Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Physiology

Postnatal induction of muscle fatty acid oxidation in mice differing in propensity to obesity: a role of pyruvate dehydrogenase

Abstract

Background/objective

Adaptation to the extrauterine environment depends on a switch from glycolysis to catabolism of fatty acids (FA) provided as milk lipids. We sought to learn whether the postnatal induction of muscle FA oxidation in mice could reflect propensity to obesity and to characterize the mechanisms controlling this induction.

Methods

Experiments were conducted using obesity-resistant A/J and obesity-prone C57BL/6J (B6) mice maintained at 30 °C, from 5 to 28 days after birth. At day 10, both A/J and B6 mice with genetic ablation (KO) of α2 subunit of AMP-activated protein kinase (AMPK) were also used. In skeletal muscle, expression of selected genes was determined using quantitative real-time PCR, and AMPK subunits content was evaluated using Western blotting. Activities of both AMPK and pyruvate dehydrogenase (PDH), as well as acylcarnitine levels in the muscle were measured.

Results

Acylcarnitine levels and gene expression indicated transient increase in FA oxidation during the first 2 weeks after birth, with a stronger increase in A/J mice. These data correlated with (i) the surge in plasma leptin levels, which peaked at day 10 and was higher in A/J mice, and (ii) relatively low activity of PDH linked with up-regulation of PDH kinase 4 gene (Pdk4) expression in the 10-day-old A/J mice. In contrast with the Pdk4 expression, transient up-regulation of uncoupling protein 3 gene was observed in B6 but not A/J mice. AMPK activity changed during the development, without major differences between A/J and B6 mice. Expression of  neither Pdk4 nor other muscle genes was affected by AMPK-KO.

Conclusions

Our results indicate a relatively strong postnatal induction of FA oxidation in skeletal muscle of the obesity-resistant A/J mice. This induction is transient and probably results from suppression of PDH activity, linked with a postnatal surge in plasma leptin levels, independent of AMPK.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Ferre P, Decaux JF, Issad T, Girard J. Changes in energy metabolism during the suckling and weaning period in the newborn. Reprod Nutr Dev. 1986;26(2B):619–31.

    CAS  PubMed  Google Scholar 

  2. 2.

    Koldovsky O, Dobiasova M, Drahota Z, Hahn P. Developmental aspects of lipid metabolism. Physiol Res. 1995;44:353–6.

    CAS  PubMed  Google Scholar 

  3. 3.

    Hahn P. Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents. J Nutr. 1984;114:1231–4.

    CAS  PubMed  Google Scholar 

  4. 4.

    Stocker CJ, Cawthorne MA. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008;26:545–51.

    CAS  PubMed  Google Scholar 

  5. 5.

    Pico C, Jilkova ZM, Kus V, Palou A, Kopecky J. Perinatal programming of body weight control by leptin: putative roles of AMP kinase and muscle thermogenesis. Am J Clin Nutr. 2011;94:1830S–7S.

    CAS  PubMed  Google Scholar 

  6. 6.

    Palou M, Pico C, Palou A. Leptin as a breast milk component for the prevention of obesity. Nutr Rev. 2018;76:875–892.

    PubMed  Google Scholar 

  7. 7.

    Koldovsky O, Hahn P, Hromadova M, Krecek J, Macho L. Late effects of early nutritional manipulations. Physiol Res. 1995;44:357–60.

    CAS  PubMed  Google Scholar 

  8. 8.

    Pico C, Oliver P, Sanchez J, Miralles O, Caimari A, Priego T, et al. The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int J Obes. 2007;31:1199–209.

    CAS  Google Scholar 

  9. 9.

    Sanchez J, Priego T, Palou M, Tobaruela A, Palou A, Pico C. Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life. Endocrinology. 2008;149:733–40.

    CAS  PubMed  Google Scholar 

  10. 10.

    Schuster S, Hechler C, Gebauer C, Kiess W, Kratzsch J. Leptin in maternal serum and breast milk: association with infants’ body weight gain in a longitudinal study over 6 months of lactation. Pediatr Res. 2011;70:633–7.

