Caloric regulation of food intake in man.

Investigated caloric regulation in normal 18-36 yr old human Ss on a liquid diet. In Exp I, 8 Ss failed to compensate for changes in the caloric density of a preload (.25-1.8 kcal/ml) by adjusting meal size within 1 meal or from 1 meal to the next. In Exp II, 15 Ss were required to ingest nothing but the liquid diet for 10-21 days. They were given adlib access to a standard liquid diet (1.0 kcal/ml) for 4-9 days followed by 4-14 days on a diluted diet (.5 kcal/ml). 9 Ss failed to regulate their caloric intake in the time allowed. 6 Ss failed to regulate their caloric intake in the time allowed. 6 Ss compensated dramatically for the caloric dilution by increasing both meal size and meal frequency. Regulation was slow to occur (2-5 days) and usually was not perfect (mean level of 87%). Results are discussed in the light of work with animals and man on the mechanisms controlling regulation of food intake. (30 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glucocorticoid regulation of leptin synthesis and secretion in humans: elevated plasma leptin levels in Cushing's syndrome

Leptin, the obese (ob) gene product, is an adipocyte-derived satiety factor that is involved in the regulation of food ingestion and body weight. To investigate glucocorticoid regulation of leptin synthesis and secretion in humans, we measured plasma leptin levels in patients with Cushing's syndrome with adrenal or pituitary adenoma and in patients with iatrogenic Cushing's syndrome. Plasma leptin levels in patients with Cushing's syndrome were significantly elevated compared to those in nonobese healthy subjects and obese subjects without any metabolic or endocrine diseases at a given percentage of body fat by analysis of covariance. In patients with adrenal or pituitary adenoma, after the tumor resection, plasma leptin levels were reduced, with a concurrent decrease in plasma cortisol levels. With no significant changes in body weight, plasma leptin levels were also elevated significantly in lean healthy volunteers 24 h after the administration of 1 mg dexamethasone. Dexamethasone potently induced ob gene expression and leptin secretion in the organ culture of human adipose tissue. The data demonstrate that glucocorticoids act, at least in part, directly on the adipose tissue and increase leptin synthesis and secretion in humans.     

Intracerebroventricular administration of mouse leptin does not reduce food intake in the chicken

Recently, it has been suggested that leptin plays an important role in regulation of food intake and metabolism in rats and mice, however, the effect of central administration of leptin on food intake in chicks has not been reported. We have investigated the anorexigenic effect of leptin administered by intracerebroventricular (i.c.v.) injection in chicks using mouse leptin, which shows 97% homology to chicken leptin. Three experiments were conducted. After being deprived of food for 3 h, male broiler chicks were administered leptin by i.c.v. injection at dose levels of 0, 0.2, 1.0 and 5.0 microg (Experiment 1) or 0, 2.5 and 5.0 microg (Experiment 2). The birds were allowed free access to the diet for 2 h (Experiment 1) and 24 h (Experiment 2) after treatment. Male Single Comb White Leghorn chicks were used in Experiment 3 and were treated in the same manner as in Experiment 1. In all experiments, central administration of mouse leptin did not influence food intake in the time periods examined. It appears that either mouse leptin does not bind to the chicken leptin receptor or in the chicken brain the leptin receptor may be absent.     

