Exploring the cellular network of metabolic flexibility in the adipose tissue

Tareen, Samar; Kutmon, Martina; Adriaens, Michiel E.; Mariman, E.C.M.; Kok, Theo M. de; Arts, Ilja C. W.; Evelo, Chris T.

doi:10.1186/s12263-018-0609-3

Cited by 18 publications

(20 citation statements)

References 32 publications

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“…Metabolic flexibility gene list. In a previous study 20 , we explored the cellular processes involved in cellular metabolic flexibility and presented them as a combined network of rate limiting steps involved in these processes. In the current study, we utilised the network and processes from this review to curate a list of genes/proteins involved in the regulation of cellular metabolic flexibility.…”

Section: Proteomicsmentioning

confidence: 99%

“…The purpose of this exercise is to identify and analyse expression profiles of individuals clustered by cellular metabolism centring on metabolic flexibility. In our previous studies 9,20,21 , we have shown how the cellular regulation of the tricarboxylic acid cycle, as well as the switching of substrates between glucose and fatty acids have a central role to play in obesity and chronic ailments such as type 2 diabetes mellitus and metabolic syndrome. Capitalising on this work, we curated a list of 291 genes involved in, or associated with the regulation of, cellular metabolism and substrate switching.…”

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confidence: 99%

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Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

Tareen

Kutmon

Kok

et al. 2020

Sci Rep

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Obesity is a global epidemic, contributing significantly to chronic non-communicable diseases, such as type 2 diabetes mellitus, cardiovascular diseases and metabolic syndrome. Metabolic flexibility, the ability of organisms to switch between metabolic substrates, is found to be impaired in obesity, possibly contributing to the development of chronic illnesses. Several studies have shown the improvement of metabolic flexibility after weight loss. In this study, we have mapped the cellular metabolism of the adipose tissue from a weight loss study to stratify the cellular metabolic processes and metabolic flexibility during weight loss. We have found that for a majority of the individuals, cellular metabolism was downregulated during weight loss, with gene expression of all major cellular metabolic processes (such as glycolysis, fatty acid β-oxidation etc.) being lowered during weight loss and weight maintenance. Parallel to this, the gene expression of immune system related processes involving interferons and interleukins increased. previously, studies have indicated both negative and positive effects of post-weight loss inflammation in the adipose tissue with regards to weight loss or obesity and its co-morbidities; however, mechanistic links need to be constructed in order to determine the effects further. Our study contributes towards this goal by mapping the changes in gene expression across the weight loss study and indicates possible cross-talk between cellular metabolism and inflammation.

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Section: Proteomicsmentioning

confidence: 99%

mentioning

confidence: 99%

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

Tareen

Kutmon

Kok

et al. 2020

Sci Rep

Self Cite

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“…Investigations by many laboratories over the past several decades emphasized the integral role of the mitochondrial pyruvate dehydrogenase complex (PDC) in regulating fuel metabolism and organismal homeostasis in health and during both physiologic and pathologic stress . Under aerobic conditions, PDC catalyzes the rate‐determining step in aerobic glucose oxidation by irreversibly decarboxylating glycolytically derived pyruvate to acetyl coenzyme A (acetyl‐CoA), which condenses with oxaloacetate to form citrate in the tricarboxylic acid (TCA) cycle.…”

Section: Introductionmentioning

confidence: 99%

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Zhu

Long

Zabalawi

et al. 2020

Journal of Leukocyte Biology

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The pyruvate dehydrogenase complex (PDC)/pyruvate dehydrogenase kinase (PDK) axis directs the universal survival principles of immune resistance and tolerance in monocytes by controlling anabolic and catabolic energetics. Immune resistance shifts to immune tolerance during inflammatory shock syndromes when inactivation of PDC by increased PDK activity disrupts the tricarboxylic acid (TCA) cycle support of anabolic pathways. The transition from immune resistance to tolerance also diverts the TCA cycle from citrate‐derived cis‐aconitate to itaconate, a recently discovered catabolic mediator that separates the TCA cycle at isocitrate and succinate dehydrogenase (SDH). Itaconate inhibits succinate dehydrogenase and its anabolic role in mitochondrial ATP generation. We previously reported that inhibiting PDK in septic mice with dichloroacetate (DCA) increased TCA cycle activity, reversed septic shock, restored innate and adaptive immune and organ function, and increased survival. Here, using unbiased metabolomics in a monocyte culture model of severe acute inflammation that simulates sepsis reprogramming, we show that DCA‐induced activation of PDC restored anabolic energetics in inflammatory monocytes while increasing TCA cycle intermediates, decreasing itaconate, and increasing amino acid anaplerotic catabolism of branched‐chain amino acids (BCAAs). Our study provides new mechanistic insight that the DCA‐stimulated PDC homeostat reconfigures the TCA cycle and promotes anabolic energetics in monocytes by reducing levels of the catabolic mediator itaconate. It further supports the theory that PDC is an energy sensing and signaling homeostat that restores metabolic and energy fitness during acute inflammation.

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“…In a recent review [5], we explored the various cellular processes involved in maintaining cellular metabolic flexibility in the adipose tissue. The two major energy production mechanisms, glycolysis and fatty acid oxidation, are tied to the TCA cycle – glycolysis through the production of pyruvate and its conversion to acetyl coenzyme A (acetyl-CoA), and fatty acids through their breakdown to acyl coenzyme A and transportation into the mitochondria through the carnitine transport mechanism for eventual conversion to acetyl-CoA.…”

Section: Introductionmentioning

confidence: 99%

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level

et al. 2019

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Background Metabolic flexibility is the ability of an organism to switch between substrates for energy metabolism, in response to the changing nutritional state and needs of the organism. On the cellular level, metabolic flexibility revolves around the tricarboxylic acid cycle by switching acetyl coenzyme A production from glucose to fatty acids and vice versa. In this study, we modelled cellular metabolic flexibility by constructing a logical model connecting glycolysis, fatty acid oxidation, fatty acid synthesis and the tricarboxylic acid cycle, and then using network analysis to study the behaviours of the model. Results We observed that the substrate switching usually occurs through the inhibition of pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinases (PDK), which moves the metabolism from glycolysis to fatty acid oxidation. Furthermore, we were able to verify four different regulatory models of PDK to contain known biological observations, leading to the biological plausibility of all four models across different cells and conditions. Conclusion These results suggest that the cellular metabolic flexibility depends upon the PDC-PDK regulatory interaction as a key regulatory switch for changing metabolic substrates.

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Exploring the cellular network of metabolic flexibility in the adipose tissue

Cited by 18 publications

References 32 publications

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

Stratifying cellular metabolism during weight loss: an interplay of metabolism, metabolic flexibility and inflammation

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level

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