Current Protein and Peptide Science - Volume 12, Issue 4, 2011

Energy balance of mammals is a complex system that involves a great variety of factors: ingestion of calorie containing substances has to be counterbalanced by various components of the overall metabolic rate and energy expenditure (e.g., heat loss). When this balance is well established, it means an optimal development and later stable maintenance of body weight, well-regulated body temperature [1, 2] and it is also connected with nutrient utilization (intermediary metabolism). However, individual components of this balance (regulation of food intake, body weight, body temperature, etc.) are determined by a plethora of factors including age and/or body composition [2-4]. The overall energy balance must be positive and must lead to weight gain in juvenile age-groups until reaching young adulthood. However, in the course of further development and aging it often remains positive leading to obesity, particularly in middle-aged mammals (both humans and animals). In very old populations on the other hand, a negative balance is reflected by the aging anorexia and cachexia. These age-related changes are accompanied by alterations in body composition and in intermediary metabolism: middle-aged obesity in most cases refers to visceral fat accumulation, with adjoining decrease in insulin sensitivity or manifest diabetes [5], while aging anorexia and cachexia means a dramatic fall in active tissues, especially that of skeletal muscles leading to sarcopenia and fragility in old age-groups [6]. Great complexity characterizes the regulatory mechanisms that determine energy balance at any age. Peripheral neural and humoral signals not only contribute to the short-term modifications of the system (hunger/satiety, thermal balance, nutrient utilization), but they also affect the long-term regulations including regulation of body weight, body composition, or peripheral insulin sensitivity [2, 7]. The great variety of peripheral signals may act through activation/inhibition of the basic central components of regulation or at least in conjunction with their activities. In this respect, the hypothalamic and brainstem nuclei are the central structures of utmost importance [8]. Among the multitude of signals that finally determine the function of central regulatory systems, various peptides play an extraordinary role. Some of these peptides originate from peripheral tissues and influence brainstem and hypothalamic regulatory processes of energy balance, others are produced in neurons of the central nervous system (neuropeptides) as important participants in these regulations, and they can also influence processes of peripheral tissue metabolism. Leptin, a peptide hormone of the adipose tissue as well as insulin of peripheral origin acts centrally (mainly in the hypothalamic arcuate nucleus) and, via downstream pathways, both peptides have catabolic actions (e.g., they enhance the activity of the melanocortin system and inhibit that of neuropeptide Y) [9]. Via the vagus and the brainstem, brain-gut peptide cholecystokinin (CCK) also exhibits catabolic effects [10, 11]. Plasma level of a number of these peptides increases, while their anorexigenic and overall catabolic efficacy decreases with age [12], although food restriction at least partially prevents this decrease [5, 12]. In contrast, ghrelin originating from the stomach is orexigenic, but its efficacy has also been shown to decline with age [13]. Some other hypothalamic neuropeptides (e.g. orexin) have been demonstrated to lose from their orexigenic [13] activities in the course of aging, although enhanced expression of anorexigenic peptides (e.g. cocaine-amphetamine regulated transcript) has also been reported [14]. The short reviews in the present issue of Current Protein and Peptide Science are either related to the role of various peptides in (or to peptide effects on) the regulation of factors of energy balance in function of age, or they are related to the ageassociated insulin resistance. Peripheral ghrelin and CCK actions have been analyzed by Stengel and Tache, one peptide being orexigenic, the other one anorexigenic. One of the important findings is that the amount of orexigenic ghrelin, which is produced by the X/A cells of the stomach and acts via the vagus and the nucleus of the solitary tract, depends on the action of ghrelin-O-acyltransferase. Changes in the activity of this enzyme can alter the ratio of the active ghrelin and its non-orexigenic form desacyl-ghrelin and thereby the enzyme may influence the overall orexigenic activity. Regarding CCK actions, nesfatin (originating from the same gastric cells partly in response to peripheral CCK) is anorexigenic. Simultaneously, CCK also suppresses ghrelin level. The peptide itself may also act as an anorexigenic mediator (via CCK2 receptors) on central structures. The orexigenic and antidipsogenic actions of ghrelin constitute the topic of another paper by Hashimoto and Ueta. This analysis may be of importance, since in some studies of food intake liquid food is applied [15] and the antidipsogenic effects of ghrelin may be relevant in the evaluation of the results of such experiments. An extensive review of Kmiec deals with thorough analysis of the role of peripheral and central peptides in age-related changes of food intake. This work describes that in rodents both the expression and activity of orexigenic and anorexigenic peptides may change with aging. Another review from Petervari et al. (also on basis of experiments on rodents) summarizes the continuously changing role of these peptides in the overall regulation of energy balance during the course of aging, and possibly offers an explanation for the high prevalence of obesity in middle-aged animals and for that of aging anorexia in the old ones. Age-related development of leptin and insulin resistance with and without visceral adiposity, with and without calorie restriction is analyzed in another remarkable review by Carrascosa et al. In this paper data for the possible role of inflammatory cytokines in cases of increased adiposity are also collected - apparently, these cytokines may influence metabolism of peripheral tissues. Although the authors could not reach a decisive conclusion on the role of age vs. adiposity in these processes, they presented and very thoroughly discussed the available data regarding this problem.....

