Role of the liver in the control of glucose‐lipid utilization and body weight

Purpose of review This review depicts recent developments concerning the role of the liver in control of carbohydrate and lipid utilization from ingestion to storage; it covers the liver's influence on food intake, post‐absorptive nutrient metabolism and body weight. The mechanisms involved have implications for the pathogenesis of obesity and type II diabetes. Recent findings Recent studies have identified some of the molecular and biochemical mechanisms which control whole body and hepatic carbohydrate and lipid metabolism, thus providing the basis of the liver's role in the control of food intake, metabolism, and body weight. Fatty acids are known to effect gene transcription in various ways. Advances in our understanding of the control of glucose and lipid utilization by the liver include (1) a better functional characterization of some newly discovered transcription factors, (2) new discoveries concerning the physiological and pathophysiological role of hepatic glucokinase and of the glycogen‐targeting subunits of protein phosphatase‐1, and (3) the demonstration of substantial overlap in the molecular control mechanisms of glucose‐lipid utilization. Also, impaired insulin signaling due to a certain gene (Foxo1) has emerged as a possible unifying mechanism for various common metabolic abnormalities of type II diabetes. Finally, recent findings confirm and extend previous knowledge about the important role of hepatic nerves in the control of liver and whole body glucose‐lipid utilization. Summary The identification of new molecular and neural mechanisms of the hepatic control of glucose‐lipid utilization and body weight provides a focus for future studies and may eventually help to develop new treatments for obesity and type II diabetes.

[1]  N. Keim,et al.  Fructose, weight gain, and the insulin resistance syndrome. , 2002, The American journal of clinical nutrition.

[2]  A. Cherrington,et al.  Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs. , 2002, American journal of physiology. Endocrinology and metabolism.

[3]  T. Wolever,et al.  Inverse association between the effect of carbohydrates on blood glucose and subsequent short-term food intake in young men. , 2002, The American journal of clinical nutrition.

[4]  R. Seeley,et al.  Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. , 2002, Diabetes.

[5]  F. Gonzalez,et al.  The Coactivator PGC-1 Is Involved in the Regulation of the Liver Carnitine Palmitoyltransferase I Gene Expression by cAMP in Combination with HNF4α and cAMP-response Element-binding Protein (CREB)* , 2002, The Journal of Biological Chemistry.

[6]  R. Bergman Pathogenesis and prediction of diabetes mellitus: lessons from integrative physiology. , 2002, The Mount Sinai journal of medicine, New York.

[7]  I. G. Fantus,et al.  Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ , 2002 .

[8]  R. DeFronzo,et al.  Free fatty acids reduce splanchnic and peripheral glucose uptake in patients with type 2 diabetes. , 2002, Diabetes.

[9]  D. Accili,et al.  Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1 , 2002, Nature Genetics.

[10]  G. Boden Interaction between free fatty acids and glucose metabolism , 2002, Current opinion in clinical nutrition and metabolic care.

[11]  E. Duplus,et al.  Is there a single mechanism for fatty acid regulation of gene transcription? , 2002, Biochemical pharmacology.

[12]  A. McIntosh,et al.  Liver Fatty Acid-binding Protein Targets Fatty Acids to the Nucleus , 2002, The Journal of Biological Chemistry.

[13]  G. Rousseau,et al.  Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6 , 2002, Diabetologia.

[14]  A. Baudry,et al.  Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver , 2002, Diabetologia.

[15]  F. Pi‐Sunyer Glycemic index and disease. , 2002, The American journal of clinical nutrition.

[16]  A. Leeds Glycemic index and heart disease. , 2002, The American journal of clinical nutrition.

[17]  J. Manson,et al.  Glycemic index, glycemic load, and risk of type 2 diabetes. , 2002, The American journal of clinical nutrition.

[18]  K. Jungermann,et al.  Activation of glucokinase gene expression by hepatic nuclear factor 4alpha in primary hepatocytes. , 2002, The Biochemical journal.

[19]  M. Mozzoli,et al.  FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. , 2002, American journal of physiology. Endocrinology and metabolism.

[20]  Takumi Kawaguchi,et al.  Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. , 2002, Biochemical pharmacology.

[21]  G. Ronnett,et al.  C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Gašperíková,et al.  Fatty Acid Regulation of Gene Expression , 2002 .

[23]  E. Ravussin,et al.  Increased Fat Intake, Impaired Fat Oxidation, and Failure of Fat Cell Proliferation Result in Ectopic Fat Storage, Insulin Resistance, and Type 2 Diabetes Mellitus , 2002, Annals of the New York Academy of Sciences.

[24]  A. Cherrington,et al.  Direct and indirect effects of insulin on glucose uptake and storage by the liver. , 2002, Diabetes.

[25]  D. Ludwig,et al.  The glycemic index: physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. , 2002, JAMA.

[26]  E. Parks Changes in fat synthesis influenced by dietary macronutrient content , 2002, Proceedings of the Nutrition Society.

[27]  S. Eaton Control of mitochondrial beta-oxidation flux. , 2002, Progress in lipid research.

[28]  E. Parks Dietary carbohydrate's effects on lipogenesis and the relationship of lipogenesis to blood insulin and glucose concentrations , 2002, British Journal of Nutrition.

[29]  T. Kadowaki,et al.  A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes , 2002, Diabetologia.

