergic activities and suggest that enhanced VMN DA and 5-HT activities may be part of an IL-1alpha-initiated cascade involved in IL-1alpha-associated anorexia.
Animals↗
Use of orchiectomy and testosterone replacement to explore meal number-to-meal size relationship in male rats.
Because food intake is a function of meal number and meal size and because gender-related hormones are involved in feeding regulation, we explored effects of orchiectomy and testosterone replacement on the relationship between meal number and size and changes in resulting feeding patterns in adult male rats, randomized into orchiectomy and sham-operation groups. A rat eater meter measured feeding indexes for 1 wk before and 2 wk after castration and during 8 days of testosterone replacement. Orchiectomy leads to an immediate change in the meal number-to-size relationship, resulting in 1) change in pattern of feeding; 2) a significant decrease in dark-phase meal number; 3) a significant increase in dark-phase meal size, but insufficient to offset decrease in meal number, so total food intake significantly decreased during dark phase; 4) no significant change in light-phase meal number; and 5) an increase in meal size leading to an increased food intake during light phase, which offset decreased food intake in dark cycle and resulted in no net significant change in food intake after orchiectomy. Testosterone replacement acutely reversed effects of orchiectomy on meal number-to-meal size relationship, restoring feeding pattern. Data suggest that androgens immediately influence the meal number-to-meal size relationship. The speed of onset seen after orchiectomy suggests that the influence of testosterone on food intake may also occur partially via a nongenomic effect.
Animals↗
Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats.
With progression of tumor growth, rats demonstrate anorexia and reduced food intake, a function of meal number and meal size. Tumor necrosis factor-alpha (TNF-alpha), a recognized anorectic agent, reacts with two different receptors (type I: 55 kDa; type II: 75 kDa). We used a dimeric, pegylated 55-kDa TNF receptor construct to test its effects on food intake, meal number, and meal size, which were continuously measured with a rat eater meter in 16 Fischer 344 male rats injected with 10(6) viable methylcholanthrene cells. When anorexia developed, rats received a subcutaneous injection of either 0.25 mg/kg body wt of soluble TNF receptor construct (study) or vehicle (tumor-bearing control). Before TNF inhibitor injection, no differences were observed in food intake, meal number, or meal size between the two groups. After the TNF inhibitor injection, study vs. control rats significantly improved food intake as a result of an increase in meal number and meal size. Rats also showed a significant improvement in body weight. These data suggest that TNF-alpha, in addition to other cytokines, contributes to the anorexia of tumor growth, probably mediated via the hypothalamus.
Animals↗
Food intake equals meal size times mean number.
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Animals↗
Effects of oral 5-hydroxy-tryptophan on energy intake and macronutrient selection in non-insulin dependent diabetic patients.
OBJECTIVE: In obese patients, brain serotonergic stimulation via orally administered 5-hydroxy-tryptophan (5-HTP), the precursor of serotonin, causes decreased carbohydrate intake and weight loss. Since diabetes mellitus is associated with depressed brain serotonin, hyperphagia and carbohydrate craving, we hypothesized that in diabetic patients, orally administered 5-HTP stimulates brain serotonergic activity and thus normalizes eating behaviour. To test this hypothesis, we investigated whether in diabetic patients: 1) predicted brain serotonin concentrations are depressed as a result of decreased availability of the precursor, tryptophan; and 2) oral 5-HTP is effective in reducing energy and carbohydrate intake. SUBJECTS AND METHODS: 25 overweight non-insulin dependent diabetic outpatients were enrolled in a double-blind, placebo-controlled study, and randomized to receive either 5-HTP (750 mg/d) or placebo for two consecutive weeks, during which no dietary restriction was prescribed. Energy intake and eating behaviour, as expressed by macronutrient selection, were evaluated using a daily diet diary. Plasma amino acid concentrations and body weight, as well as serum glucose, insulin and glycosylated haemoglobin were assessed. RESULTS: 20 patients (nine from the 5-HTP group and 11 from the Placebo group) completed the study. Brain tryptophan availability in diabetic patients was significantly reduced when compared to a group of healthy controls. Patients receiving 5-HTP significantly decreased their daily energy intake, by reducing carbohydrate and fat intake, and reduced their body weight. CONCLUSIONS: These data confirm the role of the serotonergic system in reducing energy intake, by predominantly inhibiting carbohydrate intake, and suggest that 5-HTP may be safely utilized to improve the compliance to dietary prescriptions in non-insulin dependent diabetes mellitus.
