Age-related changes in acute central leptin effects on energy balance are promoted by obesity.

Leptin is a key catabolic regulator of food intake (FI) and energy expenditure. Both aging and obesity have been shown to induce leptin-resistance. The present study aimed to analyze age-related changes in the anorexigenic and hypermetabolic responsiveness to acute intracerebroventricular leptin administration in different age-groups of normally fed male Wistar rats (adult and old rats from 3 to 24months of age, NF3 to NF24, respectively). The expressions of the long form of the leptin receptor (Ob-Rb) and inhibitory SOCS3 genes were also assessed by quantitative RT-PCR in the arcuate nucleus (ARC). The influence of high-fat diet-induced obesity (HF) on the anorexigenic leptin effects were also tested in younger and older middle-aged groups (HF6 and HF12). Leptin-induced anorexia varied with age: leptin suppressed re-feeding FI (following 48-h fasting) strongly in young adult (NF3), but not in younger or older middle-aged (NF6 or NF12) or in aging (NF18) rats. However, anorexigenic leptin effects reached statistical significance again in old NF24 rats. Leptin-induced hypermetabolism, on the other hand, showed monotonous age-related decline and disappeared by old age. Ob-Rb expression declined until 12months of age followed by a partial recovery in NF18 and NF24 groups. On the other hand, SOCS3 expression was high in NF6 and NF18 and to some extent in NF24 rats. Age-related alterations of Ob-Rb and SOCS3 expression in the ARC may partly contribute to the explanation of age-related variations in anorexigenic but not hypermetabolic leptin effects. High-fat diet-induced obesity was associated with resistance to leptin-induced anorexia in HF6, similar to that seen in NF6. However, instead of the expected leptin-resistance in HF12, a strong leptin-induced suppression of re-feeding was detected in these obese middle-aged rats. Our results suggest that acute central effects of leptin on anorexia and hypermetabolism change in disparate ways during aging, implying separate mechanisms (e.g. signal transduction pathways) of different leptin actions. The age-related pattern shown by leptin-induced anorexia may contribute to the explanation of middle-aged obesity, and partly to that of aging anorexia. Our findings concerning obese rats are in accord with previous observations on anorexigenic effects of peripherally administered cholecystokinin: diet-induced obesity appeared to accelerate the development of age-related regulatory alterations. Similarly, our present data also raise the possibility that chronic diet-induced obesity promotes responsiveness to centrally applied leptin at least concerning anorexigenic effects.

Age-related alterations in the central thermoregulatory responsiveness to alpha-MSH.

Alpha-melanocyte-stimulating-hormone (alpha-MSH) is a neuropeptide that induces weight loss via its anorexigenic and hypermetabolic/hyperthermic effects. Two major public health problems of the human population involving energy balance (i.e. middle-aged obesity and aging cachexia) also appear in other mammals, therefore age-related regulatory alterations may also be assumed in the background. Previous studies demonstrated characteristic age-related shifts in the anorexigenic effects of centrally applied alpha-MSH with strong effects in young adult, diminished efficacy in middle-aged and very pronounced responsiveness in old rats. The present study aimed to investigate age-related changes in the acute central thermoregulatory responsiveness to an alpha-MSH injection in rats and to compare them with those of food intake-related responsiveness. Oxygen consumption (VO2), core (Tc) and tail skin temperatures (Ts, indicating heat loss) of male Wistar rats of different age groups (from 2 to 24 months of age), were recorded in an indirect calorimeter complemented by thermocouples upon intracerebroventricular alpha-MSH administration (0, 5 µg) at a slightly subthermoneutral environment (25-26 °C). Acute alpha-MSH-induced rises in VO2 and Tc were most pronounced in the young adult age-group. In these rats the hyperthemic effects were somewhat diminished by an activation of heat loss. Juvenile animals showed weaker hyperthermic responses, middle-aged rats none at all. Alpha-MSH-induced hyperthermia became significant again in old rats. Acute thermoregulatory (hypermetabolic/hyperthermic) responsiveness to alpha-MSH shows a distinct age-related pattern similar to that of acute anorexigenic responsiveness. Thus, our results may also contribute to the explanation of both middle-aged obesity and aging cachexia.

Age and nutritional state influence the effects of cholecystokinin on energy balance.

