Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Antagonist binding to PPARalpha leading to starvation-like body-weight loss||KE||Strong|
|Homo sapiens||Homo sapiens||Strong||NCBI|
|Mus musculus||Mus musculus||Strong||NCBI|
|Rattus rattus||Rattus rattus||Moderate||NCBI|
Level of Biological Organization
How this Key Event works
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 for gluconeogenesis in order to support systemic energy needs results in loss of muscle mass which contributes to loss of overall body weight.
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Glutamate and glutamine were measured in fresh plasma taken from human subjects that were fasted and those in a postabsorptive state using enzymatic assays (Mariliss et al 1971).
In Kashiwaya et al (1994), perfused rat hearts were prepared for metabolic flux experiments. Measurement of enzyme kinetics involved in glycoloysis and gluconeogenesis were measured using fluorometric procedures measuring the oxidation or reduction of pyridine nucleotides. Radio-labeled substrates were used to track metabolite flux during glucolysis / gluconeogenesis.
Goodman et al provided in vitro assessment of gluconeogenic capacity of renal cortex in rats. Glutamatic acid and other ketogenic substrates were added and measure in the system and measured as net glucose content.
All amino acids were measured in Felig et al (1970A), however the analytical methods that were references were not found using Google Scholar search.
Evidence Supporting Taxonomic Applicability
Evidence for mouse provided in (Cahill 2006, Marliss et al 1971, Gelig et al 1970A, 1970B). Evidence for rat provided in Kashiwaya et al 1994, Goodman et al 1966). Evidence for human provided in (Cahill 2006).
Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1-22.
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.
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.