Upstream eventNot Increased, Circulating Ketone Bodies
Increased, Catabolism of Muscle Protein
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Antagonist binding to PPARα leading to body-weight loss||non-adjacent||Moderate||Low|
Life Stage Applicability
Key Event Relationship Description
A fundamental process in all biological systems is the production of metabolic fuel for use in meeting the energy demands of cells and the systemic energy needs of multi-cellular organisms. Physiological studies of the progression of human starvation have identified that the preferred metabolic fuel is glucose in the fed state and progressing through two days of fasting, afterward ketone bodies become increasingly important for meeting energy demands (Cahill 2006, Owen et al 2005). Substrates derived from carbohydrates, fats and protein can contribute to gluconeogenesis (Cahill 2006, Gerich et al 2001) whereas substrates derived from fatty acids are the primary contributors to ketogenesis (KE5, Desvergne and Wahli 1999). Mobilization of fatty acids as a metabolic fuel source increase dramatically during fasting to support both gluconeogenesis and ketogenesis (Evans et al 2004). Cahill (2006) and colleagues have demonstrated the importance of ketone body production, especially β-hydroxybutyrate, for maintaining energy homeostasis during starvation. β-hydroxybutyrate serves as an alternative substrate to glucose for providing energy to the brain in the starvation state, providing ATP at higher efficiency relative to the glucose substrate (Cahill 2006). Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Badman et al 2007, Potthoff 2009, Sengupta et al 2010). The Badman et al (2007) study indicated that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was inhibited under PPARα knockout. Increased concentrations of circulating ketone bodies is indicative of potential metabolic fuel deficits in fasting animals (Cahill 2006), and a lack of increase in circulating ketone bodies during fasting, especially in conjunction with elevated blood triglycerides, indicates impaired ketogenesis and potentially impaired bioenergetic potential.
After two to three days of fasting in humans, dietary glucose has been long-since expended and contribution to blood glucose from glycogen metabolism is reduced to zero (Cahill 2006). At this point, about two fifths of fatty acid metabolism in the whole body is dedicated to hepatic ketogenesis, largely in support of the energy demands of the brain, however the brain is still significantly supported by glucose derived from gluconeogenesis (Cahill 2006). PPARα knockout mice that were either fasted or exercised to exhaustion had diminished capacity for maintaining energetic substrates in serum (glucose and lactate) while showing diminished capacity for fatty acid oxidation (serum nonesterified fatty acids) and decreased ketogenesis resulting in hypoketonemia (decreased serum β-hydroxybutyrate) relative to wild types (Muoio et al 2002). As fatty acid stores are depleted or become unusable (as in the PPARα knockout condition described above), gluconeogenesis from other substrates becomes increasingly important including muscle protein catabolism in situ for supporting muscle function as well as releasing glutamine (Marliss et al 1971) and alanine (Felig et al 1970A) which can be recycled to glucose by gluconeogenesis in the kidney (Goodman et al 1966, Kashiwaya et al 1994, Cahill 2006). Renal gluconeogenesis from glutamine and alanine supports two fifths of new glucose production while the remaining three fifths is produced in liver from, (a) alanine derived from muscle and nonhepatic splanchnic bed, (b) recycled lactate and pyruvate from red blood cells and renal medulla, (c) glycerol from adipose lipolysis and (d) small amounts of β-hydroxybutyrate are recycled to glucose (Cahill 2006). Blood concentrations of alanine exert control over hepatic glucose production and thus also represent a diagnostic of alanine contribution from muscle to support gluconeogenesis (Cahill 2006, Felig et al 1970B). In prolonged starvation events, the catabolism of muscle protein (KE6) for gluconeogenesis in order to support systemic energy needs results in loss of muscle mass which contributes to loss of overall body weight. Although it has not yet been investigated experimentally, it is plausible based on the results described above for Muoio et al (2002) that diminished PPARα signaling capacity could exacerbate muscle wasting in long-term fasting and/or malnutrition events.
Evidence Supporting this KER
The scoring for the KER, where the KE, “no increase in circulating ketone bodies” -> the KE, increased, catabolism of muscle protein” reflected the observation that amino acid recycling to glucose via renal gluconeogenesis (Goodman et al. 1966, Kashiwaya et al. 1994) is a broadly separate process and under separate regulatory control from ketogenesis (Felig et al. 1970B, Sengupta et al. 2010). However, under starvation conditions in conjunction with diminished circulating ketone bodies to serve as fuel for systemic metabolism, an increase in catabolism of muscle protein would be required to support renal gluconeogensis to sustain the systemic energy budget. Therefore, although the KER, for the KE, “no increase in circulating ketone bodies” -> the KE, increased, catabolism of muscle protein” lacks a mechanistic connection, a strong correlative relationship exists between the KEs regarding energy homeostasis, hence the weight of evidence for the KER was scored as “moderate” however the quantitative understanding was scored as “weak”.
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
Include consideration of temporal concordance here
As described in the bullets above, there is fairly robust empirical support for this KER, although dedicated assays providing mechanistic / quantitative relationships between amino acid recycling for energy production relative to ketogenesis-based energy production are still needed.
Uncertainties and Inconsistencies
See previous section.
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
Although the KER, for the KE, “no increase in circulating ketone bodies” -> the KE, “increased, catabolism of muscle protein” lacks a mechanistic connection, a strong correlative relationship exists between the KEs regarding energy homeostasis. Discovering response-response relationships regarding this complex signaling network represents a key basic research question related to systemic energy metabolism. We are not currently aware of any models available to extrapolate results among KEs.
The timescale is dependent on availability of alternative energy reserves including glycogen and fatty acids.
Known modulating factors
Availability of alternative energy substrates may chance the dynamics of this KER.
Known Feedforward/Feedback loops influencing this KER
Ketogenesis diminishes after transition from a fasted state to a fed state
Domain of Applicability
The relationships described herein have been primarily established in human and rodent models.
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