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.