    CAS  PubMed  Google Scholar 

  11. 11.

    Devaskar SU, Ollesch C, Rajakumar RA, Rajakumar PA. Developmental changes in ob gene expression and circulating leptin peptide concentrations. Biochem Biophys Res Commun. 1997;238:44–7.

    CAS  PubMed  Google Scholar 

  12. 12.

    Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest. 1998;101:1020–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Mistry AM, Swick A, Romsos DR. Leptin alters metabolic rates before acquisition of its anorectic effect in developing neonatal mice. Am J Physiol. 1999;277:R742–R7.

    CAS  PubMed  Google Scholar 

  14. 14.

    Flier JS, Maratos-Flier E. Obesity and the hypothalamus: novel peptides for new pathways. Cell. 1998;92:437–40.

    CAS  PubMed  Google Scholar 

  15. 15.

    Stehling O, Doring H, Nuesslein-Hildesheim B, Olbort M, Schmidt I. Leptin does not reduce body fat content but augments cold defense abilities in thermoneutrally reared rat pups. Pflugers Arch. 1997;434:694–7.

    CAS  PubMed  Google Scholar 

  16. 16.

    Blumberg MS, Deaver K, Kirby RF. Leptin disinhibits nonshivering thermogenesis in infants after maternal separation. Am J Physiol. 1999;276:R606–R10.

    CAS  PubMed  Google Scholar 

  17. 17.

    Ukropec J, Anunciado RV, Ravussin Y, Kozak LP. Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress. Endocrinology. 2006;147:2468–80.

    CAS  PubMed  Google Scholar 

  18. 18.

    Muoio DM, Dohm GL, Fiedorek FT Jr, Tapscott EB, Coleman RA. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes . 1997;46:1360–3.

    CAS  PubMed  Google Scholar 

  19. 19.

    Hardie DG, Hawley SA, Scott JW. AMP-activated protein kinase--development of the energy sensor concept. J Physiol . 2006;574(Pt 1):7–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Viollet B, Andreelli F, Jorgensen SB, Perrin C, Flamez D, Mu J, et al. Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models. Biochem Soc Trans. 2003;31(Pt 1):216–9.

    CAS  PubMed  Google Scholar 

  21. 21.

    Solinas G, Summermatter S, Mainieri D, Gubler M, Pirola L, Wymann MP, et al. The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation. FEBS Lett. 2004;577:539–44.

    CAS  PubMed  Google Scholar 

  22. 22.

    Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–43.

    CAS  PubMed  Google Scholar 

  23. 23.

    Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y. Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase. Mol Cell Biol. 2007;27:4317–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, et al. Activators of peroxisome proliferator-activated receptor-a induce the expression of the uncoupling protein-3 gene in skeletal muscle. Diabetes. 1999;48:1217–22.

    CAS  PubMed  Google Scholar 

  25. 25.

    Garratt ES, Vickers MH, Gluckman PD, Hanson MA, Burdge GC, Lillycrop KA. Tissue-specific 5’ heterogeneity of PPARalpha transcripts and their differential regulation by leptin. PLoS ONE. 2013;8:e67483.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–33.

    CAS  PubMed  Google Scholar 

  27. 27.

    Fritzen AM, Lundsgaard AM, Jeppesen J, Christiansen ML, Bienso R, Dyck JR, et al. 5’-AMP activated protein kinase alpha2 controls substrate metabolism during post-exercise recovery via regulation of pyruvate dehydrogenase kinase 4. J Physiol. 2015;593:4765–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Flachs P, Adamcova K, Zouhar P, Marques C, Janovska P, Viegas I, et al. Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype. Int J Obes. 2017;41:372–80.

    CAS  Google Scholar 

  29. 29.

