Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health

Abstract

Over the past 20 years, growing interest in the biochemistry, nutrition, and pharmacology of l-arginine has led to extensive studies to explore its nutritional and therapeutic roles in treating and preventing human metabolic disorders. Emerging evidence shows that dietary l-arginine supplementation reduces adiposity in genetically obese rats, diet-induced obese rats, finishing pigs, and obese human subjects with Type-2 diabetes mellitus. The mechanisms responsible for the beneficial effects of l-arginine are likely complex, but ultimately involve altering the balance of energy intake and expenditure in favor of fat loss or reduced growth of white adipose tissue. Recent studies indicate that l-arginine supplementation stimulates mitochondrial biogenesis and brown adipose tissue development possibly through the enhanced synthesis of cell-signaling molecules (e.g., nitric oxide, carbon monoxide, polyamines, cGMP, and cAMP) as well as the increased expression of genes that promote whole-body oxidation of energy substrates (e.g., glucose and fatty acids) Thus, l-arginine holds great promise as a safe and cost-effective nutrient to reduce adiposity, increase muscle mass, and improve the metabolic profile in animals and humans.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

ACC:

Acetyl-CoA carboxylase

AMPK:

AMP-activated protein kinase

Arg:

l-Arginine

BAT:

Brown adipose tissue

CPT-1:

Carnitine palmitoyl transferase-1

DIO:

Diet-induced obese

GC:

Guanylyl cyclase

LCFA:

Long-chain fatty acid

NO:

Nitric oxide

NOS:

Nitric oxide synthase

PGC-1α:

Peroxisome proliferator-activated receptor γ coactivator-1α

UPC1:

Uncoupling protein-1

WAT:

White adipose tissue

ZDF:

Zucker diabetic fatty

References

  1. Baker DH (2009) Advances in protein-amino acid nutrition of poultry. Amino Acids 37:29–41

    Article  CAS  PubMed  Google Scholar 

  2. Böger RH, Bode-Böger SM (2001) The clinical pharmacology of l-arginine. Annu Rev Pharmacol Toxiol 41:79–99

    Article  Google Scholar 

  3. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359

    Article  CAS  PubMed  Google Scholar 

  4. CDC (2009) Obesity and overweight for professionals: data and statistics. http://www.cdc.gov/obesity/data/index.html. Accessed 20 Nov 2009

  5. Chung KY, Choi CB, Kawachi H et al (2005) Trans-10, cis-12 conjugated linoleic acid antagonizes arginine-promoted differentiation of bovine preadipocytes. Adipocytes 2:93–100

    Google Scholar 

  6. Cypess AM, Lehman S, Williams G et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517

    Article  CAS  PubMed  Google Scholar 

  7. De Luca B, Monda M, Sullo A (1995) Changes in eating behavior and thermogenic activity following inhibition of nitric oxide formation. Am J Physiol 268:R1533–R1538

    PubMed  Google Scholar 

  8. Deng D, Yin YL, Chu WY et al (2009) Impaired translation initiation activation and reduced protein synthesis in weaned piglets fed a low-protein diet. J Nutr Biochem 20:544–552

    Article  CAS  PubMed  Google Scholar 

  9. Eklou-Lawson M, Bernard F, Neveux N et al (2009) Colonic luminal ammonia and portal blood l-glutamine and l-arginine concentrations: a possible link between colon mucosa and liver ureagenesis. Amino Acids 37:751–760

    Article  CAS  PubMed  Google Scholar 

  10. Elango R, Ball RO, Pencharz PB (2009) Amino acid requirements in humans: with a special emphasis on the metabolic availability of amino acids. Amino Acids 37:19–27

    Article  CAS  PubMed  Google Scholar 

  11. Flegal KM, Carroll MD, Ogden CL et al (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303:235–241

    Article  CAS  PubMed  Google Scholar 

  12. Flynn NE, Bird JG, Guthrie AS (2009) Glucocorticoid regulation of amino acid and polyamine metabolism in the small intestine. Amino Acids 37:123–129

    Article  CAS  PubMed  Google Scholar 

  13. Fu WJ, Haynes TE, Kohli R et al (2005) Dietary l-arginine supplementation reduces fat mass in Zucker diabetic fatty rats. J Nutr 135:714–721

