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Clinical Studies and Practice

Relatively low endogenous fatty acid mobilization and uptake helps preserve insulin sensitivity in obese women

International Journal of Obesity volume 39, pages 149–155 (2015) Cite this article

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Abstract

Background:

Although obesity is commonly linked with metabolic disease risk, some obese adults do not develop metabolic abnormalities, such as insulin resistance.

Objectives:

The primary aim of this study was to determine whether alterations in fatty acid mobilization and uptake underlie differences in insulin sensitivity (Si) among a seemingly homogeneous cohort of obese women.

Methods:

Insulin sensitivity (frequently sampled intravenous glucose tolerance test), basal fatty acid rate of disappearance from plasma (Rd), resting whole-body fat oxidation, intramyocellular triacylglycerol (IMTG) concentration and markers of skeletal muscle inflammation were measured in 21 obese women. Participants were divided into tertiles based on their Si. The subset of participants with the lowest Si (LOW-Si; Si⩽2.1 (mU/l)−1 min−1; n=7) was compared with the subset of participants with the highest Si, who exhibited relatively normal insulin sensitivity (NORM-Si; Si⩾3.4 (mU/l)−1 min−1; n=8).

Results:

Despite nearly identical physical characteristics in LOW-Si vs NORM-Si (body mass index: 34±2 vs 34±1 kg m−2; %body fat: 48±1 vs 47±1%; waist circumference: 104±2 vs 104±2 cm; VO2 max: 2.2±0.2 vs 2.3±0.1 l min−1), fatty acid Rd was nearly 30% lower in NORM (P=0.02). Importantly, the greater rate of fatty acid uptake in LOW-Si vs NORM-Si did not translate to higher rate of fat oxidation (3.5±0.2 vs 3.7±0.2 μmol kg−1 min−1) or to a measureable difference in IMTG content (68.3±12.7 vs 63.7±6.7 μmol g−1 dry weight). In conjunction with the lower fatty acid Rd in NORM-Si vs LOW-Si, activation of inflammatory pathways known to impair insulin action in skeletal muscle was also lower (lower phosphorylated c-jun N-terminal kinase (JNK) and higher inhibitor of κB (IκB-α) abundance). In contrast, LOW-Si and NORM-Si exhibited no differences in plasma markers of inflammation (TNFα, IL-6 (interleukin-6), MCP-1).

Conclusion:

These findings suggest that obese women who maintain a relatively low rate of endogenous fatty acid uptake may be somewhat ‘protected’ against the development of insulin resistance potentially by less activation of inflammatory pathways within skeletal muscle.

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References

  1. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement executive summary. Diabetes Care 2010; 33: 2692–2696.

    Article  Google Scholar 

  2. Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med 2008; 168: 1617–1624.

    Article  Google Scholar 

  3. Horowitz JF, Coppack SW, Paramore D, Cryer PE, Zhao G, Klein S . Effect of short-term fasting on lipid kinetics in lean and obese women. Am J Physiol 1999; 276: E278–E284.

    CAS  PubMed  Google Scholar 

  4. Roust LR, Jensen MD . Postprandial free fatty acid kinetics are abnormal in upper body obesity. Diabetes 1993; 42: 1567–1573.

    Article  CAS  Google Scholar 

  5. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97: 2859–2865.

    Article  CAS  Google Scholar 

  6. Kelley DE, Mokan M, Simoneau JA, Mandarino LJ . Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 1993; 92: 91–98.

    Article  CAS  Google Scholar 

  7. Bajaj M, Suraamornkul S, Romanelli A, Cline GW, Mandarino LJ, Shulman GI et al. Effect of a sustained reduction in plasma free fatty acid concentration on intramuscular long-chain fatty Acyl-CoAs and insulin action in type 2 diabetic patients. Diabetes 2005; 54: 3148–3153.

    Article  CAS  Google Scholar 

  8. Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ et al. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 1999; 48: 1836–1841.

    Article  CAS  Google Scholar 

  9. Worm D, Henriksen JE, Vaag A, Thye-Ronn P, Melander A, Beck-Nielsen H . Pronounced blood glucose-lowering effect of the antilipolytic drug acipimox in noninsulin-dependent diabetes mellitus patients during a 3-day intensified treatment period. J Clin Endocrinol Metab 1994; 78: 717–721.

    CAS  PubMed  Google Scholar 

  10. Itani SI, Ruderman NB, Schmieder F, Boden G . Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005–2011.

    Article  CAS  Google Scholar 

  11. Boden G . Obesity and free fatty acids. Endocrinol Metab Clin North Am 2008; 37: 635–646.

    Article  CAS  Google Scholar 

  12. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333–336.

