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Tissue damage is a threat to well-being because it is self-promoting; that is, hydrolases released from inflammatory or injured cells cause further injury and provide substrate for formation and propagation of free radicals. For this reason, the body must localise and limit the injury and clear tissue debris. To perform these functions, the organism has developed an acute-phase response that includes stereotyped, coordinated adaptations ranging from behavioural to physiological [ 1 ]. The acute-phase response includes the hepatic synthesis of large quantities of proteins. The functions of the acute-phase proteins vary widely and include binding proteins (opsonins), protease inhibitors, complement factors, apoproteins, fibrinogen, and others.

With the tremendous increase in scientific knowledge about cytokines and their immune functions, it has also become clear that cytokines have systemic and local effects that are only partly related to their coordinating functions in the immune system. Thus, proinflammatory cytokines are the major endogenous mediators of anorexia and cachexia during chronic diseases. They have substantial hypermetabolic effects, which are at the core of the organism’s fever reaction, and, last but not least, they are implicated in the metabolic disturbances and several other comorbidities of obesity, in particular by contributing to insulin resistance. This chapter summarises current knowledge of these effects: it describes studies including different levels of scientific analysis, from the molecular through cellular to the systemic and behavioural levels, which reveal interesting features of the role of cytokines in these phenomena.

A general chronology of growth hormone-releasing peptide (GHRP) and ghrelin and their shared receptor is shown in Table 1 [ 1 ] [ 3 ]. The discovery of the natural hormone ghrelin appears to be the exciting beginning of a new unusual hormone system. Initially, in 1980, GH-releasing activity of the unnatural GHRPs was thought to represent the activit y of the as-yet unidentified natural hypophysiotrophic hormone GH-releasing hormone (GHRH). However, in 1982, GHRH was isolated from a pancreatic tumour and the hypothalamus and chemically identified as 44 and 40 amino acid linear peptides. Although the GH-releasing activity of GHRPs and GHRH are similar, it is also apparent that they are definitely chemically and functionally different because of the uniqueness of the action of GHRP on GH secretion in vitro as well as in vivo in a variety of animal species. In 1984, it was postulated that GHRP reflected the activity of another new hypothalamic hormone involved in the increased secretion of GH and thus was in need of isolation.

Ghrelin is a 28 amino acid peptide predominantly produced by the stomach, although it is also expressed in many other central and peripheral endocrine and non-endocrine tissues [ 1 ], [ 3 ]. Ghrelin displays strong growth hormone (GH)releasing activity mediated by the activation of the GH secretagogue receptor type 1a (GHS-R 1a) [ 1 ], [ 3 ]. Prior to the discovery of ghrelin, this orphan receptor had been shown to be specific for a family of synthetic peptidyl and non-peptidyl molecules known as GH secretagogues (GHS) [ 1 ], [ 3 ], [ 4 ]. GHS-R are concentrated in the hypothalamic -pituitary unit but are also distributed in other central and peripheral tissues [ 1 ] [ 4 ]. Apart from the potent GH-releasing effect, ghrelin exhibits additional actions including stimulation of prolactin and ACTH secretion, negative influence on gonadal axis, stimulation of appetite and positive influence on energy balance, endocrine and nonendocrine gastro-entero-pancreatic functions, cardiovascular actions and modulation of cell viability [ 3 ], [ 5 ], [ 6 ].

Obesity, eating disorders and cachexia endanger the lives of millions of people worldwide. Fortunately, during the past decade, there has been a rapid and substantial progress toward uncovering the molecular and neural mechanisms by which energy imbalance develops. Central to this research has been the identification and characterisation of certain peripheral metabolic signals, such as leptin and ghrelin, which serve as fundamental indices of energy sufficiency [ 1 ].

As summarised in previous chapters, chronic (neoplastic, necrotic, infectious) pathophysiological processes of various systems are frequently accompanied by wasting and cachexia. The pathophysiology of wasting and cachexia is complex [ 1 ] [ 10 ] and multiple brain mechanisms [ 11 ] [ 13 ] can be involved including neurological, psychiatric, psychological, physiological, biochemical/ metabolic, immunological, and chemical per se (e.g. neurotransmitter-, neuropeptideand cytokine-related). These mechanisms can interact/synergise with peripheral/systemic processes or dysfunctions (e.g. gastrointestinal malabsorption and body losses such as via ulcers, effusions, haemorrhage).

The epidemic increasing incidence and prevalence of obesity and diabetes mellitus have underlined the necessity of understanding the regulation and control of appetite and energy metabolism.

Energy is constantly required in human life, whereas it is supplied only by intermittent food intake. Therefore, food is usually ingested in excess of the immediate caloric needs, and the extra calories are stored in the form of hepatic and muscle glycogen, adipose tissue triglycerides, and to a certain extent as muscle protein. In turn, these fuel reservoirs are broken down during starvation to provide energy for the body. The amount of glycogen stored in skeletal muscle is about 400 g (1600 Kcal), the amount of glycogen in liver is about 75 g (300 Kcal), and the amount of triglycérides stored in adipose tissue is about 15 000 g (141 000 Kcal), at overnight fasting state in healthy men.

Body weight is determined by the complex interaction of caloric intake, absorption and utilisation of nutrients. Multiple factors (age, health status, neural, hormonal and metabolic influences, and medications) influence this interaction. The major site of this integration is represented by the hypothalamic area, where complex and specific neural circuits receive feedback from peripheral signals and coordinate the response in terms of stimulation or inhibition of food intake and energy balance [ 1 ] [ 3 ]. Among these peripheral signals, the adipocyte-derived hormone leptin informs the brain regarding the need to inhibit food intake and limit fat accumulation [ 4 , 5 ]. In contrast, the gastric hormone ghrelin (see chapter by Broglio et al.) induces a sensation of hunger and is involved in energy homeostasis by inducing the storage of fat in adipose tissue [ 6 ].

Changes in appetite and weight loss are commonly occurring symptoms in various psychiatric diseases; however, it is clear that a disturbance of appetite is a cardinal feature of depressive disorders. There is a large amount of data available about the epidemiology, phenomenology, associated neurobiological findings, and pharmacological interventions that bear on the links between mood disorders and appetite. The findings may ultimately contribute to our understanding of appetite regulation per se.