Exp Clin Endocrinol Diabetes 2007; 115(4): 244-251
DOI: 10.1055/s-2007-956166

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Concerted Action of Leptin in Regulation of Fatty Acid Oxidation in Skeletal Muscle and Liver

S. Wein 1 [*] [**] , J. Ukropec 1 [*] , D. Gašperíková 1 , I. Klimeš 1 , E. Šeböková 1
  • 1Diabetes and Nutrition Research Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
Further Information

Publication History

Received 28. 7. 2006 first decision 15. 9. 2006

Accepted 4. 10. 2006

Publication Date:
03 May 2007 (online)


Central action of leptin on food intake and energy expenditure is integrated with leptin's peripheral action modulating the fatty acid and glucose metabolism and preventing the accumulation of lipids in nonadipose tissues. However, exact mechanism(s) of the leptin's action in the peripheral tissues has not yet been fully elucidated. Therefore, we investigated the effect of a single intravenous injection of leptin on palmitoyl-CoA and palmitoyl-carnitine oxidation rate in liver and skeletal muscle followed by measurements of the carnitine-palmitoyl transferase 1 (CPT1) activity and activities of ß-oxidation enzymes in mitochondria (acyl-CoA dehydrogenase) and in peroxisomes (acyl-CoA oxidase) of rats. Animals were euthanized and tissues and serum harvested 15 min, 1 hour, 3 hours and 6 hours after leptin administration. Intravenous leptin injection increased mitochondrial palmitoyl-CoA oxidation rate in both liver (95%; P<0.025) and skeletal muscle (2.7-fold; P<0.05). This was paralleled by lowering hepatic (-156%; P<0.001) and skeletal muscle (-191%; P<0.001) triglyceride content. Leptin-induced elevation of palmitoyl-CoA oxidation rate in liver was paralleled by increased CPT1 activity (52%; P<0.05) and ß-oxidation capacity (52%; P<0.05). Lack of the leptin's effect on the CPT1-activity in muscle (20%; p=0.09) suggests the existence of an alternative pathway for increasing the palmitoyl-CoA-oxidation rate bypassing the CPT1 regulatory step. Interestingly, leptin stimulated the overall ß-oxidation capacity in muscle by 69% (P=0.027). This may indicate to an involvement of mitochondrial acyl-CoA dehydrogenases as well as of peroxisomal fat catabolism. Taken together, we showed that leptin acutely increases palmitoyl-CoA oxidation rate in liver and in skeletal muscle, which was associated with tissue specific effect on the CPT1 activity as well as on the downstream enzymes of fatty acid oxidation pathways in rat mitochondria and peroxisomes. Tangible evidence for the leptin-induced increase of fatty acid catabolism was provided by a lowered skeletal muscle and hepatic lipid deposition.