    Article  CAS  Google Scholar 

  13. Sriwijitkamol A, Christ-Roberts C, Berria R, Eagan P, Pratipanawatr T, DeFronzo RA et al. Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes 2006; 55: 760–767.

    Article  CAS  Google Scholar 

  14. Nguyen MTA, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 2005; 280: 35361–35371.

    Article  CAS  Google Scholar 

  15. Tuvdendorj D, Chandalia M, Batbayar T, Saraf M, Beysen C, Murphy EJ et al. Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin-resistant humans. Am J Physiol Endocrinol Metab 2013; 305: E999–E1006.

    Article  CAS  Google Scholar 

  16. Girousse A, Tavernier G, Valle C, Moro C, Mejhert N, Dinel AL et al. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 2013; 11: e1001485.

    Article  CAS  Google Scholar 

  17. Schenk S, Harber MP, Shrivastava CR, Burant CF, Horowitz JF . Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity. J Physiol 2009; 587: 4949–4961.

    Article  CAS  Google Scholar 

  18. Schenk S, Cook JN, Kaufman AE, Horowitz JF . Postexercise insulin sensitivity is not impaired after an overnight lipid infusion. Am J Physiol Endocrinol Metab 2005; 288: E519–E525.

    Article  CAS  Google Scholar 

  19. Patterson BW, Zhao G, Klein S . Improved accuracy and precision of gas chromatography/mass spectrometry measurements for metabolic tracers. Metabolism 1998; 47: 706–712.

    Article  CAS  Google Scholar 

  20. Newsom SA, Schenk S, Thomas KM, Harber MP, Knuth ND, Goldenberg N et al. Energy deficit after exercise augments lipid mobilization but does not contribute to the exercise-induced increase in insulin sensitivity. J Appl Physiol 2010; 108: 554–560.

    Article  CAS  Google Scholar 

  21. Wolfe RR . Radioactive and Stable Isotope Tracers in Biomedicine: Principles and Practice of Kinetic Analysis. Wiley-Liss: New York, 1992.

    Google Scholar 

  22. Frayn KN, Maycock PF . Skeletal muscle triacylglycerol in the rat: methods for sampling and measurement, and studies of biological variability. J Lipid Res 1980; 21: 139–144.

    CAS  PubMed  Google Scholar 

  23. Frayn KN . Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 1983; 55: 628–634.

    Article  CAS  Google Scholar 

  24. Steele R . Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci 1959; 82: 420–430.

    Article  CAS  Google Scholar 

  25. Bergman RN, Prager R, Volund A, Olefsky JM . Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp. J Clin Invest 1987; 79: 790–800.

    Article  CAS  Google Scholar 

  26. Saad MF, Anderson RL, Laws A, Watanabe RM, Kades WW, Chen YD et al. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study. Diabetes 1994; 43: 1114–1121.

    Article  CAS  Google Scholar 

  27. Tai MM . A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care 1994; 17: 152–154.

    Article  CAS  Google Scholar 

  28. Caumo A, Bergman RN, Cobelli C . Insulin sensitivity from meal tolerance tests in normal subjects: a minimal model index. J Clin Endocrinol Metab 2000; 85: 4396–4402.

    Article  CAS  Google Scholar 

  29. Schenk S, Horowitz JF . Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest 2007; 117: 1690–1698.

    Article  CAS  Google Scholar 

  30. Karin M . The beginning of the end: IkappaB kinase (IKK) and NF-kappaB activation. J Biol Chem 1999; 274: 27339–27342.

    Article  CAS  Google Scholar 

  31. Pajunen P, Kotronen A, Korpi-Hyovalti E, Keinanen-Kiukaanniemi S, Oksa H, Niskanen L et al. Metabolically healthy and unhealthy obesity phenotypes in the general population: the FIN-D2D Survey. BMC Public Health 2011; 11: 754.

    Article  Google Scholar 

  32. Morino K, Petersen KF, Shulman GI . Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006; 55 (Suppl 2): S9–S15.

    Article  CAS  Google Scholar 

  33. Holloszy JO . ‘Deficiency’ of mitochondria in muscle does not cause insulin resistance. Diabetes 2013; 62: 1036–1040.

    Article  CAS  Google Scholar 

  34. Han DH, Hancock CR, Jung SR, Higashida K, Kim SH, Holloszy JO . Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. PLoS One 2011; 6: e19739.

