ASPECTS OF METABOLIC REGULATION

Metabolism is tightly regulated at many levels and, if disrupted, can lead to severe metabolic disorders such as insulin-resistant diabetes and cardiovascular disease. So, building an understanding of metabolic regulation is essential if we are to begin to combat many of the disorders that characterise metabolic syndrome and the obesity crisis. David Wasserman and colleagues at Vanderbilt University School of Medicine, USA discuss the control of glucose flux in muscle (p. 254). Describing the delivery of glucose to muscle tissue, transport in and glucose phosphorylation – which traps glucose in the muscle and completes the uptake process – Wasserman explains that glucose uptake is under distributed control by all three of these processes. Ultimately, the team hopes that ‘one or more of these steps should be effective targets for treatment of glucose intolerance and insulin resistance’.Considering the role of diffusion in metabolic processes, Stephen Kinsey and colleagues from the University of North Carolina, Wilmington and Florida State University, USA explain that ‘metabolic processes are often represented as a group of metabolites that interact through enzymatic reactions’. However, they go on to add that diffusion may exert greater control over reaction rates as distances increase and reaction rates rise or diffusion coefficients decrease. Focusing on muscle fibres, which vary enormously in size, Kinsey and his colleagues discuss the effects of muscle fibre organisation and the intracellular environment on metabolic diffusion (p. 263) and conclude that ‘metabolic processes in muscles... are not greatly limited by diffusion,’ but add, ‘the influence of diffusion is apparent in patterns of fibre growth and metabolic organization’.Life in the cold has profound effects on metabolism for ectotherms. Kristin O'Brien from the University of Alaska Fairbanks, USA says, ‘As temperature declines, one of the greatest challenges is maintaining the production of ATP’. One strategy for survival in frigid conditions is to increase the levels of enzymes involved in aerobic metabolism by increasing the volume of mitochondria in cells. O'Brien reviews the current understanding of the molecular pathways that govern mitochondrial molecular remodelling (p. 275). She also outlines the consequences of increased mitochondrial density, such as increased lipid densities, raised oxygen solubility and reduced diffusion distances. As well as increasing protein synthesis levels, O'Brien explains that cold-adapted fish also increase membrane synthesis rates, and she speculates about the signalling molecules that regulate the process of mitochondrial biosynthesis.Animals also have to select which metabolic fuels they use in response to different energetic demands. Jean-Michel Weber from the University of Ottawa, Canada explains that each fuel type has different strengths and weaknesses. Lipids are light to transport and abundant but are insoluble in water and slow to produce ATP. Alternatively, carbohydrates can synthesise ATP rapidly but are heavy and scarce, so a particular fuel is only selected for use when its advantages outweigh its disadvantages. Weber explains that animals use a variety of strategies to optimise fuel use (p. 286), including AMPK regulation of fuel selection and the recruitment of specific muscle fibre types that metabolise the most appropriate fuel for a particular activity. Migrating animals that maintain intense exercise for days at a time must also be able to sustain record fluxes of fuel to their locomotory muscles. They do so by boosting lipid mobilisation, transport and oxidation to maximise aerobic ATP production during their marathon odysseys.

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