Fibroblast growth factor-21 potentiates glucose transport in skeletal muscle fibers

in Journal of Molecular Endocrinology
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  • 1 Physiology and Biophysics Program and Center for Studies on Exercise, Metabolism, and Cancer, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
  • 2 Facultad de Ciencias de la Educación, Universidad San Sebastián, Santiago, Chile
  • 3 Advanced Center for Chronic Diseases, Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile

Correspondence should be addressed to E Jaimovich: ejaimovi@uchile.cl
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Fibroblast growth factor 21 (FGF21) is a pleiotropic peptide hormone that is considered a myokine playing a role in a variety of endocrine functions, including regulation of glucose transport and lipid metabolism. Although FGF21 has been associated with glucose metabolism in skeletal muscle cells, its cellular mechanism in adult skeletal muscle fibers glucose uptake is poorly understood. In the present study, we found that FGF21 induced a dose−response effect, increasing glucose uptake in skeletal muscle fibers from the flexor digitorum brevis muscle of mice, evaluated using the fluorescent glucose analog 2-NBDG (300 µM) in single living fibers. This effect was prevented by the use of either cytochalasin B (5 µM) or indinavir (100 µM), both antagonists of GLUT4 activity. The use of PI3K inhibitors such as LY294002 (50 µM) completely prevented the FGF21-dependent glucose uptake. In fibers electroporated with the construct encoding GLUT4myc-eGFP chimera and stimulated with FGF21 (100 ng/mL), a strong sarcolemmal GLUT4 label was detected. This effect promoted by FGF21 was demonstrated to be dependent on atypical PKC-ζ, by using selective PKC inhibitors. FGF21 at low concentrations potentiated the effect of insulin on glucose uptake but at high concentrations, completely inhibited the uptake in the presence of insulin. These results suggest that FGF21 regulates glucose uptake by a mechanism mediated by GLUT4 and dependent on atypical PKC-ζ in skeletal muscle.

Supplementary Materials

    • Fig. 1. Subcellular characterization and distribution of FGFR1 and KLB in fibers isolated from skeletal muscle. A: Representative Western blot of FGFR1 and KLB, homogenized liver samples (20 µg of proteins, lane 1), WAT (20 µg of proteins, lane 2) and skeletal muscle FDB (10, 20 and 30 µg of proteins, lane 3, 4 and 5 respectively), (n = 3). B-C: Confocal images of the medial section of fibers isolated from FDB muscle (1 μm). The fibers were permeabilized and co-incubated with anti-FGFR1 (1: 200) or anti-KLB (1: 200) and anti-DHPR (1: 300) monoclonal antibody; then Alexa Fluor 488 and 546 secondary antibodies were used; (representative figures of at least 10 fibers analyzed). Scale: 20 μm.
    • Fig. 2. FGF21-dependent glucose uptake it is independent of AMPK phosphorylation. A-B: Representative Western blot and quantification of p-AMPK in Thr172 (n = 6) and p-ACC in Ser79 (n = 4) in homogenate from FDB muscle samples. Values are mean ± SEM. Mann-Whitney test.
    • Fig. 3. Effects of FGF21 on glucose uptake are independent of the phosphorylation of AS160, IR and ERK1/2. A-C: Representative Western blot and quantification of p-AS160 in Thr642 (n = 5-6), p-IR in Tyr1150/1151 (n = 3-4), and p-ERK1/2 in Thr202/Tyr204 (n = 3-5) in homogenate from FDB muscle samples. Values are mean ± SEM. * p <0.05 vs basal; Kruskal-Wallis test followed by Dunn’s post-test.