    Horakova O, Hansikova J, Bardova K, Gardlo A, Rombaldova M, Kuda O, et al. Plasma acylcarnitines and amino acid levels as an early complex biomarker of propensity to high-fat diet-induced obesity in mice. PLoS ONE. 2016;11:e0155776.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kus V, Prazak T, Brauner P, Hensler M, Kuda O, Flachs P, et al. Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance. Am J Physiol Endocrinol Metab. 2008;295:E356–67.

    CAS  PubMed  Google Scholar 

  31. 31.

    Bardova K, Horakova O, Janovska P, Hansikova J, Kus V, van Schothorst EM, et al. Early differences in metabolic flexibility between obesity-resistant and obesity-prone mice. Biochimie. 2016;124:163–70.

    CAS  PubMed  Google Scholar 

  32. 32.

    Collins S, Daniel KW, Petro AE, Surwit RS. Strain-specific response to beta3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology. 1997;138:405–13.

    CAS  PubMed  Google Scholar 

  33. 33.

    Guerra C, Koza RA, Yamashita H, King KW, Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest. 1998;102:412–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Viollet B, Andreelli F, Jorgensen SB, Perrin C, Geloen A, Flamez D, et al. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J Clin Invest. 2003;111:91–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Cahova M, Chrastina P, Hansikova H, Drahota Z, Trnovska J, Skop V, et al. Carnitine supplementation alleviates lipid metabolism derangements and protects against oxidative stress in non-obese hereditary hypertriglyceridemic rats. Appl Physiol Nutr Metab. 2015;40:280–91.

    CAS  PubMed  Google Scholar 

  36. 36.

    Pomar CA, Kuda O, Kopecky J, Rombaldova M, Castro H, Pico C, et al. Alterations in plasma acylcarnitine and amino acid profiles may be indicative of poor nutrition during the suckling period due to maternal intake of an unbalanced diet and predict later metabolic dysfunction. FASEB J. 2018:fj201800327RR.

  37. 37.

    Jelenik T, Rossmeisl M, Kuda O, Jilkova ZM, Medrikova D, Kus V, et al. AMP-activated protein kinase {alpha}2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids. Diabetes. 2010;59:2737–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Spacilova J, Hulkova M, Hrustincova A, Capek V, Tesarova M, Hansikova H, et al. Analysis of expression profiles of genes involved in F(o)F(1)-ATP synthase biogenesis during perinatal development in rat liver and skeletal muscle. Physiol Res. 2016;65:597–608.

    CAS  PubMed  Google Scholar 

  39. 39.

    McGarry JD, Mills SE, Long CS, Foster DW. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat1. Biochem J. 1983;214:21–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cha SH, Rodgers JT, Puigserver P, Chohnan S, Lane MD. Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1alpha. Proc Natl Acad Sci USA. 2006;103:15410–5.

    CAS  PubMed  Google Scholar 

  41. 41.

    Shabalina IG, Hoeks J, Kramarova TV, Schrauwen P, Cannon B, Nedergaard J. Cold tolerance of UCP1-ablated mice: a skeletal muscle mitochondria switch toward lipid oxidation with marked UCP3 up-regulation not associated with increased basal, fatty acid- or ROS-induced uncoupling or enhanced GDP effects. Biochem. Biophys. Acta. 2010;1797:968–80.

    CAS  PubMed  Google Scholar 

  42. 42.

    MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB, Harper ME. Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes. 2005;54:2343–50.

    CAS  PubMed  Google Scholar 

  43. 43.

    Kwon HS, Harris RA. Mechanisms responsible for regulation of pyruvate dehydrogenase kinase 4 gene expression. Adv Enzyme Regul. 2004;44:109–21.

    CAS  PubMed  Google Scholar 

  44. 44.

    Schooneman MG, Achterkamp N, Argmann CA, Soeters MR, Houten SM. Plasma acylcarnitines inadequately reflect tissue acylcarnitine metabolism. Biochim Biophys Acta. 2014;1841:987–94.

    CAS  PubMed  Google Scholar 

  45. 45.

    Mihalik SJ, Goodpaster BH, Kelley DE, Chace DH, Vockley J, Toledo FG, et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010;18:1695–700.