Immune and endocrine regulation of food intake in sick animals

The evaluation of the carcinogenic potential of pharmaceuticals is currently undergoing dramatic changes. For the past 25 years the regulatory expectation for agents intended for long term use has been that lifespan studies (usually lasting 2 years) in 2 rodent species be conducted. These studies take at least 3 years to plan, execute and interpret, and use over 1200 animals. It is now recognised that the quality of the information obtained from these studies is unreliable for prediction of carcinogenic risk to humans. Over the past 4 years, the International Conference on Harmonisation (ICH) has recommended changes in approaches to assessing the carcinogenic potential of pharmaceuticals. In future, only one long term rodent study will be routinely required (usually in rats), provided this is complemented with a short or medium term test in one of the emerging new models for carcinogenicity, such as transgenic mice or newborn mice. However, the relevance of these new models to human cancer and their use in risk assessment is still largely unknown and this situation must be kept under review as knowledge accumulates. A long term study in a second rodent species is still an option. Dose selection has also been improved inasmuch as there are now several alternatives to the use of the maximum tolerated dose (MTD). In the past, the use of the MTD, when the normal homeostasis of the test animals is disturbed, has been considered one of the major problems with the rodent carcinogenicity bioassay. However, one of the alternative end-points to the use of the MTD, i.e. the comparison of plasma concentrations in rodents and humans, must be viewed with caution. While this may contribute to limiting the high dose level for agents of very low toxicity, the concept should not be interpreted as signifying that plasma concentrations provide a sound basis for comparing the carcinogenic activity of agents in different species. Recognition of the 4 properties (genotoxicity, immunosuppression, steroid hormonal activity and long term tissue damage), at least one of which is associated with each of the pharmaceuticals known to be carcinogenic to humans, should focus more attention on a search for these properties in patients. Absence of these properties at clinically relevant dose levels indicates that a pharmaceutical is highly unlikely to be carcinogenic to humans.     

Innervated liver plays an inhibitory role in regulation of food intake

BACKGROUND: With the onset of eating, the associated rise of dopamine in the lateral hypothalamus (LHA-DA) is thought to regulate quantity of food consumed per meal. Early release of LHA-DA induced by eating is facilitated by oronasal stimulation; we propose that the subsequent LHA-DA response induced by nutrients in the portal vein is dampened by the innervated liver. This was tested by measuring LHA-DA in normal rats: during parenteral feeding to bypass oronasal stimulation, while eating during parenteral feeding, and while eating only. METHODS: Rats had either total liver denervation or sham operation, with placement of a jugular vein catheter and LHA-DA microdialysis cannula. After a 3-week recovery period total liver denervated rats were randomized to parenterally fed, food only, and parenteral plus food groups each with sham-operated controls in which LHA-DA was measured. RESULTS: No difference in LHA-DA release in food only groups occurred between total liver denervated or sham-operated rats. A significantly higher rise in LHA-DA was observed in total liver denervated versus sham-operated rats in parenterally fed (129% +/- 4% versus 116% +/- 2%; p < 0.05) and parenteral plus food (151% +/- 4% versus 134% +/- 4%; p < 0.05) groups. CONCLUSIONS: In total liver denervation versus sham operation, an increase in LHA-DA release occurs during parenteral feeding and eating during parenteral feeding, suggesting that innervated liver inhibits LHA-DA release.     

Inter-organ leptin exchange in humans

To assess whether the evolution to pneumoconiosis may be suspected in coal miners, we conducted a 4-yr longitudinal study of 80 dust-exposed miners with chest X-ray findings classified 0/1 or 1/0 according to the International Labor Organization (ILO) classification (exposed to coal mine dust, suspected of pneumoconiosis [ES group]) and two control groups having normal X-rays. The first of these latter two groups included 80 miners with similar exposure to that of the first group (exposure with normal X-rays [EN]), whereas the second group consisted of markedly less exposed miners (no exposure with normal X-rays [NN]). The protocol comprised a questionnaire on respiratory symptoms and smoking, assessment of cumulative coal-mine-dust exposure, X-rays, computed tomographic (CT) scans, and lung-function tests. The study was conducted in 1990 and 1994 by the same medical team. At the end of the follow-up, 24 members of the ES group had worsened X-ray findings, and 10 of them had X-ray findings classified as 1/1 or greater. In the EN and NN groups, six and one subjects, respectively, had worsened X-ray findings. At the first examination, subjects who developed pneumoconiosis had significantly lower values for FEV1/FVC ratio, maximum midexpiratory flow (MMEF), and maximal forced expiratory flow at 25% of vital capacity (FEF25%), and higher CT-scan micronodule scores. This latter score and FEF25% were significantly associated with the evolution to pneumoconiosis in the ES group, and scanner micronodule score and MMEF were significantly associated with this in all three groups combined. Worsening findings on X-ray and change to pneumoconiosis must be controlled in coal miners. The findings in this study offer the possibility of identifying miners who especially need follow-up and monitoring.     

