Interaction of the endocrine system with inflammation: a function of energy and volume regulation

Abstract

During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases.

Figure 1

The three big energy consumers in the body use approximately 2,000 kJ/day under resting conditions. Calculation of energy expenditure for the widespread immune system is based on a recent publication that mentions 1,600 kJ/day [4]. Growth-related phenomena in adults are added to this number with 400 kJ/day. A demand reaction for energy-rich fuels (pink circular ring) can be started by one of ‘the big three’ mainly using cytokines and hormones, one of which is interleukin-6 (IL-6). The immune system is activated by external triggers such as infectious agents or self-antigens in misguided autoimmunity and thus is independent of the two other big consumers in starting the demand reaction. The brain is activated by external triggers (for example, stressful life events) or by misguided brain function (for example, major depression), and the brain is independent in starting the re-allocation program. An activated muscle demands energy-rich fuels by releasing muscular factors such as IL-6. The muscle is dependent on brain function to start the energy demand reaction. Whereas immune system activation and growth-related processes happen mainly at night, brain function and muscular function are increased during the day (indicated by the moon and the sun symbols).

Figure 2

Storage and release of energy-rich fuels. Green factors are responsible for storage of energy-rich fuels given in the green bowl. Red factors are relevant for release of energy-rich fuels and allocation to consumers. Storage organs are given (liver: 2,500 kJ as glycogen; muscle: 50,000 kJ as degradable protein; fat tissue as triglycerides: 500,000 kJ; values for an 85-kg person). ASD, androstenedione; Ca, calcium; DHEA, dehydroepiandrosterone; IGF-1, insulin-like growth factor-1; P, phosphorus; Vit. D, vitamin D.

Figure 3

Schematic representation of the consequences of insulin and insulin-like growth factor-1 (IGF-1) signaling alterations. Pro-inflammatory factors such as tumor necrosis factor (TNF) reduce signaling of insulin and IGF-1 and production of IGF-1 from liver (for example, [91]). This program affects liver, adipose tissue, and muscle, but not immune cells, because they cannot become insulin-resistant. The consequence is a deviation of energy-rich fuels from storage sites (liver, adipose tissue, and muscle) to the activated immune system and inflammatory tissue.