Figure 1

Pathophysiology of insulin resistance according to the new theory. Upper panel: Acute activation programs were positively selected for short-lived activation of either the brain or the immune system. Hierarchically, the brain and the immune system are on the same level. Activation of the brain mainly stimulates stress axes hormones and activates the sympathetic nervous system (SNS). This is supported by a mild inflammatory process that is paralleled by mental activation (A). Activation of the immune system induces cytokines, chemokines, and danger signals. In addition, the inflammatory process uncouples the locally inflamed area from the control of the brain by cytokine-induced hormone/ neurotransmitter production in the periphery independent of superordinate stress pathways. This leads to hepatic cortisol secretion [140], adrenocorticotropic hormone-independent cortisol secretion [141], and production of leukocyte hormones [142] and leukocyte neurotransmitters [143]. The activation of the immune system is accompanied by a mild stimulation of the hypothalamic-pituitary-adrenal axis (HPA) axis (albeit inadequately low in relation to inflammation) and a somewhat stronger stimulation of the SNS (B). Despite activation of the SNS, anti-inflammatory neurotransmitters of sympathetic nerve fibers do not reach the uncoupled inflamed tissue [144]. Inflammatory and mental activation are often accompanied by anorexia and sickness behavior, which aggravates energy shortage. Lower panel: Chronic energy storage and memory programs were positively selected. The major storage organs are fat tissue (glycerol, free fatty acids) and muscles (proteins). The liver is more a switchboard to interchange and renew energetic substrates. The main storage factor is insulin so that insulin resistance can be seen as a catabolic program induced by catabolic pathways (upper panel). Numbers in red give the typical time of energy provision by the respective organ (amino acids from muscle are spared from day 3 onwards). Storage is mainly supported by a positively selected program of foot intake/foraging behavior and memory. Memory is outstandingly important to spare energy-rich fuels (brain, immune system). Dashed black arrows in the lower panel demonstrate real and hypothetical connections between respective organs. Black numbers give a typical figure of stored energy in the respective organs. Dashed black line between upper and lower boxes separates the programs positively selected for acute (catabolic) versus chronic states (storage and memory). CAEN, controllable amount of energy (the energy that is regulated and negotiated between organs); 11βHSD1, 11-beta-hydroxy steroid dehydrogenase type 1 [140].