Prefrontal cortex and the regulation of food intake in the rat.

Studied the postoperative regulation of food and water intake in a total of 103 male Wistar albino rats with aspiration lesions to either the medial frontal or orbital frontal projection fields of thalamic nucleus medialis dorsalis (prefrontal cortex). These projection fields proved functionally dissociable in that orbital frontal lesions impaired immediate postoperative regulation of food and water intake for up to 2 wks, while medial frontal lesions produced finickiness. Neither lesion affected response to cellular dehydration or recovery from extended deprivation. Data are consistent with data from rhesus monkeys with prefrontal lesions and differ from animals with lateral hypothalamic lesions. (27 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Increase in plasma leptin and Lep mRNA concentrations by food intake is dependent on insulin

The difference in pregnancy rates following intrauterine insemination (IUI) for 1 vs. 2 days in the periovulatory period has been reported as either inconsequential or favoring the use of two consecutive inseminations, 24 hours apart. Our study compared the monthly fecundity and cumulative probability of pregnancy in a large group of women (n = 123) undergoing controlled ovarian hyperstimulation and 1- or 2-day inseminations with donor sperm prepared from frozen-thawed samples. All patients underwent controlled ovarian hyperstimulation employing either clomiphene citrate in 217 cycles or human menopausal gonadotropin in 185 cycles. The choice of single or double insemination was decided by the day of the week each patient received human chorionic gonadotropin for ovulation induction. Approximately 80% of all the patients underwent both single and double insemination treatments during the 2.5-year study period. Ninety-three patients received single inseminations in 180 cycles, whereas 103 patients received double inseminations in 222 cycles. Nine clinical pregnancies were achieved in the 1-day group (5% per cycle, 9.7% per patient), while 39 pregnancies occurred in the 2-day group (17.9% per cycle, 37.9% per patient). Two and five spontaneous abortions occurred in the 1- and 2-day groups, yielding take-home baby rates of 3.9% per cycle (7.5% per patient) and 15.3% per cycle (33.0% per patient), respectively. The cumulative probability of conception over 15 cycles of treatment was consistently twice as high or higher for the 2-day group. The results of this study support the use of 2-day IUI treatment cycles when using frozen-thawed donor sperm.     

Adipose tissue leptin production and plasma leptin kinetics in humans

Abdominal adipose tissue leptin production was determined in vivo by arteriovenous balance in 14 lean and obese men (mean BMI 27.0 +/- 1.9, range 21.4-45.2). Blood samples were taken simultaneously from an abdominal vein that drains subcutaneous adipose tissue and from a radial artery. Adipose tissue blood flow was measured by xenon washout. Abdominal vein leptin concentrations (mean 8.9 +/- 2.4 ng/ml, range 2.1-36.5 ng/ml) were consistently greater than arterial values (mean 6.6 +/- 1.9 ng/ml, range 1.7-28.2 ng/ml) (P < 0.001). The net rate of abdominal adipose tissue leptin production (mean 3.2 +/- 0.5 ng x 100 g(-1) x min(-1)) correlated directly with percentage body fat (rs = 0.59, P = 0.016). Estimated whole-body leptin production rate (797 +/- 283 ng x person(-1) x min(-1)) correlated directly with percent body fat (rs = 0.93, P < 0.0001) and with regional leptin production (rs = 0.81, P < 0.001). In contrast, the rate of leptin clearance from plasma (mean 1.50 +/- 0.23 ml x kg(-1) x min(-1)) and plasma leptin half-life (mean 24.9 +/- 4.4 min) was unrelated to adiposity (rs = 0.06, P = 0.30; rs = 0.16, P = 0.30, respectively). These results provide direct evidence that leptin is produced by adipose tissue in humans and that the rate of production is directly related to adiposity. A combination of greater leptin production per unit of body fat and increased production from expanded total body fat mass, rather than alterations in leptin clearance, account for the increase in plasma leptin concentrations observed in obese humans.     

