The role of substrate cycles in metabolic regulation

Newsholme, Eric A.; Arch, Jonathan R. S.; Brooks, Brian J.; Surholt, Bernhard

doi:10.1042/bst0110052

Cited by 35 publications

(23 citation statements)

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“…In fact, this point is absolutely essential for physiological metabolic regulation, to allow a change in 'sensitivity' of an entire pathway to various effectors. These concepts are clearly approached and described by Newsholme et al [31]. Thus, a small increase in the forward direction, stimulated by an effector molecule, may dramatically increase flux through the pathway if the reverse enzyme does not change velocity.…”

Section: Substrate Cyclesmentioning

confidence: 97%

Regulatory principles in metabolism–then and now

Curi

Newsholme

Marzuca‐Nassr

et al. 2016

Biochemical Journal

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The importance of metabolic pathways for life and the nature of participating reactions have challenged physiologists and biochemists for over a hundred years. Eric Arthur Newsholme contributed many original hypotheses and concepts to the field of metabolic regulation, demonstrating that metabolic pathways have a fundamental thermodynamic structure and that near identical regulatory mechanisms exist in multiple species across the animal kingdom. His work at Oxford University from the 1970s to 1990s was groundbreaking and led to better understanding of development and demise across the lifespan as well as the basis of metabolic disruption responsible for the development of obesity, diabetes and many other conditions. In the present review we describe some of the original work of Eric Newsholme, its relevance to metabolic homoeostasis and disease and application to present state-of-the-art studies, which generate substantial amounts of data that are extremely difficult to interpret without a fundamental understanding of regulatory principles. Eric's work is a classical example of how one can unravel very complex problems by considering regulation from a cell, tissue and whole body perspective, thus bringing together metabolic biochemistry, physiology and pathophysiology, opening new avenues that now drive discovery decades thereafter.

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Section: Substrate Cyclesmentioning

confidence: 97%

Regulatory principles in metabolism–then and now

Curi

Newsholme

Marzuca‐Nassr

et al. 2016

Biochemical Journal

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“…Before the reasons behind the choice of enzyme can be understood, the difference between near-equilibrium and nonequilibrium reactions must be explained, and the meaning of the term flux-generating step must be appreciated (for detailed reviews, see Newsholme and Crabtree, 1976Crabtree, ,1981.…”

Section: Theoretical Basis For the Use Of Maximum Enzyme Activities Amentioning

confidence: 99%

Maximum catalytic activity of some key enzymes in provision of physiologically useful information about metabolic fluxes

Newsholme

Crabtree²

1986

J. Exp. Zool.

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The energy required by tissues (e.g., for movement, biosynthesis, ion transport, and for maintenance of structures) is obtained at a molecular level by the hydrolysis of ATP to ADP. The resynthesis of ATP occurs in the processes of fuel oxidation within the cell. Since ATP is not stored in the cell, any increase in the rate of energy demand by a cell must result in an immediate and precise increase in the rate of fuel oxidation to provide the necessary ATP. In addition to these rapid regulatory responses, many animals and plants are subject to longer term changes in both the capacity for energy production and its utilisation by virtue of seasonal changes in environmental temperature, food availability, reproductive requirements, and behavioural demands. The modifications in metabolic pathways of energy storage, production, and utilisation with the progression of the seasons clearly enables organisms to take advantage of favourable conditions, as well as to survive particularly unfavourable conditions.Various fuels (e.g., glucose, glycogen, fatty acids, triglyceride, and amino acids) are available for oxidation by the individual tissues and these follow different routes or pathways of metabolism. One very important question for biologists and physiologists is: Which fuel(s) is being used to provide most of the energy for a given tissue? Indeed, knowledge of the maximum capacity of energy-producing pathways is required before the physiological importance of the pathway can be appreciated and, in some cases, before the physiological role of the tissue can be properly assessed.Various experimental techniques for the precise measurement of flux through a pathway have been developed largely over the past 30 years. A description of methods has been given elsewhere (Newsholme et al., '78; Newsholme et al., '80), but one of these, which depends on the measurement of the maximum activities of certain key enzymes, is described in detail in this article. This method has several advantages over others; it is very simple, it can be used for comparative studies of a large range of animals, and it can be used in humans (or any large animal), usually with minimum surgical intervention. Unfortunately, its very simplicit has led to its misapplication leading to a lac$ of confidence in the technique. For this reason, the theoretical practical basis for the choice of enzymes that can be used as flux indicators is described below, together with details of the practical approach to obtaining the quantitative information and, finally, some examples of its use. THEORETICAL BASIS FOR THE USE OF MAXIMUM ENZYME ACTIVITIES AS INDICATORS OF MAXIMUM FLUXBefore the reasons behind the choice of enzyme can be understood, the difference between near-equilibrium and nonequilibrium reactions must be explained, and the meaning of the term flux-generating step must be appreciated (for detailed reviews, see Newsholme and Crabtree, 1976,1979. Near-equilibrium, nonequilibrium and flux-generating reactionsNear-equilibrium and nonequilibrium reactionsReac...

