Energy regulation and neuroendocrine–immune control in chronic inflammatory diseases

Abstract

Abstract. Straub RH, Cutolo M, Buttgereit F, Pongratz G (University Hospital Regensburg, Regensburg, Germany; University of Genova, Genova, Italy; and Charité University Medicine Berlin, Berlin, Germany). Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases (Review). J Intern Med 2010; 267: 543-560.Energy regulation (EnR) is most important for homoeostatic regulation of physiological processes. Neuroendocrine pathways are involved in EnR. We can separate factors that provide energy-rich fuels to stores [parasympathetic nervous system (PSNS), insulin, insulin-like growth factor-1, oestrogens, androgens and osteocalcin] and those that provide energy-rich substrates to consumers [sympathetic nervous system (SNS), hypothalamic-pituitaryadrenal axis, thyroid hormones, glucagon and growth hormone]. In chronic inflammatory diseases (CIDs), balanced energy-rich fuel allocation to stores and consumers, normally aligned with circadian rhythms, is largely disturbed due to the vast fuel consumption of an activated immune system (up to 2000 kJ day )1 ). Proinflammatory cytokines such as tumour necrosis factor or interleukins 1b and 6, circulating activated immune cells and sensory nerve fibres signal immune activation to the rest of the body. This signal is an appeal for energy-rich fuels as regulators are switched on to supply energy-rich fuels ('energy appeal reaction'). During evolution, adequate EnR evolved to cope with nonlife-threatening diseases, not with CIDs (huge negative selection pressure and reduced reproduction). Thus, EnR is inadequate in CIDs leading to many abnormalities, including sickness behaviour, anorexia, hypovitaminosis D, cachexia, cachectic obesity, insulin resistance, hyperinsulinaemia, dyslipidaemia, fat deposits near inflamed tissue, hypoandrogenaemia, mild hypercortisolaemia, activation of the SNS (hypertension), CID-related anaemia and osteopenia. Many of these conditions can contribute to the metabolic syndrome. These signs and symptoms become comprehensible in the context of an exaggerated call for energy-rich fuels by the immune system. We propose that the presented pathophysiological framework may lead to new therapeutical approaches and to a better understanding of CID sequence.

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…At least two studies have reported differences in the induction of cytokines in response to immune challenge [66,79]. Intriguingly, Straub et al [45] outline the possible relationships between chronic inflammatory diseases (which demand that increased energy resources are shifted to the immune response) and many metabolic abnormalities. We can only imagine how these relationships could be exacerbated under conditions of competition for energy when mice are chronically cold stressed.…”

“…In addition to a role for adrenergic stress in causing immunosuppression, there may also be a role for abnormal energy balance in mildly coldstressed mice. It has been noted by others [45] that the increase in fuel consumption required for activation of the immune system (up to 2000 kJ/day) is enough to disrupt most other homeostatic needs of the body. It is likely that with the burden of rapid tumor growth, expansion of immune cell populations would compete for energy needed for thermogenesis such that, ultimately, immunosuppression may protect the ability of the organism to maintain body temperature.…”

Cachexia – The Interplay Between the Immune System, Brain Control and Metabolism

“…A lasting anorexia ultimately leads to devastating state of malnutrition followed by inevitable muscle proteocatabolism. In fact, persistent anorexia and poor nutrient status have been observed in patients with chronic inflammatory diseases and cancer (Evans et al, 2008;Laviano et al, 2008;Straub et al, 2010). There is strong evidence approving a failure of homeostatic mechanisms that control energy balance in conditions of long-term immune activation.…”

“…This altered behavior is an energy-conservation and -redistribution strategy of the body towards defense against noxious agents and generation of fever that exert a high energetic cost (Lorton et al, 2008). Generally, basal metabolic rate goes up about 25% by the activation of the immune system (Straub et al, 2010). Thus sickness behavior represents a valuable homeostatic mechanism for survival towards energy reserves not to be depleted by immune processes.…”

Proactive strategies to avoid infectious disease

“…In humans, the immune system (considering just leucocytes) uses around 1600 kJ per day, and when stimulated by pathogens energy demands increase significantly, raising basal metabolic rate between 9 and 30 per cent or more (e.g. 50% in the case of sepsis) [3]. Not surprisingly, there is likely to be a considerable adaptive value in evolving systems that reduce the likelihood of becoming infected, thus avoiding the risk and energy costs of fighting an infection.…”