    CAS  PubMed  Google Scholar 

  14. Garcia-Villafranca J, Guillen A, Castro J (2003) Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes. Biochem Pharmacol 65:807–812

    Article  CAS  PubMed  Google Scholar 

  15. Gaudiot N, Jaubert AM, Charbonnier E et al (1998) Modulation of white adipose tissue lipolysis by nitric oxide. J Biol Chem 273:13475–13481

    Article  CAS  PubMed  Google Scholar 

  16. Gouill EL, Jimenez M, Binnert C et al (2007) Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial β-oxidation. Diabetes 56:2690–2696

    Article  PubMed  Google Scholar 

  17. Haas B, Mayer P, Jennissen K et al (2009) Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Sci Signal 2(99):ra78

    Article  PubMed  Google Scholar 

  18. Haynes TE, Li P, Li XL et al (2009) l-Glutamine or l-alanyl-l-glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes. Amino Acids 37:131–142

    Article  CAS  PubMed  Google Scholar 

  19. He QH, Kong XF, Wu G et al (2009) Metabolomic analysis of the response of growing pigs to dietary l-arginine supplementation. Amino Acids 37:199–208

    Article  CAS  PubMed  Google Scholar 

  20. Himmshagen J (1990) Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J 4:2890–2898

    CAS  Google Scholar 

  21. Jobgen WS, Fried SK, Fu WJ et al (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 17:571–588

    Article  CAS  PubMed  Google Scholar 

  22. Jobgen W, Meininger CJ, Jobgen SC et al (2009a) Dietary l-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats. J Nutr 139:230–237

    CAS  PubMed  Google Scholar 

  23. Jobgen W, Fu WJ, Gao H, Li P et al (2009b) High fat feeding and dietary l-arginine supplementation differentially regulate gene expression in rat white adipose tissue. Amino Acids 37:187–198

    Article  CAS  PubMed  Google Scholar 

  24. Kamerman PR, Laburn HP, Mitchell D (2003) Inhibitors of nitric oxide synthesis block cold-induced thermogenesis in rats. Can J Physiol Pharmacol 81:834–838

    Article  CAS  PubMed  Google Scholar 

  25. Kersten S (2001) Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep 2:282–286

    Article  CAS  PubMed  Google Scholar 

  26. King DE, Mainous AG, Geesey ME (2008) Variation in l-arginine intake follow demographics and lifestyle factors that may impact cardiovascular disease risk. Nutr Res 28:21–24

    Article  CAS  PubMed  Google Scholar 

  27. Kohli R, Meininger CJ, Haynes TE et al (2004) Dietary l-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr 134:600–608

    CAS  PubMed  Google Scholar 

  28. Lehman JJ, Barger PM, Kovacs A et al (2000) Peroxisome proliferator-activated receptor gamma coactivator 1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856

    Article  CAS  PubMed  Google Scholar 

  29. Li X, Bazer FW, Gao H et al (2009) Amino acids and gaseous signaling. Amino Acids 37:65–78

    Article  PubMed  Google Scholar 

  30. Lira VA, Soltow QA, Long JH et al (2007) Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. Am J Physiol Endocrinol Metab 293:E1062–E1068

    Article  CAS  PubMed  Google Scholar 

  31. Lucotti P, Setola E, Monti LD et al (2006) Beneficial effects of a long-term oral l-arginine added to a hypocaloric diet and exercise training program in obese, insulin-resistant 2 diabetic patients. Am J Physiol Endocrinol Metab 291:E906–E912

    Article  CAS  PubMed  Google Scholar 

  32. Ma XY, Lin YC, Jiang ZY et al (2010) Dietary arginine supplementation enhances antioxidative capacity and improves meat quality of finishing pigs. Amino Acids 38:95–102

    Article  CAS  PubMed  Google Scholar 

  33. Madsen KL, Brockway PD, Johnson LR et al (1996) Role of ornithine decarboxylase in enterocyte mitochondrial function and integrity. Am J Physiol 270:G789–G797

    CAS  PubMed  Google Scholar 

  34. McConell GK, Ng GP, Phillips M et al (2009) Central role of nitric oxide synthase in AICAR and caffeine induced mitochondrial biogenesis in L6 myocytes. J Appl Physiol. doi:10.1152/japplphysiol.00377.2009

