Relationship:884

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Circulating Ketone Bodies, Not Increased Catabolism of Muscle Protein, Increased

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Antagonist binding to PPARalpha leading to starvation-like body-weight loss Indirectly Leads to Moderate Weak

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

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). As fatty acid stores are depleted, 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.

Weight of Evidence

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

Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.

Empirical Support for Linkage

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 or 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.

Evidence Supporting Taxonomic Applicability

The relationships described herein have been primarily established in human and rodent models.

References


Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 2007, 5(6):426-437.

Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1-22.

Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.

Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361.

Felig P, Pozefsky T, Marliss E, Cahill GF, Jr.: Alanine: key role in gluconeogenesis. Science 1970A, 167(3920):1003-1004.

Felig P, Marliss E, Pozefsky T, Cahill GF, Jr.: Amino acid metabolism in the regulation of gluconeogenesis in man. Am J Clin Nutr 1970B, 23(7):986-992.

Gerich JE, Meyer C, Woerle HJ, Stumvoll M: Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001, 24(2):382-391.

Goodman AD, Fuisz RE, Cahill GF: Renal gluconeogenesis in acidosis, alkalosis, and potassium deficiency: its possible role in regulation of renal ammonia production. J Clin Invest 1966, 45(4):612-619.

Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL, Passonneau JV: Control of glucose utilization in working perfused rat heart. J Biol Chem 1994, 269(41):25502-25514.

Marliss EB, Aoki TT, Pozefsky T, Most AS, Cahill GF: Muscle and splanchnic glutamine and glutamate metabolism in postabsorptive and starved man. J Clin Invest 1971, 50(4):814-817.

Owen OE: Ketone bodies as a fuel for the brain during starvation. Biochem Mol Biol Educ 2005, 33(4):246-251.

Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA et al: FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proceedings of the National Academy of Sciences 2009, 106(26):10853-10858.

Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010, 468(7327):1100-1104.

Veech RL: The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004, 70(3):309-319.

Williamson DH, Mellanby J, Krebs HA: Enzymic determination of d(−)-β-hydroxybutyric acid and acetoacetic acid in blood. Biochem J 1962, 82(1):90-96.