[30]  M. Osbakken,et al.  High-fat diet prevents eating response and attenuates liver ATP decline in rats given 2,5-anhydro-D-mannitol. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[31]  P. Jones,et al.  Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity. , 2002, The Journal of nutrition.

[32]  R. Bergman,et al.  Extreme insulin resistance of the central adipose depot in vivo. , 2002, Diabetes.

[33]  M. Osbakken,et al.  Interactions of dietary fat and 2,5-anhydro-D-mannitol on energy metabolism in isolated rat hepatocytes. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[34]  H. Yamashita,et al.  Mechanism for Fatty Acid “Sparing” Effect on Glucose-induced Transcription , 2002, The Journal of Biological Chemistry.

[35]  C. Chu,et al.  Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs. , 2002, American journal of physiology. Endocrinology and metabolism.

[36]  P. Hsieh,et al.  Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs. , 2002, American journal of physiology. Endocrinology and metabolism.

[37]  C. Newgard,et al.  Glycogen-targeting Subunits and Glucokinase Differentially Affect Pathways of Glycogen Metabolism and Their Regulation in Hepatocytes* , 2002, The Journal of Biological Chemistry.

[38]  C. Newgard,et al.  Reversal of Diet-induced Glucose Intolerance by Hepatic Expression of a Variant Glycogen-targeting Subunit of Protein Phosphatase-1* , 2002, The Journal of Biological Chemistry.

[39]  K. Kondo,et al.  Effects of Dietary Medium-Chain Triacylglycerols on Serum Lipoproteins and Biochemical Parameters in Healthy Men , 2002, Bioscience, biotechnology, and biochemistry.

[40]  I. G. Fantus,et al.  Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-delta. , 2002, American journal of physiology. Endocrinology and metabolism.

[41]  M. Latour,et al.  Insulin sensitivity regulated by feeding in the conscious unrestrained rat. , 2002, Canadian journal of physiology and pharmacology.

[42]  D. Gašperíková,et al.  Fatty acid regulation of gene expression: a genomic explanation for the benefits of the mediterranean diet. , 2002, Annals of the New York Academy of Sciences.

[43]  P. Even,et al.  Body weight, body composition, and energy metabolism in lean and obese Zucker rats fed soybean oil or butter. , 2002, The American journal of clinical nutrition.

[44]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[45]  M. Sakurai,et al.  A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  W. Langhans,et al.  Intrameal hepatic-portal infusion of glucose reduces spontaneous meal size in rats , 2001, Physiology & Behavior.

[47]  W. Lautt,et al.  Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[48]  R. Bergman,et al.  Hypoglycemic detection does not occur in the hepatic artery or liver: findings consistent with a portal vein glucosensor locus. , 2001, Diabetes.

[49]  R. Bergman,et al.  Free Fatty Acids and Pathogenesis of Type 2 Diabetes Mellitus , 2000, Trends in Endocrinology & Metabolism.

[50]  Xia Li,et al.  Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[51]  R. Bergman,et al.  Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin. , 2000, American journal of physiology. Endocrinology and metabolism.

[52]  H. Berman,et al.  Distinctive Regulatory and Metabolic Properties of Glycogen-targeting Subunits of Protein Phosphatase-1 (PTG, GL, GM/RGl) Expressed in Hepatocytes* , 2000, The Journal of Biological Chemistry.

[53]  R. N. Bergman,et al.  Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein? , 2000, Diabetologia.

[54]  R. Bergman,et al.  Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. , 2000, Diabetes.

[55]  W. Langhans Portal-Hepatic Sensors for Glucose, Amino Acids, Fatty Acids, and Availability of Oxidative Products , 1999 .

[56]  N. Barzilai,et al.  Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action. , 1999, American journal of physiology. Endocrinology and metabolism.

[57]  A. Cherrington,et al.  Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. , 1999, Diabetes.

[58]  N. Barzilai,et al.  Surgical removal of visceral fat reverses hepatic insulin resistance. , 1999, Diabetes.

[59]  A. Treloar,et al.  Expression of Human Hepatic Glucokinase in Transgenic Mice Liver Results in Decreased Glucose Levels and Reduced Body Weight , 1997, Diabetes.

[60]  A. Takahashi,et al.  Effects of hepatic nerve stimulation on blood glucose and glycogenolysis in rat liver: studies with in vivo microdialysis. , 1996, Journal of the autonomic nervous system.

[61]  L. Rossetti,et al.  Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis. , 1996, The American journal of physiology.

[62]  A. Niijima Afferent impulse discharges from glucoreceptors in the liver of the guinea pig. , 1996, Nutrition.

[63]  N. Rawson,et al.  Phosphate loading prevents the decrease in ATP and increase in food intake produced by 2,5-anhydro-D-mannitol. , 1994, The American journal of physiology.

[64]  N. Rawson,et al.  Hepatic phosphate trapping, decreased ATP, and increased feeding after 2,5-anhydro-D-mannitol. , 1994, The American journal of physiology.

[65]  M. Tordoff,et al.  2,5-anhydro-D-mannitol acts in liver to initiate feeding. , 1991, The American journal of physiology.

[66]  A. Niijima,et al.  Neural control of blood glucose level. , 1986, The Japanese journal of physiology.

[67]  A. Niijima,et al.  Reflex control of the autonomic nervous system activity from the glucose sensors in the liver in normal and midpontine-transected animals. , 1984, Journal of the autonomic nervous system.