  35. Mendez JD, Balderas F (2001) Regulation of hyperglycemia and dyslipidemia by exogenous l-arginine in diabetic rats. Biochimie 83:453–458

    Article  CAS  PubMed  Google Scholar 

  36. Mersmann HJ, Smith SB (2005) Development of white adipose tissue lipid metabolism. In: Burrin DG, Mersmann HJ (eds) Biology of metabolism in growing animals. Elsevier, Oxford, pp 275–302

    Google Scholar 

  37. Nisoli E, Carruba MO (2004) Emerging aspects of pharmacotherapy for obesity and metabolic syndrome. Pharmacol Res 50:453–469

    Article  CAS  PubMed  Google Scholar 

  38. Nisoli E, Clementi E, Paolucci C et al (2003) Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 299:896–899

    Article  CAS  PubMed  Google Scholar 

  39. Nisoli E, Falcone S, Tonello C et al (2004) Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci USA 101:16507–16512

    Article  CAS  PubMed  Google Scholar 

  40. Nisoli E, Cozzi V, Carruba MO (2008) Amino acids and mitochondrial biogenesis. Am J Cardiol 101S:22E–25E

    Article  Google Scholar 

  41. Palii SS, Kays CE, Deval C et al (2009) Specificity of amino acid regulated gene expression: analysis of gene subjected to either complete or single amino acid deprivation. Amino Acids 37:79–88

    Article  CAS  PubMed  Google Scholar 

  42. Petrovic V, Buzadzic B, Korac A et al (2008) Antioxidative defence alterations in skeletal muscle during prolonged acclimation to cold: role of l-arginine/NO-producing pathway. J Exp Biol 211:114–120

    Article  CAS  PubMed  Google Scholar 

  43. Petrović V, Korać A, Buzadzić B et al (2005) The effects of l-arginine and l-NAME supplementation on redox-regulation and thermogenesis in interscapular brown adipose tissue. J Exp Biol 208:4263–4271

    Article  PubMed  Google Scholar 

  44. Petrović V, Korać A, Buzadzić B et al (2008) Nitric oxide regulates mitochondrial re-modelling in interscapular brown adipose tissue: ultrastructural and morphometric-stereologic studies. J Microsc 232:542–548

    Article  PubMed  Google Scholar 

  45. Petrović V, Buzadžić B, Korać A et al (2010) Antioxidative defense and mitochondrial thermogenic response in brown adipose tissue. Genes Nutr. doi:10.1007/s12263-009-0162-1

  46. Phang JM, Donald SP, Pandhare J et al (2008) The metabolism of proline, as a stress substrate, modulates carcinogenic pathways. Amino Acids 35:681–690

    Article  CAS  PubMed  Google Scholar 

  47. Pi-Sunyer X (2003) A clinical view of the obesity problem. Science 299:859–860

    Article  CAS  PubMed  Google Scholar 

  48. Power GG (1989) Biology of temperature: the mammalian fetus. J Dev Physiol 12:295–304

    CAS  PubMed  Google Scholar 

  49. Puigserver P, Wu ZD, Park CW et al (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839

    Article  CAS  PubMed  Google Scholar 

  50. Rhoads JM, Wu G (2009) Glutamine, arginine, and leucine signaling in the intestine. Amino Acids 37:111–122

    Article  CAS  Google Scholar 

  51. Saha SK, Ohinata H, Kuroshima A (1996) Effects of acute and chronic inhibition of nitric oxide synthase on brown adipose tissue thermogenesis. Jpn J Physiol 46:375–382

    Article  CAS  PubMed  Google Scholar 

  52. Satterfield MC, Bazer FW, Smith SB et al (2009) Arginine nutrition and fetal brown fat development. Amino Acids 37(Suppl. 1):6–7

    Google Scholar 

  53. Scammell TE, Elmquist JK, Saper CB (1996) Inhibition of nitric oxide synthase produces hypothermia and depresses lipopolysaccharide fever. Am J Physiol 271:R333–R338

    CAS  PubMed  Google Scholar 

  54. Stipanuk MH, Ueki I, Dominy JE et al (2009) Cysteine dioxygenase: a robust system for regulation of cellular cysteine levels. Amino Acids 37:55–63