  • 1 Ahima RS, Flier JS. Leptin.  Ann Rev Physiol. 2000;  62 413-437
  • 2 Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting.  Nature. 1996;  382 250-252
  • 3 Barazzoni R, Zanetti M, Bosutti A, Biolo G, Vitali-Serdoz L, Stebel M, Guarnieri G. Moderate caloric restriction, but not physiological hyperleptinemia per se, enhances mitochondrial oxidative capacity in rat liver and skeletal muscle-tissue-specific impact on tissue triglyceride content and AKT activation.  Endocrinology. 2005;  146 2098-2106
  • 4 Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery.  Recent Prog Horm Res. 2004;  59 305-331
  • 5 Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification.  Can J Biochem Physiol. 1959;  37 911-917
  • 6 Campfield LA, Smith FJ, Burn P. The OB protein (leptin) pathway-a link between adipose tissue mass and central neural networks.  Horm Metab Res. 1996;  28 619-632
  • 7 Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin.  Science. 1996;  274 1185-1188
  • 8 Considine RV. Regulation of leptin production.  Rev Endocr Metab Disord. 2001;  2 357-363
  • 9 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL. et al . Serum immunoreactive-leptin concentrations in normal-weight and obese humans.  N Engl J Med. 1996;  334 292-295
  • 10 Dyck DJ. Leptin sensitivity in skeletal muscle is modulated by diet and exercise.  Exerc Sport Sci Rev. 2005;  33 189-194
  • 11 Eaton S. Control of mitochondrial β-oxidation flux.  Prog Lipid Res. 2002;  41 197-239
  • 12 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals.  Nature. 1998;  395 763-770
  • 13 Guzman M, Geelen MJ. Regulation of fatty acid oxidation in mammalian liver.  Biochim Biophys Acta. 1993;  1167 227-241
  • 14 Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene.  Science. 1995;  269 543-546
  • 15 Hardie DG, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?.  Annu Rev Biochem. 1998;  67 821-855
  • 16 Hashimoto T. Peroxisomal β-oxidation: enzymology and molecular biology.  Ann N Y Acad Sci. 1996;  804 86-98
  • 17 Hulver MW, Berggren JR, Cortright RN, Dudek RW, Thompson RP, Pories WJ, MacDonald KG, Cline GW, Shulman GI, Dohm GL, Houmard JA. Skeletal muscle lipid metabolism with obesity.  Am J Physiol Endocrinol Metab. 2003;  284 E741-747
  • 18 Jequier E. Leptin signaling, adiposity, and energy balance.  Ann N Y Acad Sci. 2002;  967 379-388
  • 19 Kamohara S, Burcelin R, Halaas JL, Friedman JM, Charron MJ. Acute stimulation of glucose metabolism in mice by leptin treatment.  Nature. 1997;  389 374-377
  • 20 Koves TR, Noland RC, Bates AL, Henes ST, Muoio DM, Cortright RN. Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism.  Am J Physiol Cell Physiol. 2005;  288 C1074-1082
  • 21 Kunau WH, Dommes V, Schulz H. β-oxidation of fatty acids in mitochondria, peroxisomes, and bacteria: a century of continued progress.  Prog Lipid Res. 1995;  34 267-342
  • 22 Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice.  Nature. 1996;  379 632-635
  • 23 Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation.  J Clin Invest. 2006;  116 1776-1783
  • 24 McGarry JD. Travels with carnitine palmitoyltransferase I: from liver to germ cell with stops in between.  Biochem Soc Trans. 2001;  29 ((Pt 2)) 241-245
  • 25 McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.  Eur J Biochem. 1997;  244 1-14
  • 26 McGarry JD, Foster DW. Regulation of hepatic fatty acid oxidation and ketone body production.  Annu Rev Biochem. 1980;  49 395-420
  • 27 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 nonhepatic tissues of the rat.  Biochem J. 1983;  214 21-28
  • 28 Minokoshi Y, Kahn BB. Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle.  Biochem Soc Trans. 2003;  31 ((Pt 1)) 196-201
  • 29 Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.  Nature. 2002;  415 339-343
  • 30 Muoio DM, Dohm GL, Fiedorek Jr FT, Tapscott EB, Coleman RA. Leptin directly alters lipid partitioning in skeletal muscle.  Diabetes. 1997;  46 1360-1363