    CAS  Google Scholar 

  46. 46.

    Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7:45–56.

    CAS  PubMed  Google Scholar 

  47. 47.

    Muoio DM, Noland RC, Kovalik JP, Seiler SE, Davies MN, DeBalsi KL, et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab. 2012;15:764–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Mounier R, Lantier L, Leclerc J, Sotiropoulos A, Pende M, Daegelen D, et al. Important role for AMPKalpha1 in limiting skeletal muscle cell hypertrophy. FASEB J. 2009;23:2264–73.

    CAS  PubMed  Google Scholar 

  49. 49.

    Fu X, Zhu M, Zhang S, Foretz M, Viollet B, Du M. Obesity Impairs skeletal muscle regeneration through inhibition of AMPK. Diabetes. 2016;65:188–200.

    CAS  PubMed  Google Scholar 

  50. 50.

    Porter C, Constantin-Teodosiu D, Constantin D, Leighton B, Poucher SM, Greenhaff PL. Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent. J Physiol. 2017;595:5765–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Soeters MR, Serlie MJ, Sauerwein HP, Duran M, Ruiter JP, Kulik W, et al. Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): an identified ketosis-induced metabolite. Metabolism. 2012;61:966–73.

    CAS  PubMed  Google Scholar 

  52. 52.

    Gong DW, He Y, Karas M, Reitman M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. J Biol Chem. 1997;272:24129–32.

    CAS  PubMed  Google Scholar 

  53. 53.

    Brun S, Carmona MC, Mampel T, Vinas O, Giralt M, Iglesias R, et al. Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids. FEBS Lett. 1999;453:205–9.

    CAS  PubMed  Google Scholar 

  54. 54.

    Brauner P, Kopecky P, Flachs P, Kuda O, Vorlicek J, Planickova L, et al. Expression of uncoupling protein 3 and GLUT4 gene in skeletal muscle of preterm newborns: possible control by AMP-activated protein kinase. Pediatr Res. 2006;60:569–75.

    CAS  PubMed  Google Scholar 

  55. 55.

    Rinnankoski-Tuikka R, Silvennoinen M, Torvinen S, Hulmi JJ, Lehti M, Kivela R, et al. Effects of high-fat diet and physical activity on pyruvate dehydrogenase kinase-4 in mouse skeletal muscle. Nutr Metab. 2012;9:53.

    CAS  Google Scholar 

  56. 56.

    Zhang S, Hulver MW, McMillan RP, Cline MA, Gilbert ER. The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab. 2014;11:10.

    Google Scholar 

  57. 57.

    Hue L, Taegtmeyer H. The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab. 2009;297:E578–E91.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Broderick TL, Quinney HA, Lopaschuk GD. Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J Biol Chem. 1992;267:3758–63.

    CAS  PubMed  Google Scholar 

  59. 59.

    Wan Z, Thrush AB, Legare M, Frier BC, Sutherland LN, Williams DB, et al. Epinephrine-mediated regulation of PDK4 mRNA in rat adipose tissue. Am J Physiol Cell Physiol. 2010;299:C1162–70.

    CAS  PubMed  Google Scholar 

  60. 60.

    Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, Rodrigues B. The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. Endocrinology. 2010;151:2306–18.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The research was supported by the Czech Science Foundation (MITOCENTRE, GB14-36804G). We thank J. Bemova, S. Hornova, and D. Salkova for technical assistance, D. Grahame Hardie (University of Dundee, UK) for the AMPKα1 and AMPKα2 antibodies, and B. Viollet (Institute Cochin, Paris, France) for the AMPK-KO-B6 mice [34].

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jan Kopecky.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Buresova, J., Janovska, P., Kuda, O. et al. Postnatal induction of muscle fatty acid oxidation in mice differing in propensity to obesity: a role of pyruvate dehydrogenase. Int J Obes 44, 235–244 (2020). https://doi.org/10.1038/s41366-018-0281-0

Download citation

Further reading

Search

Quick links