Cholecystokinin (CCK) is anorexic, irrespective whether it is applied intraperitoneally (IP) or intracerebroventricularly (ICV) in male Wistar rats. The metabolic effects depend on the route of administration: by the IP route it elicits hypothermia (presumably by type-1 receptors, CCK1R-s), while ICV administration is followed by fever-like hypermetabolism and hyperthermia via activation of CCK2R-s, which latter response seems to be most important in the postprandial (compensatory) hypermetabolism. The efficacy of the IP injected CCK varies with age: it causes strong anorexia in young adult 4 and 6-months old and again in old rats (aged 18-24 months), but the middle-aged (12-month old) ones seem to be resistant to this effect. Such pattern of effects may contribute to the explanation of age-related obesity observed in middle-aged animals as well as to the aging anorexia and loss of body weight in old ones. Diet-induced obesity accelerates the appearance of CCK-resistance as well as the return of high sensitivity to CCK in further aging, while chronic calorie-restriction prevents the development of resistance, as if the speed of the age-related regulatory changes was altered by the nutritional state. The effects of ICV applied CCK also change with age: the characteristic anorexic and hypermetabolic/hyperthermic effects can be observed in young adult rats, but the effects gradually and monotonically decline with age and disappear by the old age of 24 months. These disparate age-related patterns of CCK efficacy upon peripheral or central administration routes may indicate that although both peripheral and central CCKR-s exert anorexic effects, they may have dissimilar roles in the regulation of overall energy balance.

Alterations in the peptidergic regulation of energy balance in the course of aging.

With advancing age most aspects of the peptidergic regulation of energy balance are altered. The alteration involves both the peripheral peptides derived from the adipose tissue or the gastrointestinal tract and the peptides of the central nervous system (brainstem and hypothalamus). In general, the expression of orexigenic peptides and their receptors decreases with age, while that of the anorexic ones rather increases, but not simultaneously and not in a linear fashion. Apart from such quantitative changes, the efficacy of the related peptides may also change with age. These changes are not necessarily linear, either: instead of continuous decline or increase of its effects, the effects of a peptide may become less pronounced in some phases of aging and much enhanced in other ones. Comparing the individual peptides, the phasic alterations in their anabolic or catabolic roles in the regulation of energy balance may exhibit dissimilar time-patterns. In addition, within the overall anabolic or catabolic effects, the feeding and metabolic actions of certain peptides may not change simultaneously. Altogether, as compared with young adults, in middle-aged animals or individuals the anabolic processes (increased food intake with decreased energy expenditure) seem to prevail, which processes may contribute to the explanation of age-related obesity, while in the old ones the catabolic processes (anorexia with enhanced metabolic rate) dominate, which possibly explain the aging anorexia, frailty and sarcopenia.

Central alpha-MSH infusion in rats: disparate anorexic vs. metabolic changes with aging.

UNLABELLED: Changes of the anorexigenic and hypermetabolic components of the overall catabolic effect of alpha-MSH were studied in rats as a function of age. In male Wistar rats a 7 day-long intracerebroventricular infusion of alpha-MSH suppressed food intake and caused a fall in body weight in 2 and 3-4 month-old (young) groups, but it was most effective in the 24 month-old group and had hardly any effect in the 12 month-old (middle-aged) animals. In contrast, metabolic rate as well as biotelemetric measurements of core temperature and heart rate revealed the most pronounced hypermetabolic effects of such infusions at age 12 months. The hypermetabolic effect was still high in the oldest group, but low in the younger groups. IN CONCLUSION: Changes of the anorexigenic and hypermetabolic effects in the course of aging are not concordant. The overall catabolic activity of alpha-MSH is smallest in the middle-aged and highest in the oldest group.

Age-dependence of alpha-MSH-induced anorexia.

Long-term regulation of energy balance involves two major trends: first age-related obesity develops in the middle-aged, later it is followed by anorexia of aging (sarcopenia and/or cachexia). A dynamic balance between orexigenic and anorexigenic neuropeptides is essential for the regulation of energy homeostasis. Special imbalances of neuropeptide effects may be assumed corresponding to different age-periods. Anorexia induced by acute alpha-MSH (alpha-melanocyte stimulating hormone; endogenous melanocortin agonist) injections was analyzed in male Wistar rats aged 6-9 weeks (juvenile), 3-4 months (young adult), 6 or 12 months (two middle-aged groups), 18 months (aging) and 24-26 months (old). Alpha-MSH injected through a preimplanted intracerebroventricular (ICV) cannula (compared with saline injection) dose-dependently suppressed spontaneous food intake and also re-feeding following 24-h fasting, but the rate of suppression varied between age-groups. An ICV injection of 5 microg alpha-MSH attenuated the 2-h re-feeding by 21.9+/-3.2% in juvenile rats, strongly (68.7+/-2.5%) suppressed it in young adults, the suppression became progressively weaker in the two middle-aged groups (55.7+/-4.9%, vs. 26.4+/-4.9%, respectively), but it turned extreme in aging (94.7+/-4.2%) and old (74.3+/-4.5%) rats. Body composition also changed with age: unlike the tibialis anterior muscle, the epididymal and retroperitoneal fat pads increased until middle-age and remained large even in old animals, while the measured indicator of muscle mass decreased in the oldest group. The food intake suppressing and body weight decreasing effects of a 7-day-long ICV infusion of 1 microg/h alpha-MSH were weakest in the 12-month-old and most pronounced in the 24 month-old rats. In conclusion, responsiveness to the anorexic effect of alpha-MSH varies with age, with a nadir of the curve in the middle-aged, and a peak in the aging and old animals. This age-related nadir of melanocortin-responsiveness may promote obesity in middle-aged rats, while the tendency for anorexia and incipient sarcopenia of old (still obese) rats may result from age-related melanocortin-hypersensitivity rather than from adiposity.