    Article  CAS  PubMed  Google Scholar 

  55. Suryawan A, O’Connor PMJ, Bush JA et al (2009) Differential regulation of protein synthesis by amino acids and insulin in peripheral and visceral tissues of neonatal pigs. Amino Acids 37:97–104

    Article  CAS  PubMed  Google Scholar 

  56. Tan BE, Yin YL, Liu ZQ et al (2009) Dietary l-arginine supplementation increases muscle gain and reduces body fat mass in growing-finishing pigs. Amino Acids 37:169–175

    Article  CAS  PubMed  Google Scholar 

  57. Tan B, Yin Y, Kong X et al (2010) l-Arginine stimulates proliferation and prevents endotoxin-induced death of intestinal cells. Amino Acids. doi:10.1007/s00726-009-0334-8

  58. van Marken Lichtenbelt WD, Vanhommerig JW et al (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508

    Article  PubMed  Google Scholar 

  59. Virtanen KA, Lidell ME, Orava J et al (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  CAS  PubMed  Google Scholar 

  60. Wadley GD, McConell GK (2007) Effect of nitric oxide synthase inhibition on mitochondrial biogenesis in rat skeletal muscle. J Appl Physiol 102:314–320

    Article  CAS  PubMed  Google Scholar 

  61. Wang XQ, Ou DY, Yin JD et al (2009a) Proteomic analysis reveals altered expression of proteins related to glutathione metabolism and apoptosis in the small intestine of zinc oxide-supplemented piglets. Amino Acids 37:209–218

    Article  PubMed  Google Scholar 

  62. Wang WW, Qiao SY, Li DF (2009b) Amino acids and gut function. Amino Acids 37:105–110

    Article  CAS  PubMed  Google Scholar 

  63. Wang JJ, Wu G, Zhou HJ et al (2009c) Emerging technologies for amino acid nutrition research in the post-genome era. Amino Acids 37:86–177

    CAS  Google Scholar 

  64. World Health Organization (WHO) (2009) World health statistics-2009. http://www.who.int. Accessed 2 Mar 2010

  65. Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37:1–17

    Article  PubMed  Google Scholar 

  66. Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629

    CAS  PubMed  Google Scholar 

  67. Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    CAS  PubMed  Google Scholar 

  68. Wu ZD, Puigserver P, Anderson U et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124

    Article  CAS  PubMed  Google Scholar 

  69. Wu G, Bazer FW, Cudd TA et al (2007a) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137:1673S–1680S

    CAS  PubMed  Google Scholar 

  70. Wu G, Collins JK, Perkins-Veazie P et al (2007b) Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr 137:2680–2685

    CAS  PubMed  Google Scholar 

  71. Wu G, Bazer FW, Davis TA et al (2009) Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153–168

    Article  CAS  PubMed  Google Scholar 

  72. Yao K, Yin YL, Chu W et al (2008) Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs. J Nutr 138:867–872

    CAS  PubMed  Google Scholar 

  73. Yin FG, Liu YL, Yin YL et al (2009) Dietary supplementation with astragalus polysaccharide enhances ileal digestibilities and serum concentrations of amino acids in early weaned piglets. Amino Acids 37:263–270

    Article  CAS  PubMed  Google Scholar 

  74. Yongyi B, Sun L, Yang T et al (2009) Increase in fasting vascular endothelial function after short-term oral l-arginine is effective when baseline flow-mediated dilation is low: a mega-analysis of randomized controlled trials. Am J Clin Nutr 89:77–84

    Google Scholar 

Download references

Acknowledgments

We thank Frances Mutscher and Merrick Gearing for assistance in manuscript preparation. This work was supported, in part, by grants from National Institutes of Health (R21 HL094689), National Research Initiative Competitive Grants (2008-35206-18762, 2008-35206-18764, 2008-35203-19120 and 2009-35206-05211) from the USDA Cooperative State Research, Education, and Extension Service, American Heart Association (0655109Y and 0755024Y), and Texas AgriLife Research (H-8200).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Guoyao Wu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

McKnight, J.R., Satterfield, M.C., Jobgen, W.S. et al. Beneficial effects of l-arginine on reducing obesity: potential mechanisms and important implications for human health. Amino Acids 39, 349–357 (2010). https://doi.org/10.1007/s00726-010-0598-z

Download citation

Keywords

  • Arginine
  • Fat metabolism
  • Brown adipose tissue
  • NO