Effect of ammonia via prepyriform cortex on regulation of food intake in the rat

Studies were made on whether ammonia, which is an obligatory intermediate of amino acid metabolism, depresses the food intake of rats fed a low-casein (basal) diet containing imbalanced amino acid mixtures (imbalanced diets). Bilateral lesions in the prepyriform cortex caused normalization of food intake of rats fed amino acid-imbalanced diets, confirming the work of Leung and Rogers (Am. J. Physiol. 221:929-935, 1971). Unlike normal rats, animals with prepyriform cortical lesions consumed as much of a diet containing 3% NH4Cl as they did of the basal diet. However, like normal rats, they rejected a diet containing a mixture of keto acids. Unilateral injection of NH4Cl into prepyriform cortical areas reduced the food intake to a greater extent than injection of NaCl into these areas or injection of NH4Cl into other parts of the brain. These results suggest that ammonium ions influence the appetite through their effect on prepyriform cortical areas.     

Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans

Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.     

Four-week ethanol intake decreases food intake and body weight but does not affect plasma leptin, corticosterone, and insulin levels in pubertal rats

Long-term intake of ethanol decreases food intake and inhibits growth in experimental rats. The aim of this study was to determine the effect of 4-week oral ethanol ingestion on plasma leptin and adrenal function. Male 45-day-old Wistar rats were divided into three groups: absolute control (AC), ethanol (E) administered 10% (wt/vol) ethanol instead of tap water, and pair-fed (PF) given an amount of food corresponding to the food intake of E animals. E rats consumed less pelleted diet (74% cumulative total intake); however, this caloric deficit was compensated by ethanol ingestion. Net water intake in E animals was 76% of that in the control groups. The body growth of both E and PF rats was stunted compared with AC animals, but E rats were heavier than PF rats. The plasma leptin level was similar in E and AC and decreased in PF animals. There were no differences in plasma osmolality or glycemia among the three groups. Plasma insulin was decreased in PF compared with both AC and E rats. Plasma corticosterone was not affected by ethanol, but was increased in the food-restricted (PF) group. Although there were no differences in basal adrenal corticosterone production in vitro, there was a slightly higher response to corticotropin (ACTH) in E rats. We conclude that drinking 10% ethanol decreased the dietary intake and body growth. These changes were not mediated by plasma leptin changes. Although alcohol ingestion and its energy content theoretically normalized the total energy intake and prevented the decrease of plasma leptin, the growth of young rats was inhibited. Drinking 10% ethanol instead of tap water for 4 weeks did not stimulate basal adrenal activity.     

Effect of fenfluramine on food intake, mood, and performance of humans living in a residential laboratory

Five male and four female normal weight research volunteers, participating in 13-day residential studies, received oral fenfluramine (20, 40 mg) or placebo at 09:30 and 17:00. Food intake, performance, and subjective ratings were measured throughout the day. Carbohydrate intake was manipulated by providing lunch meals high (males: 120 g; females: 80 g) or low (males: 25 g; females: 16 g) in carbohydrate on 8 days; on the remaining days subjects self-selected lunch. Total caloric intake (approximately 2800 Kcal) did not differ among the low- and high-carbohydrate, and self-selected lunch conditions when subjects received placebo, indicating caloric compensation. Total carbohydrate intake was significantly less, however, when subjects consumed the low-carbohydrate lunch compared to the other lunch conditions. Fenfluramine significantly decreased total caloric intake (approximately 500 kcal) by decreasing meal size, not number, only when subjects consumed the low-carbohydrate lunch. Fenfluramine was only an effective anorectic drug when subjects consumed a lunch with fewer calories and a lower carbohydrate:protein ratio than self-selected baseline. Also, fenfluramine improved performance on a range of computer tasks and increased ratings of "Alert," "Friendly," and "Talkative," while decreasing ratings of "Tired" and "Irritable."     

Affect regulation and food intake in bulimia nervosa: Emotional responding to food cues after deprivation and subsequent eating.