Aging affects energy homeostasis and fuel metabolism in a form of either an increased body mass and glucose intolerance that may lead to obesity and type 2 diabetes or loss of appetite that also may seriously compromise health status. The data, obtained mainly in rat, suggest that aging suppresses the expression and action of potent orexigenic peptides such as predominantly neuropeptides NPY and orexins and peripheral hormone, ghrelin. Senescent animals show over-responsiveness to αMSH, the major anorexigenic neuropeptide. However, central anorexigenic action of leptin is clearly diminished in aging, most likely due to the impaired leptin signal transduction. The age-related central resistance to leptin and insulin does not reduce their inhibitory effects on the activity of NPY and AgRP neurons. Thus, in rodents aging is associated with the altered expression and activity of both orexigenic and anorexigenic peptides. If similar changes in the central regulation of food intake occur during human aging, they may partially explain ‘anorexia of aging’ and loss of body weight observed at the end-of-life period. Additionally, increased plasma cholecystokinin concentrations in healthy old subjects may also contribute to the loss of appetite characteristic for the elderly. Further studies of the central and peripheral mechanisms that control food intake during aging may provide novel therapeutic strategies to improve the nutritional status of the elderly.

Ghrelin is a stomach-derived peptide discovered as a ligand of the orphan G-protein coupled receptor. Ghrelin is now recognized as a major orexigenic neuropeptide. Immunohistochemical studies demonstrated that centrally administered ghrelin induced c-fos protein expression in many areas in the brain. Indeed, centrally administered ghrelin has various effects such as stimulating feeding, arousal, increasing gastric acid secretion, release of hormones from the pituitary, and inhibition of water intake. In particular, we recently showed that ghrelin was an antidipsogenic peptide with a simultaneous orexigenic effect. This may be of important, because most spontaneous daily water intake is temporally associated with feeding. Here, we summarise recent findings on the integration of central effects of ghrelin that regulate feeding, release hormones from the pituitary and inhibit fluid/water intake.

Anapyrexia, which is a regulated fall in core temperature, is beneficial for animals and humans when the oxygen supply is limited, e.g., hypoxic, ischemic, or histotoxic hypoxia, since at low body temperature the tissues require less oxygen due to Q10. Besides hypoxia, anapyrexia can be induced various exogenous and endogenous substances, named cryogens. However, there are only a few reports investigating endogenous cryogens in mammals. We have experienced one patient who suffered from severe hypothermia. The patient seemed to be excessively producing endogenous peptidergic cryogenic substances the molecular weight of which may be greater than 30 kDa. In animal studies, the patient's cryogen appeared to affect metabolic functions, including thermogenic threshold temperatures, and then to produce hypothermia. Since endogenous cryogenic substances may be regarded as useful tool in human activities, e.g., during brain hypothermia therapy or staying in a space station or spaceship, further studies may be needed to identify human endogenous cryogens.

Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide 1 interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/nesfatin-1) which have been investigated for their influence on food intake.

Aging in mammals associates with the development of peripheral insulin resistance. Additionally, adiposity usually increases with aging and this could play a relevant role in the gradual impairment of insulin action. In fact, fat accretion leads to changes in the expression and circulating concentrations of factors originated in adipose tissue like leptin, resistin and inflammatory cytokines which have been shown to modulate insulin signaling in insulin target tissues acting both, directly or through the central nervous system. Even insulin action on peripheral target tissues has been recently demonstrated to be partially mediated by its central action, suggesting that a decrease in central insulin action could be involved in the development of peripheral insulin resistance. In the present review we analyze the available research data on aging-associated insulin resistance making emphasis in the following aspects: 1) The time-course of development of overall insulin resistance and the evolution of changes in circulating adipokines; 2) The effect of caloric restriction and the decrease of adiposity in insulin action; 3) The influence of changes in the central action of factors like leptin or insulin in the development and maintenance of insulin resistance during 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.

Cations are specifically recognized by numerous proteins. Cations may play a structural role, as cofactors stabilizing their binding partners, or a functional role, as cofactors activating their binding partners or being themselves involved in enzymatic reactions. Despite their small size, their charge density and their specific interaction with highly charged residues allow them to induce significant conformational changes on their binding proteins. The protein conformational change induced by cation binding may be as large as to account for the complete folding of a protein (as evidenced in Hepatitis C NS3 protease, or human rhinovirus 2A protease), and they may also trigger oligomerization (as in calcium-binding protein 1). Especially intriguing is the ability of cation-binding proteins of discriminating between very similar cations. In particular, calcium and magnesium are recognized by proteins with markedly different binding affinities and cause significantly different conformational changes and stabilization effects in the binding proteins (as in the fifth ligand binding repeat of the LDL receptor binding domain, calcium-binding protein 1, or parvalbumin). This article summarizes recent findings on the structural and energetic impact of cation binding to different proteins. A general framework can be envisaged in which cations can be considered as a special type of allosteric effectors able to modulate the functional properties of proteins, in particular the ability to interact with biological targets, by altering their conformational equilibrium.