    Article  CAS  Google Scholar 

  35. Schenk S, Saberi M, Olefsky JM . Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 2008; 118: 2992–3002.

    Article  CAS  Google Scholar 

  36. Samuel VT, Petersen KF, Shulman GI . Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010; 375: 2267–2277.

    Article  CAS  Google Scholar 

  37. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11: 191–198.

    Article  CAS  Google Scholar 

  38. Gual P, Le Marchand-Brustel Y, Tanti JF . Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005; 87: 99–109.

    Article  CAS  Google Scholar 

  39. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM . Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 2005; 54: 2351–2359.

    Article  CAS  Google Scholar 

  40. Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982; 54: 254–260.

    Article  CAS  Google Scholar 

  41. Bjorntorp P . Abdominal obesity and the development of noninsulin-dependent diabetes mellitus. Diabetes Metab Rev 1988; 4: 615–622.

    Article  CAS  Google Scholar 

  42. Janssen I, Katzmarzyk PT, Ross R . Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med 2002; 162: 2074–2079.

    Article  Google Scholar 

  43. Despres JP, Lemieux I . Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881–887.

    Article  CAS  Google Scholar 

  44. Goodpaster BH, Krishnaswami S, Harris TB, Katsiaras A, Kritchevsky SB, Simonsick EM et al. Obesity, regional body fat distribution, and the metabolic syndrome in older men and women. Arch Intern Med 2005; 165: 777–783.

    Article  Google Scholar 

  45. Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R et al. Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults. JAMA 2012; 308: 1150–1159.

    Article  CAS  Google Scholar 

  46. Fox CS, Massaro JM, Hoffmann U, Pou KM, Maurovich-Horvat P, Liu CY et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007; 116: 39–48.

    Article  Google Scholar 

  47. Janssen I, Heymsfield SB, Allison DB, Kotler DP, Ross R . Body mass index and waist circumference independently contribute to the prediction of nonabdominal, abdominal subcutaneous, and visceral fat. Am J Clin Nutr 2002; 75: 683–688.

    Article  CAS  Google Scholar 

  48. Bolinder J, Kager L, Ostman J, Arner P . Differences at the receptor and postreceptor levels between human omental and subcutaneous adipose tissue in the action of insulin on lipolysis. Diabetes 1983; 32: 117–123.

    Article  CAS  Google Scholar 

  49. Ostman J, Arner P, Engfeldt P, Kager L . Regional differences in the control of lipolysis in human adipose tissue. Metabolism 1979; 28: 1198–1205.

    Article  CAS  Google Scholar 

  50. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD . Splanchnic lipolysis in human obesity. J Clin Invest 2004; 113: 1582–1588.

    Article  CAS  Google Scholar 

  51. Nurjhan N, Campbell PJ, Kennedy FP, Miles JM, Gerich JE . Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 1986; 35: 1326–1331.

    Article  CAS  Google Scholar 

  52. Magkos F, Fabbrini E, Conte C, Patterson BW, Klein S . Relationship between adipose tissue lipolytic activity and skeletal muscle insulin resistance in nondiabetic women. J Clin Endocrinol Metab 2012; 97: E1219–E1223.

    Article  CAS  Google Scholar 

  53. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G . Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001; 280: E745–E751.

    Article  CAS  Google Scholar 

  54. Ouchi N, Parker JL, Lugus JJ, Walsh K . Adipokines in inflammation and metabolic disease. Nat Rev Immunol 2011; 11: 85–97.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was primarily supported by grants from the American Diabetes Association (1-03JF10) and the National institutes of Health (R01DK077966). Additional support was provided by the Michigan Clinical Research Center (2UL1TR000433) and the University of Michigan Nutrition and Obesity Research Center (P30DK089503). We are very thankful to Dr Alexander Hinko for his assistance with the fatty acid tracer analysis, the nursing staff of the Michigan Clinical Research Center for their clinical support throughout the study, to the Chemistry Core of the Michigan Diabetes Research Center (P30DK020572) for measuring plasma insulin concentration and finally, we are particularly grateful to the study subjects for their participation in this project.

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Authors and Affiliations

  1. Substrate Metabolism Laboratory, School of Kinesiology, University of Michigan, Ann Arbor, MI, USA

    D W Van Pelt, S A Newsom, S Schenk & J F Horowitz

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  2. S A Newsom
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Correspondence to J F Horowitz.

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Van Pelt, D., Newsom, S., Schenk, S. et al. Relatively low endogenous fatty acid mobilization and uptake helps preserve insulin sensitivity in obese women. Int J Obes 39, 149–155 (2015). https://doi.org/10.1038/ijo.2014.70

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