 

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  • Balendran A, Biondi RM, Cheung PCF, Casamayor A, Deak M & Alessi DR 2000 A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Cζ (PKCζ) and PKC-related kinase 2 by PDK1. Journal of Biological Chemistry 275 2080620813. (https://doi.org/10.1074/jbc.M000421200)

    • Search Google Scholar
    • Export Citation
  • Bandyopadhyay G, Standaert ML, Galloway L, Moscat J & Farese RV 1997 Evidence for involvement of protein kinase C (PKC)-ζ and noninvolvement of diacylglycerol-sensitive PKCs in insulin-stimulated glucose transport in L6 myotubes. Endocrinology 138 47214731. (https://doi.org/10.1210/endo.138.11.5473)

    • Search Google Scholar
    • Export Citation
  • Beg M, Abdullah N, Thowfeik FS, Altorki NK & McGraw TE 2017 Distinct Akt phosphorylation states are required for insulin regulated Glut4 and Glut1-mediated glucose uptake. eLife 6 122. (https://doi.org/10.7554/eLife.26896)

    • Search Google Scholar
    • Export Citation
  • Braiman L, Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T & Sampson SR 2001 Activation of protein kinase C-zeta induces serine phosphorylation of VAMP2 in the GLUT4 compartment and increases glucose transport in skeletal muscle. Molecular and Cellular Biology 21 78527861. (https://doi.org/10.1128/MCB.21.22.7852-7861.2001)

    • Search Google Scholar
    • Export Citation
  • Bryant NJ, Govers R & James DE 2002 Regulated transport of the glucose transporter GLUT4. Nature Reviews: Molecular Cell Biology 3 267277. (https://doi.org/10.1038/nrm782)

    • Search Google Scholar
    • Export Citation
  • Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE, 2006 Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55 26882697. (https://doi.org/10.2337/db05-1404)

    • Search Google Scholar
    • Export Citation
  • Casas M, Figueroa R, Jorquera G, Escobar M, Molgó J & Jaimovich E 2010 IP3-dependent, post-tetanic calcium transients induced by electrostimulation of adult skeletal muscle fibers. Journal of General Physiology 136 455467. (https://doi.org/10.1085/jgp.200910397)

    • Search Google Scholar
    • Export Citation
  • Chambers MA, Moylan JS, Smith JD, Goodyear LJ & Reid MB 2009 Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase. Journal of Physiology 587 33633373. (https://doi.org/10.1113/jphysiol.2008.165639)

    • Search Google Scholar
    • Export Citation
  • Contreras-Ferrat AE, Toro B, Bravo R, Parra V, Vasquez C, Ibarra C, Mears D, Chiong M, Jaimovich E, Klip A, 2010 An inositol 1,4,5-triphosphate (IP3)-IP3 receptor pathway is required for insulin-stimulated glucose transporter 4 translocation and glucose uptake in cardiomyocytes. Endocrinology 151 46654677. (https://doi.org/10.1210/en.2010-0116)

    • Search Google Scholar
    • Export Citation
  • Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE & Kharitonenkov A 2008 Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149 60186027. (https://doi.org/10.1210/en.2008-0816)

    • Search Google Scholar
    • Export Citation
  • Cuevas-Ramos D, Almeda-Valdés P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez FJ, Mehta R, Oseguera-Moguel J & Aguilar-Salinas CA 2012 Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS ONE 7 e38022. (https://doi.org/10.1371/journal.pone.0038022)

    • Search Google Scholar
    • Export Citation
  • Czech MP & Corvera S 1999 Signaling mechanisms that regulate glucose transport. Journal of Biological Chemistry 274 18651868. (https://doi.org/10.1074/jbc.274.4.1865)

    • Search Google Scholar
    • Export Citation
  • DiFranco M, Quinonez M, Capote J & Vergara J 2009 DNA transfection of mammalian skeletal muscles using in vivo electroporation. Journal of Visualized Experiments 32 17. (https://doi.org/10.3791/1520)

    • Search Google Scholar
    • Export Citation
  • Donate-Correa J, Martín-Núñez E, Delgado NP, de Fuentes MM, Arduan AO, Mora-Fernández C & Navarro González JF 2016 Implications of fibroblast growth factor/klotho system in glucose metabolism and diabetes. Cytokine and Growth Factor Reviews 28 7177. (https://doi.org/10.1016/j.cytogfr.2015.12.003)

