Skip to main content
SpringerLink
Log in

Leucine and Calcium Regulate Fat Metabolism and Energy Partitioning in Murine Adipocytes and Muscle Cells

  • Original Article
  • Published:
Lipids

Abstract

Dietary calcium modulation of adiposity is mediated, in part, by suppression of calcitriol, while the additional effect of dairy products is mediated by additional components; these include the high concentration of leucine, a key factor in the regulation of muscle protein turnover. We investigated the effect of leucine, calcitriol and calcium on energy metabolism in murine adipocytes and muscle cells and on energy partitioning between adipocytes and skeletal muscle. Leucine induced a marked increase in fatty acid oxidation in C2C12 muscle cells (P < 0.001) and decreased FAS expression by 66% (P < 0.001) in 3T3-L1 adipocytes. Calcitriol decreased muscle cell fatty acid oxidation by 37% (P < 0.001) and increased adipocyte FAS gene expression by threefold (P < 0.05); these effects were partially reversed by either leucine or calcium channel antagonism with nifedipine. Co-culture of muscle cells with adipocytes or incubation with 48-h adipocyte conditioned medium decreased muscle fatty acid oxidation by 62% (P < 0.001), but treating adipocytes with leucine and/or nifedipine attenuated this effect. Leucine, nifedipine and calcitriol also modulated adiponectin production and thereby exerted additional indirect effects on fatty acid oxidation in C2C12 myotubes. Adiponectin increased IL-15 and IL-6 release by myotubes and partially reversed the inhibitory effects of calcitriol. Comparable effects of leucine, calcitriol and adiponectin were found in myotubes treated with conditioned medium derived from adipocytes or co-cultured with adipocytes. These data suggest that leucine and nifedipine promote energy partitioning from adipocytes to muscle cells, resulting in decreased energy storage in adipocytes and increasing fatty acid utilization in muscle.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Coppack SW (2001) Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 60:349–356

    PubMed  CAS  Google Scholar 

  2. Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339

    Article  PubMed  CAS  Google Scholar 

  3. Ajuwon KM, Jacobi SK, Kuske JL, Spurlock ME (2004) Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon- gamma in primary pig adipocytes. Am J Physiol Regul Integr Comp Physiol 286:R547–R553

    PubMed  CAS  Google Scholar 

  4. Okamoto Y, Kihara S, Funahashi T, Matsuzawa Y, Libby P (2006) Adiponectin: a key adipocytokine in metabolic syndrome. Clin Sci (Lond) 110:267–278

    Article  CAS  Google Scholar 

  5. Chan MH, Carey AL, Watt MJ, Febbraio MA (2004) Cytokine gene expression in human skeletal muscle during concentric contraction: evidence that IL-8, like IL-6, is influenced by glycogen availability. Am J Physiol Regul Integr Comp Physiol 287:R322–R327

    PubMed  CAS  Google Scholar 

  6. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK (2002) IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283:E1272–E1278

    PubMed  CAS  Google Scholar 

  7. Zemel MB (2005) Calcium and dairy modulation of obesity risk. Obes Res 13:192–193

    Article  PubMed  Google Scholar 

  8. Zemel MB, Richards J, Milstead A, Campbell P (2005) Effects of calcium and dairy on body composition and weight loss in African-American adults. Obes Res 13:1218–1225

    PubMed  CAS  Google Scholar 

  9. Zemel MB, Shi H, Greer B, DiRienzo D, Zemel PC (2000) Regulation of adiposity by dietary calcium. FASEB J 14:1132–1138

    PubMed  CAS  Google Scholar 

  10. Sun X, Zemel MB (2006) Dietary calcium regulates ROS production in aP2- agouti transgenic mice on high-fat/high-sucrose diets. Int J Obes (Lond) 30:1341–1346

    Article  CAS  Google Scholar 

  11. Shi H, Halvorsen YD, Ellis PN, Wilkison WO, Zemel MB (2000) Role of intracellular calcium in human adipocyte differentiation. Physiol Genomics 3:75–82

    PubMed  CAS  Google Scholar 

  12. Xue B, Greenberg AG, Kraemer FB, Zemel MB (2001) Mechanism of intracellular calcium ([Ca2+]i) inhibition of lipolysis in human adipocytes. FASEB J 15:2527–2529

    PubMed  CAS  Google Scholar 

  13. Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2001) 1α,25-dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action. FASEB J 15:2751–2753

