Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide

Aims/hypothesisIntramyocellular lipids, including diacylglycerol (DAG) and ceramides, have been linked to insulin resistance. This randomised repeated-measures study examined the effects of diet-induced weight loss (DIWL) and aerobic exercise (EX) on insulin sensitivity and intramyocellular triacylglycerol (IMTG), DAG and ceramide.MethodsSixteen overweight to obese adults (BMI 30.6 ± 0.8; 67.2 ± 4.0 years of age) with either impaired fasting glucose, or impaired glucose tolerance completed one of two lifestyle interventions: DIWL (n = 8) or EX (n = 8). Insulin sensitivity was determined using hyperinsulinaemic–euglycaemic clamps. Intramyocellular lipids were measured in muscle biopsies using histochemistry and tandem mass spectrometry.ResultsInsulin sensitivity was improved with DIWL (20.6 ± 4.7%) and EX (19.2 ± 12.9%). Body weight and body fat were decreased by both interventions, with greater decreases in DIWL compared with EX. Muscle glycogen, IMTG content and oxidative capacity were all significantly (p < 0.05) decreased with DIWL and increased with EX. There were decreases in DAG with DIWL (−12.4 ± 14.6%) and EX (−40.9 ± 12.0%). Ceramide decreased with EX (−33.7 ± 11.2%), but not with DIWL. Dihydroceramide was decreased with both interventions. Sphingosine was decreased only with EX. Changes in total DAG, total ceramides and other sphingolipids did not correlate with changes in glucose disposal. Stearoyl-coenzyme A desaturase 1 (SCD1) content was decreased with DIWL (−19.5 ± 8.5%, p < 0.05), but increased with EX (19.6 ± 7.4%, p < 0.05). Diacylglycerol acyltransferase 1 (DGAT1) was unchanged with the interventions.Conclusions/interpretationDiet-induced weight loss and exercise training both improved insulin resistance and decreased DAG, while only exercise decreased ceramides, despite the interventions having different effects on IMTG. These alterations may be mediated through differential changes in skeletal muscle capacity for oxidation and triacylglycerol synthesis.Trial registration:ClinicalTrials.gov NCT00766298Funding:ADA Clinical Research Award (B. H. Goodpaster), NIH R01 AG20128 (B. H. Goodpaster), Obesity and Nutrition Research (1P30DK46204) and Clinical and Translational Research Centers (UL1 RR024153)

[1]  M. Tarnopolsky,et al.  Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[2]  C. Bouchard,et al.  Familial aggregation of VO(2max) response to exercise training: results from the HERITAGE Family Study. , 1999, Journal of applied physiology.

[3]  R N Bergman,et al.  Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study. , 1998, JAMA.

[4]  F. Toledo,et al.  Insulin Resistance Is Associated With Higher Intramyocellular Triglycerides in Type I but Not Type II Myocytes Concomitant With Higher Ceramide Content , 2009, Diabetes.

[5]  I. Ichi,et al.  Effect of dietary cholesterol and high fat on ceramide concentration in rat tissues. , 2007, Nutrition.

[6]  B. Fielding,et al.  Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects. , 1996, Metabolism: clinical and experimental.

[7]  Sarah E. Sauers,et al.  Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited. , 2008, American journal of physiology. Endocrinology and metabolism.

[8]  B. Goodpaster,et al.  Exercise training increases intramyocellular lipid and oxidative capacity in older adults. , 2004, American journal of physiology. Endocrinology and metabolism.

[9]  W. Kraus,et al.  Sex-specific alterations in mRNA level of key lipid metabolism enzymes in skeletal muscle of overweight and obese subjects following endurance exercise. , 2009, Physiological genomics.

[10]  J. Helge,et al.  Human skeletal muscle ceramide content is not a major factor in muscle insulin sensitivity , 2008, Diabetologia.

[11]  R. DeFronzo,et al.  Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. , 2004, Diabetes.

[12]  J. Horowitz,et al.  Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. , 2007, The Journal of clinical investigation.