    • Search Google Scholar
    • Export Citation
  • Estensen RD & Plagemann PG 1972 Cytochalasin B: inhibition of glucose and glucosamine transport. PNAS 69 14301434. (https://doi.org/10.1073/pnas.69.6.1430)

    • Search Google Scholar
    • Export Citation
  • Farese RV, Sajan MP, Yang H, Li P, Mastorides S, Gower WR, Nimal S, Choi CS, Kim S, Shulman GI, 2007 Muscle-specific knockout of PKC lambda impairs glucose transport and induces metabolic and diabetic syndromes. Journal of Clinical Investigation 117 22892301. (https://doi.org/10.1172/JCI31408)

    • Search Google Scholar
    • Export Citation
  • Garofalo RS, Torchia AJ, Brees DJ, Wicks JR, Orena SJ, Coleman KG, Hildebrandt AL, McNeish JD, Stock JL, Coskran T, 2003 Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. Journal of Clinical Investigation 112 197208. (https://doi.org/10.1172/JCI200316885)

    • Search Google Scholar
    • Export Citation
  • Ge X, Chen C, Hui X, Wang Y, Lam KSL & Xu A 2011 Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. Journal of Biological Chemistry 286 3453334541. (https://doi.org/10.1074/jbc.M111.248591)

    • Search Google Scholar
    • Export Citation
  • Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF & Waterfield MD 2007 Exploring the specificity of the PI3K family inhibitor LY294002. Biochemical Journal 404 1521. (https://doi.org/10.1042/BJ20061489)

    • Search Google Scholar
    • Export Citation
  • Hansen J, Clemmesen J, Secher N, Hoene M, Drescher A, Weigert C, Pedersen B & Plomgaard P 2015 Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Molecular Metabolism 4 551-560. (https://doi.org/10.1016/j.molmet.2015.06.001)

    • Search Google Scholar
    • Export Citation
  • Hawley JA, Hargreaves M & Zierath JR 2006 Signalling mechanisms in skeletal muscle: role in substrate selection and muscle adaptation. Essays in Biochemistry 42 112. (https://doi.org/10.1042/bse0420001)

    • Search Google Scholar
    • Export Citation
  • He A, Liu X, Liu L, Chang Y & Fang F 2007 How many signals impinge on GLUT4 activation by insulin? Cellular Signalling 19 17. (https://doi.org/10.1016/j.cellsig.2006.05.018)

    • Search Google Scholar
    • Export Citation
  • Henríquez-Olguin C, Knudsen JR, Raun SH, Li Z, Dalbram E, Treebak JT, Sylow L, Holmdahl R, Richter EA, Jaimovich E, 2019 Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise. Nature Communications 10 4623. (https://doi.org/10.1038/s41467-019-12523-9)

    • Search Google Scholar
    • Export Citation
  • Hespel P, Vergauwen L, Vandenberghe K & Richter EA 1995 Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle. Diabetes 44 210215. (https://doi.org/10.2337/diab.44.2.210)

    • Search Google Scholar
    • Export Citation
  • Hruz PW & Mueckler MM 2001 Structural analysis of the GLUT1 facilitative glucose transporter (review). Molecular Membrane Biology 18 183193. (https://doi.org/10.1080/09687680110072140)

    • Search Google Scholar
    • Export Citation
  • Huang S & Czech MP 2007 The GLUT4 glucose transporter. Cell Metabolism 5 237252. (https://doi.org/10.1016/j.cmet.2007.03.006)

  • Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A & Walsh K 2008 FGF21 is an Akt-regulated myokine. FEBS Letters 582 38053810. (https://doi.org/10.1016/j.febslet.2008.10.021)

    • Search Google Scholar
    • Export Citation
  • Jeon JY, Choi SE, Ha ES, Kim TH, Jung JG, Han SJ, Kim HJ, Kim DJ, Kang Y & Lee KW 2016 Association between insulin resistance and impairment of FGF21 signal transduction in skeletal muscles. Endocrine 53 97106. (https://doi.org/10.1007/s12020-015-0845-x)