Emotional responding to salient food cues and effects of food deprivation and consumption were investigated in 32 women with bulimia and 32 control women. One half of each group was food deprived before viewing unpleasant, neutral, pleasant, and food-related pictures. Then participants could eat from a buffet before viewing a parallel picture set. Women with bulimia showed a substantial potentiation of startle responses during viewing of food cues relative to control women. This startle potentiation was attenuated by food deprivation and augmented by increased food consumption. These data support the affective regulation model suggesting that food cues prompt negative affective states in women with bulimia, who are overwhelmed by fasting. The resulting deprivation increases the incentive value of food cues and may thus trigger binge eating. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The leptin receptor mediates apparent autocrine regulation of leptin gene expression

The possibility that the leptin receptor (LEPR) mediates autocrine regulation of leptin expression in adipose tissue was examined in 10-day-old Zucker rat pups with different copy numbers of the leptin receptor mutation (Lepr(fa)). Plasma leptin concentrations and adipose tissue mRNA levels for leptin were related to copy number of the mutation (fa/fa > fa/+ > +/+). These relationships were independent of plasma insulin concentration. Reduced copy number for the functional leptin receptor apparently results in a diminished negative feedback signal to the leptin gene in adipose tissue. Thus, leptin appears to close a short regulatory loop controlling its own synthesis in adipose tissue.     

Isatin inhibits food intake in mice

Isatin (2,3-dioxindole) is an endogenous compound which is distributed throughout the central nervous system. The studies reported here demonstrate that isatin decreased food intake in food deprived TAC (SW) male mice 12-16 weeks of age. Isatin was more effective at decreasing food intake when the mice had to work harder to obtain food. Isatin also decreased sucrose, milk and water intake. When hunger was reduced by prefeeding milk to the mice, isatin was more effective at decreasing food intake. Isatin did not alter spontaneous activity in an openfield. Behaviors observed in the home cage indicated that mice which received isatin approached the food more often without eating than the controls. Movement in the home cage was significantly reduced in mice receiving isatin. Drinking, grooming and resting were not significantly affected by administration of isatin. These studies suggest that isatin may be an endogenous modulator of food intake.     

Studies on the regulation of food intake using rat total parenteral nutrition as a model

Total parenteral nutrition (TPN) is essential for maintaining the nutritional status of patients who are unable to eat sufficiently to meet their metabolic needs. However, TPN suppresses appetite and ultimately diminishes food intake. Theories concerning the role(s) of peripheral metabolites as signals, acting via the liver and the hypothalamus, for the metabolic control of food intake, have been put forward to explain the anorectic effect of TPN. In addition, it is postulated that changes in peripheral metabolites during TPN may be translated into changes in the levels of brain neurotransmitters known to decrease food intake. This review summarizes studies concerning the effect of TPN on food intake. These studies have involved: (1) characterizing the changes in feeding activity due to TPN; (2) investigating the involvement of the central nervous system; and (3) investigating the role of the periphery and its metabolites in the regulation of food intake during TPN. Some insight into the mechanism of action of TPN on food intake is provided.     

Response of leptin to short-term and prolonged overfeeding in humans

As one of the postulated roles of the ob gene product, leptin, is regulation of energy balance and preservation of normal body composition, we investigated the effect of acute and chronic calorie excess (weight gain) on serum leptin in humans. Two protocols were employed: 1) acute (12-h) massive (120 Cal/kg) voluntary overfeeding of eight healthy individuals; and 2) chronic overfeeding to attain 10% weight gain, with its subsequent maintenance for additional 2 weeks, involving six normal males. In the acute experiments (protocol 1), circulating leptin rose by 40% over baseline (P < 0.01) during the final hours of overfeeding; this increase persisted until the next morning. At the point of achievement and the 2-week maintenance of 10% weight gain (protocol 2), a more than 3-fold rise in the basal leptin concentration was observed (P < 0.01). A direct linear relationship was found between the magnitude of the leptin response to weight gain and the percent gain of body fat (r = 0.88; P < 0.01). In summary, 1) in contrast to normal food intake (8), short term massive overfeeding is associated with a moderate elevation of circulating leptin levels that persists until next feeding cycle is initiated; and 2) a 10% weight gain causes different changes in the body composition, and the resulting rise in circulating leptin parallels the increase in the percentage of body fat. In conclusion, these studies document acute elevation of leptin in response to positive energy balance and suggest that developing resistance to leptin is associated with bigger fat deposition during weight gain in humans.     

Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse

1. Intracranial administration of leptin reduces both food intake and body weight gain in the mouse. Inhibitors of nitric oxide (NO) synthase produce similar effects. 2. To investigate the role of the brain L-arginine/NO pathway in mediating this effect of leptin, we have evaluated food intake and body weight gain after daily (5 days) intracerebroventricular (i.c.v.) administration of leptin (0.5-2 microg) alone or in association with L-arginine (10 microg). Moreover, we measured diencephalic nitric oxide synthase (NOS) activity after a single i.c.v. leptin (0.25-2 microg) injection and after consecutive doses of leptin (0.25-2 microg) over 5 days. The time course of the effect of leptin on NOS activity was also evaluated. 3. I.c.v. injected leptin (1 and 2 microg) significantly and dose-dependently reduced food intake and body weight gain with respect to vehicle (food intake: 5.97+/-0.16 g 24 h(-1) and 4.27+/-0.18 g 24 h(-1), respectively, vs 8.05+/-0.34 g 24 h(-1), P<0.001, n=6 for each group; body weight gain: -10.7+/-0.46% and -15.7+/-0.65%, respectively, vs 5.14+/-0.38%, P<0.001, n=6 for each group). This effect was antagonized by L-arginine (food intake: 7.90+/-0.37 g 24 h; body weight gain: 5.11+/-0.31%, n=6). Diencephalic NOS activity was significantly reduced by the highest doses of leptin with respect to vehicle (vehicle: 0.90+/-0.04 nmol citrulline min(-1) g(-1) tissue; leptin 1 microg: 0.62+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001; leptin 2 microg: 0.44+/-0.03 nmol citrulline min(-1) g(-1) tissue, P<0.001, n=6 for each group). Similar results were obtained in animals treated with daily consecutive doses of leptin. The inhibitory effect appeared rapidly (within 30 min) and was long lasting (up to 12 h). 4. Our results suggest that the brain L-arginine/NO pathway may be involved in the central effect of leptin on feeding behaviour and body weight gain in mice.     

Effect of sensory perception of foods on appetite and food intake: a review of studies on humans

OBJECTIVE: How much do the sensory properties of food influence the way people select their food and how much they eat? The objective of this paper is to review results from studies investigating the link between the sensory perception of food and human appetite regulation. CONTENT OF THE REVIEW: The influence of palatability on appetite and food intake in humans has been investigated in several studies. All reviewed studies have shown increased intake as palatability increased, whereas assessments of the effect of palatability using measures of subjective appetite sensations have shown diverging results, for example, subjects either feel more hungry and less full after a palatable meal compared to a less palatable meal, or they feel the opposite, or there is no difference. Whether palatability has an effect on appetite in the period following consumption of a test meal is unclear. Several studies have investigated which sensory properties of food are involved in sensory-specific satiety. Taste, smell, texture and appearance-specific satieties have been identified, whereas studies on the role of macronutrients and the energy content of the food in sensory-specific satiety have given equivocal results. Different studies have shown that macronutrients and energy content play a role in sensory-specific satiety or that macronutrients and energy content are not a factor in sensory-specific satiety. Sensory-specific satiety may have an important influence on the amount of food eaten. Studies have shown that increasing the food variety can increase food and energy intake and in the short to medium term alter energy balance. Further knowledge about the importance of flavour in appetite regulation is needed, for example, which flavour combinations improve satiety most, the possible connection between flavour intensity and satiety, the effect of persistence of chemesthetic sensation on palatability and satiety, and to what extent genetic variation in taste sensitivity and perception influences dietary habits and weight control.