    PubMed  CAS  Google Scholar 

  14. Xue B, Moustaid N, Wilkison WO, Zemel MB (1998) The agouti gene product inhibits lipolysis in human adipocytes via a Ca2+-dependent mechanism. FASEB J 12:1391–1396

    PubMed  CAS  Google Scholar 

  15. Kim JH, Mynatt RL, Moore JW, Woychik RP, Moustaid N, Zemel MB (1996) The effects of calcium channel blockade on agouti-induced obesity. FASEB J 10:1646–1652

    PubMed  CAS  Google Scholar 

  16. Shi H, Norman AW, Okamura WH, Sen A, Zemel MB (2002) 1α,25- dihydroxyvitamin D3 inhibits uncoupling protein 2 expression in human adipocytes. FASEB J 16:1808–1810

    PubMed  CAS  Google Scholar 

  17. Zemel MB (2005) The role of dairy foods in weight management. J Am Coll Nutr 24:537S–546S

    PubMed  CAS  Google Scholar 

  18. Zemel MB, Miller SL (2004) Dietary calcium and dairy modulation of adiposity and obesity risk. Nutr Rev 62:125–131

    Article  PubMed  Google Scholar 

  19. Suganami T, Nishida J, Ogawa Y (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25:2062–2068

    Article  PubMed  CAS  Google Scholar 

  20. Murase T, Haramizu S, Shimotoyodome A, Nagasawa A, Tokimitsu I (2005) Green tea extract improves endurance capacity and increases muscle lipid oxidation in mice. Am J Physiol Regul Integr Comp Physiol 288:R708–R715

    PubMed  CAS  Google Scholar 

  21. Dyck DJ, Heigenhauser GJ, Bruce CR (2006) The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity. Acta Physiol (Oxf) 186:5–16

    CAS  Google Scholar 

  22. Path G, Bornstein SR, Gurniak M, Chrousos GP, Scherbaum WA, Hauner H (2001) Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function. J Clin Endocrinol Metab 86:2281–2288

    Article  PubMed  CAS  Google Scholar 

  23. Bruce CR, Dyck DJ (2004) Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab 287:E616–E621

    Article  PubMed  CAS  Google Scholar 

  24. Almendro V, Busquets S, Ametller E, Carbo N, Figueras M, Fuster G, Argiles JM, Lopez-Soriano FJ (2006) Effects of interleukin-15 on lipid oxidation: disposal of an oral [(14)C]-triolein load. Biochim Biophys Acta 1761:37–42

    PubMed  CAS  Google Scholar 

  25. McPherson R, Jones PH (2003) The metabolic syndrome and type 2 diabetes: role of the adipocyte. Curr Opin Lipidol 14:549–553

    Article  PubMed  CAS  Google Scholar 

  26. Vega GL (2004) Obesity and the metabolic syndrome. Minerva Endocrinol 29:47–54

    PubMed  CAS  Google Scholar 

  27. Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374

    Article  PubMed  CAS  Google Scholar 

  28. Ma SW, Foster DO (1986) Starvation-induced changes in metabolic rate, blood flow, and regional energy expenditure in rats. Can J Physiol Pharmacol 64:1252–1258

    PubMed  CAS  Google Scholar 

  29. Milan G, Dalla, Nora. E., Pilon C, Pagano C, Granzotto M, Manco M, Mingrone G, Vettor R (2004) Changes in muscle myostatin expression in obese subjects after weight loss. J Clin Endocrinol Metab 89:2724–2727

  30. Causey KR, Zemel MB (2003) Dairy augmentation of the anti-obesity effect of calcium in aP2-agouti transgenic mice. FASEB J 17:A746 (abstract)

    Google Scholar 

  31. Sun X, Zemel MB (2004) Calcium and dairy products inhibit weight and fat regain during ad libitum consumption following energy restriction in Ap2-agouti transgenic mice. J Nutr 134:3054–3060

    PubMed  CAS  Google Scholar 

  32. Rennie MJ, Bohe J, Smith K, Wackerhage H, Greenhaff P(2006) Branched-chain amino acids as fuels and anabolic signals in human muscle. J Nutr 136:264S–268S

    PubMed  CAS  Google Scholar 

  33. Kobayashi H, Kato H, Hirabayashi Y, Murakami H, Suzuki H (2006) Modulations of muscle protein metabolism by branched-chain amino acids in normal and muscle-atrophying rats. J Nutr 136:234S–236S