    • Search Google Scholar
    • Export Citation
  • Kanzaki M & Pessin JE 2003 Insulin signaling: GLUT4 vesicles exit via the exocyst. Current Biology 13 R574R576. (https://doi.org/10.1016/s0960-9822(03)00478-0)

    • Search Google Scholar
    • Export Citation
  • Kanzaki M, Mora S, Hwang JB, Saltiel AR & Pessin JE 2004 Atypical protein kinase C (PKCζ/λ) is a convergent downstream target of the insulin-stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways. Journal of Cell Biology 164 279290. (https://doi.org/10.1083/jcb.200306152)

    • Search Google Scholar
    • Export Citation
  • Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, 2005 FGF-21 as a novel metabolic regulator. Journal of Clinical Investigation 115 16271635. (https://doi.org/10.1172/JCI23606)

    • Search Google Scholar
    • Export Citation
  • Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB & Etgen GJ 2007 The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148 774781. (https://doi.org/10.1210/en.2006-1168)

    • Search Google Scholar
    • Export Citation
  • Kong LJ, Feng W, Wright M, Chen Y, Dallas-Yang Q, Zhou YP & Berger JP 2013 FGF21 suppresses hepatic glucose production through the activation of atypical protein kinase Ci/λ. European Journal of Pharmacology 702 302308. (https://doi.org/10.1016/j.ejphar.2012.11.065)

    • Search Google Scholar
    • Export Citation
  • Kramer HF & Goodyear LJ 2007 Exercise, MAPK, and NF-κB signaling in skeletal muscle. Journal of Applied Physiology 103 388395. (https://doi.org/10.1152/japplphysiol.00085.2007)

    • Search Google Scholar
    • Export Citation
  • Lever JE 1979 Modulation of glucose uptake in animal cells. Studies using plasma membrane vesicles isolated from nontransformed and simian virus 40-transformed mouse fibroblast cultures. Journal of Biological Chemistry 254 29612967.

    • Search Google Scholar
    • Export Citation
  • Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, Ding H, Lam KSL & Xu A 2014 FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 63 40644075. (https://doi.org/10.2337/db14-0541)

    • Search Google Scholar
    • Export Citation
  • Liu LZ, Zhao HL, Zuo J, Ho SKS, Chan JCN, Meng Y, Fang FD & Tong PCY 2006 Protein kinase C mediates insulin-induced glucose transport through actin remodeling in L6 muscle cells. Molecular Biology of the Cell 17 23222330. (https://doi.org/10.1091/mbc.e05-10-0969)

    • Search Google Scholar
    • Export Citation
  • Llanos P, Contreras-Ferrat A, Georgiev T, Osorio-Fuentealba C, Espinosa A, Hidalgo J, Hidalgo C & Jaimovich E 2015 The cholesterol-lowering agent methyl-β-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice. American Journal of Physiology: Endocrinology and Metabolism 308 E294E305. (https://doi.org/10.1152/ajpendo.00189.2014)

    • Search Google Scholar
    • Export Citation
  • Markan KR & Potthoff MJ 2016 Metabolic fibroblast growth factors (FGFs): mediators of energy homeostasis. Seminars in Cell and Developmental Biology 53 8593. (https://doi.org/10.1016/j.semcdb.2015.09.021)

    • Search Google Scholar
    • Export Citation
  • Martin SS, Haruta T, Morris AJ, Klippel A, Williams LT & Olefsk JM 1996 Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes. Journal of Biological Chemistry 271 1760517608. (https://doi.org/10.1074/jbc.271.30.17605)

    • Search Google Scholar
    • Export Citation
  • Martiny-Baron G, Kazanietz MG, Mischak H, Blumberg PM, Kochs G, Hug H, Marme D & Schachtele C 1993 Selective inhibition of protein kinase C isozymes by the indolocarbazole Gö6976. Journal of Biological Chemistry 268 91949197.

