2014
DOI: 10.1016/j.cell.2014.11.034
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Metabolic Inflexibility: When Mitochondrial Indecision Leads to Metabolic Gridlock

Abstract: Normal energy metabolism is characterized by periodic shifts in glucose and fat oxidation, as the mitochondrial machinery responsible for carbon combustion switches freely between alternative fuels according to physiological and nutritional circumstances. These transitions in fuel choice are orchestrated by an intricate network of metabolic and cell signaling events that enable exquisite crosstalk and cooperation between competing substrates to maintain energy and glucose homeostasis. By contrast, obesity-rela… Show more

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Cited by 319 publications
(338 citation statements)
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“…As a result, the excess carbon from glycolysis is secreted as lactate. Other examples are seen in the cells in diabetic tissues where excess fatty acid oxidation leads to incomplete lipid catabolism and excretion of acyl-carnitines and ketone bodies 2 . Numerous other examples are also apparent such as in the case of excess anabolic substrates released in nucleotide synthesis or the excretion of formic acid during excess one carbon metabolism 3 .…”
Section: Introductionmentioning
confidence: 99%
“…As a result, the excess carbon from glycolysis is secreted as lactate. Other examples are seen in the cells in diabetic tissues where excess fatty acid oxidation leads to incomplete lipid catabolism and excretion of acyl-carnitines and ketone bodies 2 . Numerous other examples are also apparent such as in the case of excess anabolic substrates released in nucleotide synthesis or the excretion of formic acid during excess one carbon metabolism 3 .…”
Section: Introductionmentioning
confidence: 99%
“…Excess supply of energy substrates in obesity and IR is believed to cause mitochondrial dysfunction and increased ROS production [156,201,203,204]. HCHIDs may be causally related to the production of oxidative stress, as the following section shows.…”
Section: Dietary Related Oxidative Stressmentioning
confidence: 99%
“…As insulin controls systemic flux, storage and disposal of glucose, fatty acids and amino acids, insulin sensitivity is a prerequisite for this task [203]. Therefore, development of IR causes significant metabolic perturbations.…”
Section: Citationmentioning
confidence: 99%
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“…Relevance to aging and NAFLD development in human population Muoio (2014) and proposed that the challenge on metabolic flexibility and not leaving the metabolic state at a chronic overnutrition status all the time, are the keys to the health improvement [4,30]. Chronic overnutrition leads to a state of metabolic confusion, wherein excessive carbon supply and heightened substrate competition give rise to a set of intermittent calorie restriction in humans has been reported to increase insulin sensitivity, even more than daily CR that achieves similar weight loss [44,45].…”
Section: Liver Plasticity Induced By the Diet Switchesmentioning
confidence: 99%