    PubMed  CAS  Google Scholar 

  34. Fulks RM, Li JB, Goldberg AL (1975) Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem 250:290–298

    PubMed  CAS  Google Scholar 

  35. Li JB, Jefferson LS (1978) Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim Biophys Acta 544:351–359

    PubMed  CAS  Google Scholar 

  36. Garlick PJ (2005) The role of leucine in the regulation of protein metabolism. J Nutr 135:1553S–1556S

    PubMed  CAS  Google Scholar 

  37. Anthony JC, Anthony TG, Kimball SR, Vary TC, Jefferson LS (2000) Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J Nutr 130:139–145

    PubMed  CAS  Google Scholar 

  38. Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR (2000) Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr 130:2413–2419

    PubMed  CAS  Google Scholar 

  39. Lynch CJ, Hutson SM, Patson BJ, Vaval A, Vary TC (2002) Tissue- specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab 283:E824–E835

    PubMed  CAS  Google Scholar 

  40. Nair KS, Short KR (2005) Hormonal and signaling role of branched-chain amino acids. J Nutr 135:1547S–1552S

    PubMed  CAS  Google Scholar 

  41. Roh C, Han J, Tzatsos A, Kandror KV (2003) Nutrient-sensing mTOR- mediated pathway regulates leptin production in isolated rat adipocytes. Am J Physiol Endocrinol Metab 284:E322–E330

    PubMed  CAS  Google Scholar 

  42. Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC (2002) Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab 283:E503–E513

    PubMed  CAS  Google Scholar 

  43. Tobin JF, Celeste AJ (2005) Myostatin, a negative regulator of muscle mass: implications for muscle degenerative diseases. Curr Opin Pharmacol 5:328–332

    Article  PubMed  CAS  Google Scholar 

  44. McPherron AC, Lee SJ (2002) Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 109:595–601

    Article  PubMed  CAS  Google Scholar 

  45. Sutrave P, Kelly AM, Hughes SH (1990) ski can cause selective growth of skeletal muscle in transgenic mice. Genes Dev 4:1462–1472

    PubMed  CAS  Google Scholar 

  46. Yang YT, McElligott MA (1989) Multiple actions of beta-adrenergic agonists on skeletal muscle and adipose tissue. Biochem J 261:1–10

    PubMed  CAS  Google Scholar 

  47. Spurlock ME, Cusumano JC, Ji SQ, Anderson DB, Smith CK 2nd, Hancock DL, Mills SE (1994) The effect of ractopamine on beta-adrenoceptor density and affinity in porcine adipose and skeletal muscle tissue. J Anim Sci 72:75–80

    PubMed  CAS  Google Scholar 

  48. Coletti D, Moresi V, Adamo S, Molinaro M, Sassoon D (2005) Tumor necrosis factor-alpha gene transfer induces cachexia and inhibits muscle regeneration. Genesis 43:120–128

    Article  PubMed  CAS  Google Scholar 

  49. Meadows KA, Holly JM, Stewart CE (2000) Tumor necrosis factor-alpha- induced apoptosis is associated with suppression of insulin-like growth factor binding protein-5 secretion in differentiating murine skeletal myoblasts. J Cell Physiol 183:330–337

    Article  PubMed  CAS  Google Scholar 

  50. Fong Y, Moldawer LL, Marano M, Wei H, Barber A, Manogue K, Tracey KJ, Kuo G, Fischman DA, Cerami A (1989) Cachectin/TNF or IL- 1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 256:R659–R665

    PubMed  CAS  Google Scholar 

  51. Busquets S, Figueras MT, Meijsing S, Carbo N, Quinn LS, Almendro V, Argiles JM, Lopez-Soriano FJ (2005) Interleukin-15 decreases proteolysis in skeletal muscle: a direct effect. Int J Mol Med 16:471–476

    PubMed  CAS  Google Scholar 

  52. Carbo N, Lopez-Soriano J, Costelli P, Alvarez B, Busquets S, Baccino FM, Quinn LS, Lopez-Soriano FJ, Argiles JM (2001) Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim Biophys Acta 1526:17–24

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nutrition, University of Tennessee, 1215 W. Cumberland Avenue, Knoxville, TN, 37996-1920, USA

    Xiaocun Sun & Michael B Zemel

Authors
  1. Xiaocun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael B Zemel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael B Zemel.

About this article

Cite this article

Sun, X., Zemel, M.B. Leucine and Calcium Regulate Fat Metabolism and Energy Partitioning in Murine Adipocytes and Muscle Cells. Lipids 42, 297–305 (2007). https://doi.org/10.1007/s11745-007-3029-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-007-3029-5

Keywords

Search

Navigation