    • Search Google Scholar
    • Export Citation
  • Mashili F 2011 Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. Diabetes/Metabolism Research and Reviews 27 96102. (https://doi.org/10.1002/dmrr.1177)

    • Search Google Scholar
    • Export Citation
  • Nishimura T, Nakatake Y, Konishi M & Itoh N 2000 Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochimica et Biophysica Acta 1492 203206. (https://doi.org/10.1016/s0167-4781(00)00067-1)

    • Search Google Scholar
    • Export Citation
  • Niu W, Huang C, Nawaz Z, Levy M, Somwar R, Li D, Bilan PJ & Klip A 2003 Maturation of the regulation of GLUT4 activity by p38 MAPK during L6 cell myogenesis. Journal of Biological Chemistry 278 1795317962. (https://doi.org/10.1074/jbc.M211136200)

    • Search Google Scholar
    • Export Citation
  • Ogawa Y, Kurosu H, Yamamoto M, Nandi A, Rosenblatt KP, Goetz R, Eliseenkova AV, Mohammadi M & Kuro-o M 2007 βKlotho is required for metabolic activity of fibroblast growth factor 21. PNAS 104 74327437. (https://doi.org/10.1073/pnas.0701600104)

    • Search Google Scholar
    • Export Citation
  • Olson AL 2012 Regulation of GLUT4 and insulin-dependent glucose flux. ISRN Molecular Biology 2012 856987. (https://doi.org/10.5402/2012/856987)

    • Search Google Scholar
    • Export Citation
  • Osorio-Fuentealba C, Contreras-Ferrat AE, Altamirano F, Espinosa A, Li Q, Niu W, Lavandero S, Klip A & Jaimovich E 2013 Electrical stimuli release ATP to increase GLUT4 translocation and glucose uptake via PI3Kγ-Akt-AS160 in skeletal muscle cells. Diabetes 62 15191526. (https://doi.org/10.2337/db12-1066)

    • Search Google Scholar
    • Export Citation
  • Pedersen BK 2013 Muscle as a secretory organ. Comprehensive Physiology 3 13371362. (https://doi.org/10.1002/cphy.c120033)

  • Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB & Febbraio MA 2009 Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Experimental Physiology 94 11531160. (https://doi.org/10.1113/expphysiol.2009.048561)

    • Search Google Scholar
    • Export Citation
  • Powell D, , Hajduch E, , Kular G, , & Hundal H 2003 Ceraminde disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKC-dependent mechanism. Molecular and Cellular Biology 23 77947808. (https://doi.org/10.1128/MCB.23.21.7794–7808.2003)

    • Search Google Scholar
    • Export Citation
  • Powell DJ, Turban S, Gray A, Hajduch E & Hundal HS 2004 Intracellular ceramide synthesis and protein kinase Cζ activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells. Biochemical Journal 382 619629. (https://doi.org/10.1042/BJ20040139)

    • Search Google Scholar
    • Export Citation
  • Raun SH, Ali M, Kjøbsted R, Møller LLV, Federspiel MA, Richter EA, Jensen TE & Sylow L 2018 Rac1 muscle knockout exacerbates the detrimental effect of high-fat diet on insulin-stimulated muscle glucose uptake independently of Akt. Journal of Physiology 596 22832299. (https://doi.org/10.1113/JP275602)

    • Search Google Scholar
    • Export Citation
  • Rudich A, Konrad D, Török D, Ben-Romano R, Huang C, Niu W, Garg RR, Wijesekara N, Germinario RJ, Bilan PJ, 2003 Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues. Diabetologia 46 649658. (https://doi.org/10.1007/s00125-003-1080-1)

    • Search Google Scholar
    • Export Citation
  • Saltiel AR & Kahn CR 2001 Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414 799806. (https://doi.org/10.1038/414799a)

    • Search Google Scholar
    • Export Citation
  • Sanchez-Margalet V, Goldfine ID, Vlahos CJ & Sung CK 1994 Role of PI3K in insulin receptor signaling – LY294002. Biochemical and Biophysical Research Communications 204 446452. (https://doi.org/10.1006/bbrc.1994.2480)

