Energy metabolism: the systemic function
Energy metabolism is not only a question for a single cell or a group of cells such as, for example, T cells or muscle cells, because provision and allocation of energy-rich fuels involves the entire body. Need for energy-rich substrates at a certain location in the body can induce a systemic response if local stores are not sufficient to provide necessary supplies. The systemic response redirects energy-rich fuels from stores to the site of action, the consumers [2
Such a redirection program can be started by a voluntary act when an individual decides to use muscles during exercise. In such a situation, the central nervous system activates, among others, the sympathetic nervous system (adrenaline, noradrenaline), the hypothalamic-pituitary-adrenal axis (cortisol), and the hypothalamic-pituitary-somatic axis (growth hormone, insulin-like growth factor-1), which induce gluconeogenesis,- glycogenolysis, and lipolysis. This is supported by release of IL-6 from muscles into systemic circulation, which helps activate the redirection program [73
]. Redirection of energy-rich substrates from storage sites to consumer can be called the energy appeal reaction.
If the immune system needs energy-rich fuels in the context of infection or other forms of activation, a similar energy appeal reaction is prompted [2
]. The response is a concerted action of the neuroendocrine immune network. But does the activated immune system need a lot of energy? Table presents the energy demand of the entire body, systems, and organs. Obviously, the immune system needs a lot of energy, particularly in an activated state. In an inflammatory situation, the energy appeal reaction is driven by cytokine-induced stimulation of the central nervous system, endocrine organs, and energy storage organs such as the liver, muscles, and fat tissue [2
]. IL-6 is a classical candidate that can activate these remote places (but also IFNγ, IFNα, IL-2, TNF, and others [2
Energy expenditure of systems and organs under various conditions
The question remains whether this seemingly adaptive program has been positively selected in the context of CIDs such as RA or systemic lupus erythematosus.
Evolutionary medicine, chronic inflammatory disease, and energy demand
The evolutionary principle of replication with variation and selection is undeniably fundamental and has history. This is a successful history of positive selection, which can only happen under circumstances of unrestricted gene transfer to offspring. The hypothesis is that genes which play a specific role in CIDs were not positively and specifically selected for a CID because unrestricted gene transfer was not possible in CIDs [2
]. If this is correct, regulatory mechanisms of the neuroendocrine immune network did not evolve to cope with CIDs. Instead, the neuroendocrine immune network was positively selected in the context of nonlife-threatening transient inflammatory episodes such as, for example, infection or wound healing. These episodes are usually short lived and do not last longer than 3 to 6 weeks. No prolonged adaptive program specifically exists for CIDs.
Similarly, the abovementioned energy appeal reaction as a consequence of systemic cytokine stimulation has been positively selected for transient nonlife-threatening inflammatory episodes [2
Furthermore, genes that are associated with CIDs have been positively selected independent of CIDs. The theory of antagonistic pleiotropy - formulated by Williams in the 1950s - similarly applies to CIDs [2
]. This theory suggests that genes associated with CIDs have been positively selected to improve survival at younger ages and to stimulate reproduction independent of CIDs. Recent delineation shows that several CID risk genes have a pleiotropic meaning outside CIDs at younger ages [76
The energy appeal reaction and disease sequelae
Organisms evolved under conditions that favored the development of complex mechanisms for obtaining food and for storage and allocation of energy-rich fuels. Energy regulation and cellular bioenergetics take the highest position in the hierarchy of homeostatic control. The main supporters of energy-rich fuel storage in liver, muscle, and adipose tissue are insulin, insulin-like growth factor 1, androgens/estrogens, and the parasympathetic nervous system. We can call them storing factors. In contrast, provision of energy-rich fuels to the entire body in the form of glucose, protein, and fatty acids is mainly supported by mediator substances of the sympathetic nervous system, the hypothalamic-pituitary-hormonal axes (cortisol and growth hormone), and the pancreas (glucagon). We can call them provision factors. Table describes particular aspects of the neuroendocrine immune response linking it to the energy appeal reaction.
The energy appeal reaction is not an unspecific fight-or-flight response in the sense of Hans Selye, but an adaptive program. If the adaptive program is used too long, real problems can appear that are a consequence of worn-out regulation. That exhausted regulation really exists is substantiated by the fact that patients on ICUs with severe activation of the stress system sometimes suffer from lifelong adrenal insufficiency even after overall recovery [77
A longstanding reallocation program can thus lead to acute and chronic disease sequelae as mentioned in Table . The framework explains that CID sequelae are a consequence of a continuous energy appeal reaction. The systemic response of the body - the energy appeal reaction - is important to support the immune system during short-lived inflammatory episodes, but its continuous use in CIDs is highly unfavorable.
Since disease sequelae are a significant part of clinical CID, etiology of disease sequelae is also part of CID etiology. It becomes understandable that long-term changes of the neuroendocrine immune network as a consequence of a chronic energy appeal reaction are also part of etiological considerations. We conclude that among genetic issues, environmental factors (microbes, toxins, drugs, injuries, radiation, cultural background, and geography), exaggerated immune and wound responses, and irrecoverable tissue destruction, changes of the neuroendocrine immune network in the context of a prolonged energy appeal reaction become a fifth factor of CID etiology [78