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Nigel Turner Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia
Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia

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Gregory J Cooney Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia
Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia

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Edward W Kraegen Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia
Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia

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Clinton R Bruce Department of Pharmacology, School of Medical Sciences, Diabetes and Obesity Division, St Vincent's Clinical School, Department of Physiology, University of New South Wales, Sydney, New South Wales, Australia

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Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signalling molecules. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, especially the development of type 2 diabetes (T2D). Since the first recognition of the association between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarises the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.

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Amanda E Brandon Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia
Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Ella Stuart Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Simon J Leslie Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Kyle L Hoehn Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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David E James Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Edward W Kraegen Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia
Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Nigel Turner Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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Gregory J Cooney Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia
Diabetes and Metabolism Division, St Vincent's Clinical School, School of Medical Sciences, School of Biotechnology and Biomolecular Sciences, School of Molecular Bioscience and Sydney Medical School, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

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An important regulator of fatty acid oxidation (FAO) is the allosteric inhibition of CPT-1 by malonyl-CoA produced by the enzyme acetyl-CoA carboxylase 2 (ACC2). Initial studies suggested that deletion of Acc2 (Acacb) increased fat oxidation and reduced adipose tissue mass but in an independently generated strain of Acc2 knockout mice we observed increased whole-body and skeletal muscle FAO and a compensatory increase in muscle glycogen stores without changes in glucose tolerance, energy expenditure or fat mass in young mice (12–16 weeks). The aim of the present study was to determine whether there was any effect of age or housing at thermoneutrality (29 °C; which reduces total energy expenditure) on the phenotype of Acc2 knockout mice. At 42–54 weeks of age, male WT and Acc2 −/− mice had similar body weight, fat mass, muscle triglyceride content and glucose tolerance. Consistent with younger Acc2 −/− mice, aged Acc2 −/− mice showed increased whole-body FAO (24 h average respiratory exchange ratio=0.95±0.02 and 0.92±0.02 for WT and Acc2 −/− mice respectively, P<0.05) and skeletal muscle glycogen content (+60%, P<0.05) without any detectable change in whole-body energy expenditure. Hyperinsulinaemic–euglycaemic clamp studies revealed no difference in insulin action between groups with similar glucose infusion rates and tissue glucose uptake. Housing Acc2 −/− mice at 29 °C did not alter body composition, glucose tolerance or the effects of fat feeding compared with WT mice. These results confirm that manipulation of Acc2 may alter FAO in mice, but this has little impact on body composition or insulin action.

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Keld Fosgerau In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Christian Fledelius In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Kent E Pedersen In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Jesper B Kristensen In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Jens R Daugaard In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Miguel A Iglesias In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Edward W Kraegen In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Stuart M Furler In vivoPharmacology, Rheoscience, Ledøje Bygade 23B, DK-2765 Ledøje-Smørum, Denmark
Novo Nordisk Discovery and Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark
Garvan Institute of Medical Research, 384 Victoria Street, Sydney NSW 2010, Australia

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Lipid accumulation in non-adipose tissues is strongly associated with the metabolic syndrome, possibly due to aberrant partitioning of intracellular fatty acids between storage and oxidation. In the present study, we administered the non-metabolizable fatty acid analog [9,10-3H]-(R)-2-bromopalmitate, and authentic 14C-palmitate to conscious rats, in order to directly examine the initial intracellular fate of fatty acids in a range of insulin-sensitive tissues, including white and red muscles, liver, white adipose tissue, and heart. Rats were studied after administration of an oral glucose load to examine the effect of physiological elevation of glucose and insulin. The tracer results showed that glucose administration partitioned fatty acid toward storage in white muscle (storage:uptake ratios, vehicle vs glucose; 0.64 ± 0.02 vs 0.92 ± 0.09, P < 0.05), and in liver (0.66 ± 0.07 vs 0.98 ± 0.04, P < 0.05), but not in red muscle (1.18 ± 0.07 vs 1.36 ± 0.11, P = not significant). These results demonstrate the physiological relevance of the so-called ‘reverse’ Randle cycle, but surprisingly show that it may be more important in white rather than oxidative red muscle.

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