    • Search Google Scholar
    • Export Citation
  • Sylow L, Jensen TE, Kleinert M, Mouatt JR, Maarbjerg SJ, Jeppesen J, Prats C, Chiu TT, Boguslavsky S, Klip A, 2013 Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle. Diabetes 62 11391151. (https://doi.org/10.2337/db12-0491)

    • Search Google Scholar
    • Export Citation
  • Sylow L, Nielsen IL, Kleinert M, Møller LLV, Ploug T, Schjerling P, Bilan PJ, Klip A, Jensen TE & Richter EA 2016 Rac1 governs exercise-stimulated glucose uptake in skeletal muscle through regulation of GLUT4 translocation in mice. Journal of Physiology 594 49975008. (https://doi.org/10.1113/JP272039)

    • Search Google Scholar
    • Export Citation
  • Tanimura Y, Aoi W, Takanami Y, Kawai Y, Mizushima K, Naito Y & Yoshikawa T 2016 Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiological Reports 4 426437. (https://doi.org/10.14814/phy2.12828)

    • Search Google Scholar
    • Export Citation
  • Tengholm A & Meyer T 2002 A PI3-kinase signaling code for insulin-triggered insertion of glucose transporters into the plasma membrane. Current Biology 12 18711876. (https://doi.org/10.1016/s0960-9822(02)01223-x)

    • Search Google Scholar
    • Export Citation
  • Toullec D, Pianetti P, Bellevergue P, Grand-Perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F, Duhamel L, 1991, The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. Journal of Biological Chemistry 266 1577115781.

    • Search Google Scholar
    • Export Citation
  • Wang H, Qiang L & Farmer SR 2008 Identification of a domain within peroxisome proliferator-activated receptor regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Molecular and Cellular Biology 28 188200. (https://doi.org/10.1128/MCB.00992-07)

    • Search Google Scholar
    • Export Citation
  • Watt MJ, Heigenhauser GJF, O’Neill M & Spriet LL 2003 Hormone-sensitive lipase activity and fatty acyl-CoA content in human skeletal muscle during prolonged exercise. Journal of Applied Physiology 95 314321. (https://doi.org/10.1152/japplphysiol.01181.2002)

    • Search Google Scholar
    • Export Citation
  • Welsh GI, Hers I, Berwick DC, Dell G, Wherlock M, Birkin R, Leney S & Tavaré JM 2005 Role of protein kinase B in insulin-regulated glucose uptake. Biochemical Society Transactions 33 346349. (https://doi.org/10.1042/BST0330346)

    • Search Google Scholar
    • Export Citation
  • Whitham M, Parker BL, Friedrichsen M, Hingst JR, Hjorth M, Hughes WE, Egan CL, Cron L, Watt KI, Kuchel RP, 2018 Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metabolism 27 237.e4251.e4. (https://doi.org/10.1016/j.cmet.2017.12.001)

    • Search Google Scholar
    • Export Citation
  • Xu J, Stanislaus S, Chinookoswong N, Lau YY, Hager T, Patel J, Ge H, Weiszmann J, Lu SC, Graham M, 2009 Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models – association with liver and adipose tissue effects. American Journal of Physiology: Endocrinology and Metabolism 297 E1105E1114. (https://doi.org/10.1152/ajpendo.00348.2009)

    • Search Google Scholar
    • Export Citation
  • Yu H, Fujii NL, Toyoda T, An D, Farese RV, Leitges M, Hirshman MF, Mul JD & Goodyear LJ 2015 Contraction stimulates muscle glucose uptake independent of atypical PKC. Physiological Reports 3 19. (https://doi.org/10.14814/phy2.12565)

    • Search Google Scholar
    • Export Citation
  • Zhou QL, Park JG, Jiang ZY, Holik JJ, Mitra P, Semiz S, Guilherme A, Powelka AM, Tang X, Virbasius J, 2004 Analysis of insulin signalling by RNAi-based gene silencing. Biochemical Society Transactions 32 817821. (https://doi.org/10.1042/BST0320817

    • Search Google Scholar
    • Export Citation