  • 31 Muoio DM, Newgard CB. Obesity-related derangements in metabolic regulation.  Annu Rev Biochem. 2006;  75 367-401
  • 32 Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 1995;  269 540-543
  • 33 Roepstorff C, Vistisen B, Kiens B. Intramuscular triacylglycerol in energy metabolism during exercise in humans.  Exerc Sport Sci Rev. 2005;  33 182-188
  • 34 Rossetti L, Massillon D, Barzilai N, Vuguin P, Chen W, Hawkins M, Wu J, Wang J. Short term effects of leptin on hepatic gluconeogenesis and in vivo insulin action.  J Biol Chem. 1997;  272 27758-27763
  • 35 Saggerson ED, Carpenter CA. Carnitine palmitoyltransferase and carnitine octanoyltransferase activities in liver, kidney cortex, adipocyte, lactating mammary gland, skeletal muscle and heart.  FEBS Lett. 1981;  129 229-232
  • 36 Seufert J. Leptin effects on pancreatic β-cell gene expression and function.  Diabetes. 2004;  53 ((Suppl 1)) S152-158
  • 37 Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y, Newgard CB, Unger RH. Direct antidiabetic effect of leptin through triglyceride depletion of tissues.  Proc Natl Acad Sci USA. 1997;  94 4637-4641
  • 38 Shulman GI. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-176
  • 39 Scholte HR, Yu Y, Ross JD, Oosterkamp II, Boonman AM, Busch HF. Rapid isolation of muscle and heart mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and other compounds.  Mol Cell Biochem. 1997;  174 61-66
  • 40 Souri M, Aoyama T, Hashimoto T. A sensitive assay of acyl-coenzyme. A oxidase by coupling with β-oxidation multienzyme complex.  Anal Biochem. 1994;  221 362-367
  • 41 Tanaka T, Hidaka S, Masuzaki H, Yasue S, Minokoshi Y, Ebihara K, Chusho H, Ogawa Y, Toyoda T, Sato K, Miyanaga F, Fujimoto M, Tomita T, Kusakabe T, Kobayashi N, Tanioka H, Hayashi T, Hosoda K, Yoshimatsu H, Sakata T, Nakao K. Skeletal muscle AMP-activated protein kinase phosphorylation parallels metabolic phenotype in leptin transgenic mice under dietary modification.  Diabetes. 2005;  54 2365-2374
  • 42 Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
  • 43 Trayhurn P. Leptin-a critical body weight signal and a “master” hormone?.  Sci STKE. 2003;  PE7
  • 44 Uchiyama A, Aoyama T, Kamijo K, Uchida Y, Kondo N, Orii T, Hashimoto T. Molecular cloning of cDNA encoding rat very long-chain acyl-CoA synthetase.  J Biol Chem. 1996;  271 30360-30365
  • 45 Ukropec J, Anunciado RV, Ravussin Y, Kozak LP. Leptin is required for UCP1-independent thermogenesis during cold stress.  Endocrinology. 2006;  147 2468-2480
  • 46 Ukropec J, Reseland JE, Gasperikova D, Demcakova E, Madsen L, Berge RK, Rustan AC, Klimes I, Drevon CA, Sebokova E. The hypotriglyceridemic effect of dietary n-3 FA is associated with increased β-oxidation and reduced leptin expression.  Lipids. 2003;  38 1023-1029
  • 47 Ukropec J, Sebokova E, Klimes I. Nutrient sensing, leptin and insulin action.  Arch Physiol Biochem. 2001;  109 38-51
  • 48 Unger RH. Lipotoxic diseases.  Annu Rev Med. 2002;  53 319-336
  • 49 Unger RH. Hyperleptinemia: protecting the heart from lipid overload.  Hypertension. 2005;  45 1031-1034
  • 50 Vaisse C, Halaas JL, Horvath CM, Darnell Jr JE, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.  Nat Genet. 1996;  14 95-97
  • 51 Wang ZW, Pan WT, Lee Y, Kakuma T, Zhou YT, Unger RH. The role of leptin resistance in the lipid abnormalities of aging.  Faseb J. 2001;  15 108-114
  • 52 Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes.  Am J Physiol. 1999;  277 ((1 Pt 1)) E1-10
  • 53 Zammit VA. The malonyl-CoA-long-chain acyl-CoA axis in the maintenance of mammalian cell function.  Biochem J. 1999;  343 ((Pt 3)) 505-515

1 First two authors SW and JU contributed equally to this work.

2 Current address of author, Institute of Animal Nutrition & Physiology, Christian-Albrechts-University of Kiel, Herrmann-Rodewald-Str. 9, 24098 Kiel, Germany
Email: wein@aninut.uni-kiel.de


J. UkropecPhD 

Inst. Exp. Endocrinology SAS

Vlárska Str. 3

SK-83306 Bratislava


Phone: +421/2/54 77 28 00

Fax: +421/2/54 77 26 87

Email: jozef.ukropec@savba.sk