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Shiho Fujisaka First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Sugitani, Toyama, Japan

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Yoshiyuki Watanabe First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Sugitani, Toyama, Japan

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Kazuyuki Tobe First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Sugitani, Toyama, Japan

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Physiological role of the gut microbiota Nutrient metabolism and absorption Degradation of indigestible polysaccharides Short-chain fatty acids (SCFAs) are metabolites generated from the fermentation of insoluble dietary fiber and

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Alyce M Martin College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

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Emily W Sun College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

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Damien J Keating College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

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serving distinct metabolic functions. The body’s surplus energy is primarily stored in WAT as triglycerides and liberated from the adipocyte as free fatty acids and glycerol when required. Excess adiposity secondary to increased fat storage within WAT is a

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Renata Risi Department of Experimental Medicine, Sapienza University of Rome, Sapienza University of Rome, Rome, Italy
University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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Antonio Vidal-Puig University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P. R. China
Centro de Investigacion Principe Felipe, Valencia, Spain

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Guillaume Bidault University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK

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free fatty acid (FFA) levels, notably in their saturated form, are positively associated with the incidence of T2D ( Wang et al. 2003 , Qureshi et al. 2019 ). Abnormal intracellular lipid accumulation and adipocyte infiltration in the pancreas

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Laura L Gathercole Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Nikolaos Nikolaou Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Shelley E Harris Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Anastasia Arvaniti Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Toryn M Poolman Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Jonathan M Hazlehurst Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK

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Denise V Kratschmar Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

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Marijana Todorčević Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Ahmad Moolla Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Niall Dempster Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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Ryan C Pink Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK

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Michael F Saikali Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

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Liz Bentley Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK

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Trevor M Penning Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

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Claes Ohlsson Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

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Carolyn L Cummins Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

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Matti Poutanen Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland

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Alex Odermatt Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland

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Roger D Cox Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, UK

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Jeremy W Tomlinson Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK

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–/– males had increased serum triacyclglycerols ( Fig. 4E ), monoacylglycerols and diacylglycerols ( Fig. 4F ) and non-esterified fatty acids ( Fig. 4G ), but without change in total or HDL cholesterol ( Fig. 4H ). Relative intensity values for acylglycerols

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Stephen R Bloom Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Tricia M-M Tan Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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. 2017 ). Lipid metabolism After a short period of fasting, lean GCGR −/− mice have similar levels of plasma triglycerides, free fatty acids and cholesterol to wild-type mice ( Parker et al. 2002 , Gelling et al. 2003 , Conarello et al

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Affiong Ika Oqua Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Yusman Manchanda Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Emma Rose McGlone Department of Surgery and Cancer, Imperial College London, London, UK

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Ben Jones Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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Sarah Rouse Department of Life Sciences, Imperial College, London, UK

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Alejandra Tomas Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

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gluconeogenesis, as well as hepatic amino acid uptake and ureagenesis ( Marroqui et al . 2014 ), while reducing hepatic fat accumulation by increasing fatty acid oxidation and decreasing de novo lipogenesis ( Longuet et al . 2008 ). GLP-2R is expressed mainly

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Gencer Sancar German Center for Diabetes Research, Neuherberg, Germany
Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany

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Andreas L Birkenfeld German Center for Diabetes Research, Neuherberg, Germany
Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany
Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany

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are met and its storage capacity is full, ceramides accumulate by leading to the coupling of free fatty acids to the sphingoid backbone. As ceramides accumulate, they initially could protect cells from acute increases in fatty acids and enhance

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Vicki Chen Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Gia V Shelp Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Jacob L Schwartz Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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Niklas D J Aardema Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, Utah, United States

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Madison L Bunnell Department of Nutrition, Dietetics and Food Sciences, Utah State University, Logan, Utah, United States

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Clara E Cho Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada

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-derived factors such as short-chain fatty acids ( Reigstad et al. 2015 ) as molecular targets in linking colon 5-HT and metabolic health. Fourth, we cannot ignore potential maternal influences on the establishment of the gut microbiota and serotonergic functions

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Esther Nuñez-Durán Department of Molecular and Clinical Medicine, Lundberg Laboratory for Diabetes Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Belén Chanclón Department of Molecular and Clinical Medicine, Lundberg Laboratory for Diabetes Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

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Silva Sütt Department of Molecular and Clinical Medicine, Lundberg Laboratory for Diabetes Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Joana Real Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

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Hanns-Ulrich Marschall Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Ingrid Wernstedt Asterholm Department of Metabolic Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

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Emmelie Cansby Department of Molecular and Clinical Medicine, Lundberg Laboratory for Diabetes Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Margit Mahlapuu Department of Molecular and Clinical Medicine, Lundberg Laboratory for Diabetes Research, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

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Fatty Acid Quantification Colorimetric kit (BioVision). Determination of Mitochondrial DNA (MtDNA) content Total DNA was extracted from pancreas using the EZNA Tissue DNA kit (Omega Bio-Tek). MtDNA content was measured with quantitative real

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Antonia Hufnagel University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK

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Laura Dearden University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK

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Denise S Fernandez-Twinn University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK

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Susan E Ozanne University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Cambridge, Cambridgeshire, UK

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increases glucose production and break down of fat stores in the mother, thus releasing both glucose and fatty acids from the maternal circulation to be readily taken up by the rapidly growing fetus ( Grimes & Wild 2018 ) (Fig. 2 ). It was debated up until

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