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“…Aside from its role in TG degradation, Jenkins et al (39) reported acylglycerol transacylase activity of ATGL using an oleate donor, which in the presence of monoolein or diolein produced DG and TG, respectively. This unusual finding is relevant for TG futile cycling, which is proposed to provide a continuous pool of FAs to facilitate an immediate response to the metabolic demands of organisms (56). The implications of this are discussed later.…”

Section: Regulation Of Tg Lipasesmentioning

confidence: 99%

Triacylglycerol lipases and metabolic control: implications for health and disease

Watt

Spriet

2010

American Journal of Physiology-Endocrinology and Metabolism

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Watt MJ, Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J Physiol Endocrinol Metab 299: E162-E168, 2010. First published January 12, 2010; doi:10.1152/ajpendo.00698.2009.-Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during physical activity. This review outlines the identification of the new TG lipase, adipose triglyceride lipase, the current understanding of how cellular TG lipases are regulated, and the implications for understanding the integrated control of TG lipolysis. Furthermore, this review outlines recent advances that propose a "revised" role for TG lipases in cellular function, metabolic homeostasis, and disease prevention. fatty acid; metabolism; adipose; skeletal muscle TRIACYLGLYCEROLS (TG) are stored within discrete cytosolic lipid droplets within most tissues. Contrary to the common misconception in the literature that the TG pool is "inert," these droplets are highly dynamic, and the TG within is highly labile. The overall TG content within these droplets is ultimately dependent on the balance between the rates of TG hydrolysis and fatty acid uptake, oxidation, and storage. The fatty acids derived from TG breakdown participate in a variety of cellular processes, including membrane biosynthesis, signal transduction, and, most critically for this review, ATP production after ␤-oxidation. From a systemic viewpoint, fatty acids can be derived from both intracellular and extracellular sources, and with the exception of adipose tissue, the latter is most prevalent due to limited intracellular stores. Under postprandial conditions, ϳ30% of total energy expenditure is reliant on fatty acids derived from adipose TG hydrolysis, and this becomes quantitatively more important with extended fasting or exercise. In cases of caloric surplus leading to obesity, elevated circulating fatty acids may contribute to the accumulation of intramyocellular and hepatic lipids, which are associated with secondary metabolic complications such as insulin resistance (77). Therefore, the liberation of fatty acids from adipocyte TG and release into the systemic circulation is under most conditions the first point of control in the regulation of fatty acid metabolism, and accordingly, tight control of adipocyte lipolysis is a critical mediator of whole body metabolic homeostasis. Similarly, an emerging body of evidence indicates that altering TG metabolism within ectopic tissues, such as liver and skeletal muscle, can influence local fatty acid metabolism with implications for obesity-related metabolic disorders.This review will first focus on the regulation of TG lipolysis and how the understanding of TG regulation has evolved since the discovery and partial characterization of adipose triglyceride lipase (ATGL) only 5 years ago. The review will then outline how changes in TG metabolism can influence adipocyte and skeletal muscle metabolism and summarize the recent evidence sug...

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The role of substrate cycles in metabolic regulation

Cited by 35 publications

References 0 publications

Regulatory principles in metabolism–then and now

Regulatory principles in metabolism–then and now

Maximum catalytic activity of some key enzymes in provision of physiologically useful information about metabolic fluxes

Triacylglycerol lipases and metabolic control: implications for health and disease

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