Suppression of food intake by intracerebroventricular injection of alpha-MSH varies with age in rats.

During the aging process of mammals first a phase of obesity and increased adiposity is observed in middle-aged subjects, then anorexia and loss of body weight (sarcopenia) at old age. A possible age-dependence of the anorexigenic alpha-melanocyte-stimulating-hormone (alpha-MSH) in these regulatory changes was studied. Male Wistar rats aged 6-8 weeks (juvenile), 3-4 months (young adult), 6 and 12 months (middle-aged), and 24-26 months (old) were equipped with chronic cannula to the lateral cerebral ventricle. The effect of 5 microg alpha-MSH injected through the cannula was analyzed on food intake evoked by 24-h food deprivation. Juvenile rats seemed almost resistant to alpha-MSH (21.9% suppression). In young adults alpha-MSH suppressed food intake by 68.7%. However, the alpha-MSH-induced anorexia was significantly less pronounced in middle-aged (55.7% or 26.4% in rats aged 6 or 12 months, respectively), and much more pronounced (73.3%) in old rats. The adiposity (judged by the relative amount of perirenal fat) increased until middle-age, but did not change between middle-age and old-age. It is concluded that changes in alpha-MSH responsiveness possibly contribute to both the age-related obesity in middle-aged rats and to the anorexia of old ones: first the adiposity then the age may be the important factor.

Neutron imaging of Zr-1%Nb fuel cladding material containing hydrogen.

Hydrogen distribution and hydride phases were analyzed in reactor fuel cladding pressure tube Zr-1%Nb material up to 13,300 ppm. From neutron diffraction measurements, formation of cubic delta-ZrH2 and a small amount of tetragonal gamma-ZrH was established. Texture effects were analyzed by imaging plate technique. From neutron radiography images a linear model was set up that adequately described the relationship between gray levels and nominal H-concentrations. The H-distribution was unveiled by 3D intensity histograms and fractal analysis of multilevel-segmented neutron radiography images.

Semi-simultaneous application of neutron and X-ray radiography in revealing the defects in an Al casting.

A semi-simultaneous application of neutron and X-ray radiography (NR, XR) respectively, was applied to an Al casting. The experiments were performed at the 10MW VVR-SM research reactor in Budapest (Hungary). The aim was to reveal, identify and parameterize the hidden defects in the Al casting. The joint application of NR and XR revealed hidden defects located in the Al casting. Image analysis of the NR and XR images unveiled a cone-like dimensionality of the defects. The spectral density analysis of the images showed a distinctly different character for the hidden defect region of Al casting in comparison with that of the defect-free one.

Analyzing of segregation in mixtures of 3-methylpyridine and heavy water by dynamic neutron radiography.

The closed-loop phase diagram of 3-methylpyridine-heavy water mixture was studied, to our best knowledge, for the first time with dynamic neutron radiography (DNR) at the 10MW VVR-SM Research Reactor in Budapest (Hungary). Visualized were the (i) lower temperature non-segregated states (below 38 degrees C), (ii) transition (40-43 degrees C), (iii) segregated states (46-128 degrees C), (iv) higher temperature transition (110-128 degrees C) and (v) higher temperature non-segregated states. The non-segregated state belonging to 141 degrees C, was found to be definitely dissimilar from the lower temperature state. Existence of a solid-like structure at the liquid-liquid interface was indicated.

Multiple neural mechanisms of fever.