5-Hydroxytryptophan↗
Acute adaptive changes in food intake pattern following olfactory ablation in rats.
We determined whether acute compensatory feeding pattern changes after bulbectomy persist on a chronic basis, or whether physiological adaptation occurs to normalize acute changes. Rats were randomized to olfactory bulbectomy or sham operation; all had jugular vein catheterization. Food intake, meal number and size were studied during infusion of parenteral nutrients providing 100% daily caloric intake (PN-100) to minimize post-ingestive effects. Rats were randomly assigned to acute (from day 14 after operation, PN-100 infused for 4 days, followed by 4 days of saline infusion) or chronic study (PN-100 infused for 4 days from day 40, followed by 4 days of saline infusion). After olfactory ablation, acutely decreased meal size was offset by increased meal number, but 40 days after, baseline differences between meal size and number no longer existed. No qualitative differences in response to PN-100 were noted between acute and chronic groups. Findings suggest a functional adaptation of food intake regulatory mechanism between 14 and 40 days after bulbectomy.
Adaptation, Psychological↗
Plasma tryptophan levels and anorexia in liver cirrhosis.
OBJECTIVE: Increased brain tryptophan (TRP) availability for serotonin synthesis may play a role in the pathogenesis of anorexia. Since in chronic liver failure, increased plasma and cerebrospinal fluid TRP concentrations are characteristically reported, we hypothesize that also in liver cirrhosis increased brain TRP availability may constitute the pathogenic mechanism of anorexia. To test this hypothesis, the association between anorexia and plasma TRP was investigated. METHODS: Anorexia and plasma amino acid concentrations were evaluated in 16 patients with liver cirrhosis and compared with those obtained in 13 healthy volunteers. RESULTS: According to a questionnaire, 11 cirrhotic patients were considered as anorectic. In these patients, brain TRP availability was significantly higher than in nonanorectic patients and controls. DISCUSSION: Increased brain TRP availability is also associated with anorexia in liver cirrhosis, and supports the hypothesis that increased serotonergic activity may constitute the common pathogenic mechanism for anorexia associated with different diseases.
Adult↗
Pathogenesis of cancer anorexia: personal perspective.
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Animals↗
Meal size and number: relationship to dopamine levels in the ventromedial hypothalamic nucleus.
Evidence shows a reciprocal relationship exists between the lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMN) in food intake regulation. Since a direct correlation between meal size and LHA-dopamine in Fischer rats was previously reported, we tested the hypothesis that an inverse association may exist between meal size and VMN-dopamine response. This was studied in awake 24-h food-deprived rats who were then allowed to eat freely for 20 min while the VMN-dopamine response was measured by microdialysis every 20 min for 2 h. In a second experiment, only one-half the amount freely eaten was provided during microdialysis. The following were observed. 1) Dopamine concentrations in VMN decreased during eating. 2) The degree and duration of decrease after the meal corresponded to the size of the meal. 3) When the decreased postmeal VMN-dopamine level had returned to baseline and food was available, rats ate once more. The findings show that, in normal rats, eating was associated with decreased dopamine levels in the VMN and was followed by a lag time during which no additional eating occurred. VMN dopamine levels thereby contribute to determining the duration of the intermeal interval and hence, by inference, the meal number.
Animals↗
Effects of administration of oral branched-chain amino acids on anorexia and caloric intake in cancer patients.
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Administration, Oral↗