The flux of energy in critical illness and the obesity paradox

Abstract

During critical illness, systemic inflammation causes organ-specific metabolic changes. In the immune and inflammatory compartments, predominantly anabolic reprogramming supports cellular replication and inflammatory response execution. Pari passu, catabolism of adipose tissue and skeletal muscle supplies carbon skeletons and enthalpy for inflammatory and immune cell anabolism. The liver plays a key role during these metabolic shifts in enabling adequate supply of glucose and ketone bodies to the circulation. Although often perceived as passive surrogates of prehospitalization frailty, body mass constituents are active parties of an overarching metabolic trade-off that is key for survival after acute insults. Muscle and adipose tissue remodel in response to critical illness and thus profoundly influence the systemic metabolic landscape during and after hospitalization. Whether obesity's effect on patient systemic metabolism and survival is paradoxically beneficial or not remains controversial. Substrate-induced epigenetic changes lead to abnormal transcriptional programs that in turn regulate metabolic pathways critical to patient survival. We present a summary of major mechanisms involved in the flux of energy in critical illness from body mass into immune response execution and suggest future research avenues focused on perturbed immune-metabolic and epigenetic programs that could lead to improved understanding of these processes, and eventually to better outcomes for the critically ill.

Keywords: body mass; critical illness; immune reprogramming; obesity paradox; skeletal muscle.

Figure 1:. Mitochondrial respiration and Warburg-type metabolism:

The mitochondrial tricarboxylic acid (TCA) cycle, represented on a light-blue hue background, receives oxidable substrate from multiple sources such as, prototypically, glycolysis. TCA cycle intermediates’ oxidation contribute electrons, which are transferred to the mitochondrial electron transport chain (ETC) located at the inner mitochondrial membrane and represented here on a light-yellow hue background. ETC-driven transfer of TCA-contributed electrons generates a mitochondrial intermembrane H⁺ gradient, which dissipation provides heat, and also the free energy needed for ATP generation by the ATP synthase. In cells with high demand of readily available ATP and carbon skeletons for biomass generation, such as cells executing the inflammatory response, substrate oxidation occurs extra mitochondrially via aerobic glycolysis or Warburg-type metabolism, presented on a light-green hue background. Warburg-type metabolism enables the rapid generation of ATP, and also contributes multiple intermediate species, depicted in pink-hue boxes, required for accelerated anabolism. Mitochondrial function is not dispensable during Warburg-type metabolism shown by recent evidence implicating it in the generation of reactive oxygen species (ROS) critically needed for cellular function during Warburg metabolism. Also, intermediates of the TCA cycle are needed for cellular signaling, anaplerotic reactions, epigenetic modifications and substrate building blocks. See text for details and references. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 2:. Blueprints of metabolic responses to fasting versus critical illness:

During fasting (left panel), multiple sources of carbon-containing substrate including amino acids, glycerol and lactate undergo transformation into glucose by the liver and, less significantly, the kidney. Free fatty acids released by adipose tissue lipolysis can undergo ketogenesis and contribute fuel to skeletal muscle and other tissues. During sepsis response (right panel), there is a reduced contribution of fat-derived fatty acids to ketogenesis. Gluconeogenesis-generated glucose is used by inflammatory and immune cells to fuel aerobic glycolysis and support the acute systemic inflammatory response. Amino acids released by muscle and lungs are also directly used by inflammatory and other cells to support multiple functions including protein synthesis. Note that critical illness is a state of hyperinsulinemia and insulin resistance. Glucose incorporation to skeletal muscle is lessened during fasting due to reduced insulin availability. By contrast, during critical illness and despite hyperinsulinemia, there is a reduced GLUT4 expression in the sarcolemma which undermines glucose incorporation. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 3:. The Cori cycle:

During critical illness, lactate is produced in excess by skeletal muscle and other organs. Lactate is carried by the circulatory blood into the liver where it is reconverted to pyruvate and then glucose via the Cori cycle. Glucose can then be used for oxidation avoiding lactate becoming a dead-end product. Lactate can also be used as fuel by myocardium and brain. Note that while muscle lactate generation via glycolysis yields 2 ATP per molecule of glucose, liver glucose generation uses 6 ATPs, which makes the whole process bioenergetically costly. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 4:. Epigenetic regulation induced by substrate availability.

Multiple intermediate species of cellular oxidation operate as epigenetic regulators. For example, acetyl-CoA from the TCA cycle contributes the acetyl groups needed for chromatin acetylation, which influences gene expression by regulating chromatin permissiveness. The ratio of succinate over α-ketoglutarate regulates enzymes like TETs and KDMs, which control DNA and histone methylation, respectively. These epigenetic marks are important for the establishment of the transcriptional landscape during systemin inflammation in critical illness. See text for details. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 5:. Obesity paradox and the plasticity of adipose tissue in critical illness.

While the obesity paradox has not been universally corroborated, multiple potential mechanisms have been suggested to account for the benefit of fat excess during critical illness. These mechanisms include the expansion of immunomodulatory M2 macrophages; the higher availability of substrate such as gluconeogenic glycerol and ketogenic free-fatty acids; reduced size of adipocytes, which is associated with elevated fat storing potential in subcutaneous adipose tissue, and thus limiting the ectopic depots expansion, typically associated with poorer outcomes. Also, obesity has been found to be associated with reduced incidence of hypoglycemia during critical illness. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 6:. Mechanisms of muscle proteolysis: A: Ubiquitin-proteasome pathway.

This is the predominant mechanism to degrade muscle protein and requires the attachment of a chain composed of multiple 76 amino acid protein ubiquitin (Ub). This polyubiquitin generation involves three steps: first, Ub is activated by the ubiquitin-activating enzyme E1 via an ATP-dependent reaction leading to a Ub thioester, a highly reactive form of Ub. Second, E1-bound Ub via the thioester linkage is transferred to a sulfhydryl group of one of the Ub carrier proteins, E2. Third, E3 ligases, such as MuRF1, act as scaffolds to transfer the activated Ub from E2s to the target protein such as for example myosin, which “marks” that protein for proteasome degradation. This degradation is also ATP-dependent and results in amino acids release for reuse. B: The autophagy pathway. This is a stress-response pathway that orchestrates the removal of dysfunctional proteins and organelles, which are incorporated into vesicles and delivered to lysosomes for degradation. To do that, an initial step involves the formation of an autophagosome engulfing organelles and/pr proteins; the autophagosome-lysosome fusion ensues, which eventually leads to a digestion step and recycling of substrate. Graphics were constructed with clipart supplied by BioRender.com (2024).

Figure 7:. Plasticity of skeletal muscle in critical illness.

Skeletal muscle contributes to the systemic glucose pool both directly, by reducing the glucose incorporation via endocytosis of GLUT4; and indirectly by the output of gluconeogenic amino acids, which are in turn derived from the proteolytic systems and from intracellular free amino acid pools. Also increased activity of the Na,K-ATPase (sodium) pump and, possibly, mitochondrial dysfunction, lead to higher lactate output that is used for glucose production (Cori cycle) in the liver. Muscle-derived glucose and amino acids are instrumental to support Warburg metabolism in immune and inflammatory cells. As part of muscle plasticity induced by critical illness, intramuscular fat accumulation develops as well. See text for details. Graphics were constructed with clipart supplied by BioRender.com (2024).