In rats, fevers induced by moderate-to-high doses of intravenous lipopolysaccharide consist of three phases (phases 1, 2 and 3) with body temperature peaks at approximately 1, 2, and 5 h postinjection, respectively. In this study, the effects of bilateral truncal subdiaphragmatic vagotomy and intraperitoneal capsaicin desensitization on febrile phases 1-3 were assessed in adult Wistar rats. Surgical vagotomy was performed approximately 30 d before the experiment; this procedure interrupts both afferent and efferent vagal fibers. Capsaicin was administered intraperitoneally in two consecutive injections (2 and 3 mg/kg, 3 h apart) 1 week prior to the experiment; this procedure desensitizes afferent fibers, primarily within the abdominal cavity, and does not lead to the known thermal effects of systemic capsaicin desensitization. At a neutral ambient temperature, the rats were given Escherichia coli lipopolysaccharide (10 microg/kg) through a preimplanted jugular catheter, and their colonic temperature wes measured by thermocouples for 7 h. The control rats exhibited the typical triphasic febrile responses. Confirming our earlier studies, subdiaphragmatic vagotomy did not affect phases 1 and 2; it did, however, result in a 2.5-fold reduction of phase 3. Capsaicin desensitization modified the febrile response differently: phases 2 and 3 were unaffected, but phase 1 disappeared. We suggest that neural afferent fibers (nonvagal but perhaps vagal as well) play an important role in the early febrile response (phase 1) by transducing peripheral pyrogenic signals to the brain. We also suggest that vagal efferent fibers are likely to participate in the later febrile response (phase 3) via an unknown mechanism.

Central thermoregulatory effects of neuropeptide Y and orexin A in rats.

Orexin A and neuropeptide Y that are known to induce a feeding response when applied centrally, in the present studies also caused hypothermia. Neuropeptide Y elicited hypothermia by depressing metabolic rate (without affecting heat loss mechanisms), while orexin A acted through enhancing peripheral heat loss (without affecting metabolic rate). Neither peptide induced coordinated thermoregulatory changes, both of them appeared to influence thermoregulation via different effector mechanisms.

Hyperphagia in cold-adapted rats: a possible role for neuropeptide Y.

The feeding response to intracerebroventricular injection of neuropeptide Y or to starvation is greater in cold-adapted than in non-adapted rats, suggesting that with cold-adaptation the central sensitivity to this peptide is increased. Hypometabolism and hypothermia (which usually follow the administration of neuropeptide Y) cannot, however, be demonstrated in the course of cold-adaptation per se.

Motivational conflict among water need, palatability, and cold discomfort in rats.

Rats were placed in situations pitting three motivations against each other. Two motivations, ambient temperature and need of water, were physiological drives. The third, water sweetness provided by sodium saccharin, was not considered as immediately physiological because saccharin does not provide physiological benefits for the animals; nevertheless they continued to seek the sweet taste after repeated exposure to it. Therefore, our aim was to explore whether these motivations are of the same nature for rats and, if they are, whether they are also quantitatively comparable. From the behavioral evidence we wanted to obtain information on the common currency that permits the rats to solve conflicts. Our results confirm the existence of a common currency in rats' motivations. The similarity of rats' behavior to that of humans observed in conflict situations, where maximizing the bidimensional sum of pleasure was the key to optimal behavior, allows us to suggest a role for affectivity in decision making of mammals.

Behavior of juvenile lizards (Iguana iguana) in a conflict between temperature regulation and palatable food.

Juvenile green iguanas were placed in a situation of conflict between two motivations: a thermoregulatory drive and the attraction of a palatable bait. To be able to reach the bait (lettuce), they had to leave a warm refuge, provided with standard food, and venture into a cold environment. In experiment 1 the time interval between sessions with bait, ranging from 1 to 8 days, had no effect on the duration of stay on the bait. This result shows that the lettuce was not a necessary food, deprivation of which would have had to be compensated for. In experiment 2 as the ambient temperature at the bait decreased the lizards spent less time feeding on lettuce, and they visited the bait less frequently. This result shows that the lizards traded off the palatability of the bait with the disadvantage of the cold. These findings support the hypothesis that a common currency makes it possible for lizards to compare two sensory modalities.

Grammatical choice and affective experience in a second-language test.

This study measured the affective experience of 12 subjects reading grammatically correct and incorrect versions of 50 sentences, Questionnaire I, in their second language (French). This was followed by a multiple choice grammar test, Questionnaire II, using the same 50 sentences and offering the correct and incorrect answers. Subjects tended to choose correct as well as incorrect responses corresponding to their highest affective rating within each entry. In all cases the subjects' behavior was higher than chance level and thus followed a trend to maximize pleasure. This result supports the hypothesis according to which the key to decision-making lies in the affective dimension of conscious experience.