[13]  G. Shulman,et al.  Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle* , 2002, The Journal of Biological Chemistry.

[14]  G. Heigenhauser,et al.  Endurance training in obese humans improves glucose tolerance and mitochondrial fatty acid oxidation and alters muscle lipid content. , 2006, American journal of physiology. Endocrinology and metabolism.

[15]  N. Turner,et al.  Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation. , 2009, American journal of physiology. Endocrinology and metabolism.

[16]  C. Newgard,et al.  Obesity-related derangements in metabolic regulation. , 2006, Annual review of biochemistry.

[17]  C. Schmitz‐Peiffer,et al.  Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate* , 1999, The Journal of Biological Chemistry.

[18]  L. V. van Loon,et al.  Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes. , 2004, American journal of physiology. Endocrinology and metabolism.

[19]  G. Schmitz,et al.  Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals. , 2009, The Journal of clinical endocrinology and metabolism.

[20]  A. Bielawska,et al.  Simultaneous quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. , 2006, Methods.

[21]  Simon C Watkins,et al.  Intramuscular lipid content is increased in obesity and decreased by weight loss. , 2000, Metabolism: clinical and experimental.

[22]  S. Summers,et al.  Ceramides in insulin resistance and lipotoxicity. , 2006, Progress in lipid research.

[23]  L. Nybo,et al.  Adipose triglyceride lipase in human skeletal muscle is upregulated by exercise training. , 2009, American journal of physiology. Endocrinology and metabolism.

[24]  F. Schick,et al.  Individual Stearoyl-CoA Desaturase 1 Expression Modulates Endoplasmic Reticulum Stress and Inflammation in Human Myotubes and Is Associated With Skeletal Muscle Lipid Storage and Insulin Sensitivity In Vivo , 2009, Diabetes.

[25]  Simon C Watkins,et al.  Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. , 2001, The Journal of clinical endocrinology and metabolism.

[26]  G. Shulman,et al.  Diacylglycerol-mediated insulin resistance , 2010, Nature Medicine.

[27]  M. Febbraio,et al.  Stearoyl CoA desaturase 1 is elevated in obesity but protects against fatty acid-induced skeletal muscle insulin resistance in vitro , 2006, Diabetologia.

[28]  N. Ruderman,et al.  Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and IκB-α , 2002 .

[29]  R R Wing,et al.  Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. , 1999, Diabetes.

[30]  S. Carrasco,et al.  Diacylglycerol, when simplicity becomes complex. , 2007, Trends in biochemical sciences.

[31]  P. Grimaldi,et al.  CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness. , 2004, Diabetes.

[32]  R. Kreis,et al.  Transcriptional adaptations of lipid metabolism in tibialis anterior muscle of endurance-trained athletes. , 2003, Physiological genomics.

[33]  I. Kowalska,et al.  Relationship between insulin sensitivity and sphingomyelin signaling pathway in human skeletal muscle. , 2004, Diabetes.

[34]  Y. Hannun,et al.  Bioactive sphingolipids: metabolism and function This work was supported by National Institutes of Health Grants GM-43825 and CA-87584. Published, JLR Papers in Press, November 17, 2008. , 2009, Journal of Lipid Research.

[35]  Y. Hannun,et al.  Effects of sphingosine and other sphingolipids on protein kinase C. , 2000, Methods in enzymology.

[36]  C. Kahn,et al.  Effects of diet and genetic background on sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase 1, and the development of the metabolic syndrome. , 2005, Diabetes.

[37]  G. Reaven,et al.  Isolated Impaired Fasting Glucose and Peripheral Insulin Sensitivity , 2008, Diabetes Care.

[38]  G. Cooney,et al.  Increased efficiency of fatty acid uptake contributes to lipid accumulation in skeletal muscle of high fat-fed insulin-resistant rats. , 2002, Diabetes.

[39]  R. Dobrowsky,et al.  A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids* , 2003, The Journal of Biological Chemistry.