How Energy Shifts Lead to Systemic Illness

Any change in energy availability can happen only when the inflammatory process switches on a systemic neuroendocrine response. If an inflammatory process is restricted to a local tissue compartment, no systemic response is induced, and local energy resources are used to nourish activated immune cells.1 Fortunately, in this situation, the disease is confined to a local process. In contrast, if the inflammatory process is strong, a systemic response is required to induce systemic energy allocation to the activated immune system.¹ Several pathways exist for stimulation of neuroendocrine centers in the brain by the activated immune system.¹⁸

As it persists, the inflammatory disease process enters a systemic stage to appeal for remote energy resources (glucose from the liver, amino acids from distant muscles, free fatty acids from distant fat, with the help of calcium and phosphorus from remote bone) (see Figure 1, p. 25). The presented theory states that this appeal or “energy appeal reaction” has been evolutionarily conserved as an adaptive program for transient inflammatory episodes of a systemic nature. In the context of a CID, however, the continuous energy appeal reaction leads to typical systemic disease sequelae.

Depressive Symptoms and Fatigue: Sickness Behavior

Fatigue and related depression appear to be part of an adaptive program that operates during short-lived events such as infection to limit activities of the brain and muscles. This program provides energy-rich fuels for the activated immune system and confines the affected person to a safe place. Mechanisms of sickness behavior have been described for over three decades.¹⁹

Anorexia and Malnutrition

Anorexia is a consequence of sickness behavior and is necessary to conserve energy because foraging behavior is energy consuming. Anorexia is a continuous problem in CIDs (see references in Reference 1). Unfortunately, long-term anorexia leads to malnutrition as demonstrated in CIDs.¹ Importantly, restricted intake of food can lead to deficiencies of vitamin D and vitamin K, as well as deficiencies of metal ions such as zinc, iron, copper, and magnesium, among others.

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Muscle Wasting, Cachexia, and Cachectic Obesity

Cachexia is frequent in the context of CIDs.^20,21 The basis of cachexia is at least twofold: 1) proinflammatory cytokines impair muscle growth (increased levels of myostatin); and 2) chronic loss of androgens promotes muscle wasting. In this setting, muscle proteins are degraded and the resulting amino acids are used in gluconeogenesis in the liver. During transient episodes of inflammation under conditions of anorexia, this change can help provide glucose and amino acids to an activated immune system. In addition, cachexia reduces time and energy spent by muscular work.