Thyroid Hormones, Cytokines, Physical Training and Metabolic Control

Abstract

During the acute training response, peripheral cellular mechanisms are mainly metabolostatic to achieve energy supply. During prolonged training, glycogen deficiency occurs; this is associated with increased expression of local cytokines, and decreased insulin secretion and β-adrenergic stimulation and lipolysis in adipose tissue which looses energy. This is indicated by decrease of adipocyte hormone leptin, which has inhibitory effects on excitatory hypothalamic neurons. Leptin, insulin, and cytokines such as interleukin 6 (IL-6) contribute to the metabolic error signal to the hypothalamus which result in decrease of hypothalamic release hormones and sympathoadrenergic stimulation. Thyroid stimulating hormone (TSH) is correlated to the metabolic hormones leptin and insulin, and may be used as indicator of metabolic control. Because the hypothalamus integrates various error signals (metabolic, hormonal, sensory afferents, and central stimuli), the pituitary’s releasing hormones represent the functional status of an athlete. Long-term overtraining will lead to downregulation of hypothalamic hormonal and sympathoadrenergic responses, catabolism, and fatigue. These changes contribute to myopathy with predominant expression of slow muscle fiber type and inadequacy in performance. Thyroid hormones are closely involved in the training response and metabolic control.

Key words

Training - Overtraining - Hormonal regulation - Metabolism

References

• 1 Weicker H, Strobel G. Endocrine regulation of metabolism during exercise. In: Steinacker JM, Ward SA (eds) The physiology and pathophysiology of exercise tolerance. London; Plenum 1997 1: 113-121
• 2 Steinacker J M, Lormes W, Reissnecker S, Liu Y. New aspects of the hormone and cytokine response to training.  Eur J Appl Physiol. 2004;  91 382-391
• 3 Lehmann M, Petersen K G, Liu Y, Gastmann U, Lormes W, Steinacker J M. Chronische und erschöpfende Belastungen im Sport - Einfluss von Leptin und Inhibin [Chronic exhaustive exercise in sports - Influence of leptin and inhibin].  Dtsch Z Sportmed. 2000;  51 234-243
• 4 Lehmann M, Lormes W, Opitz-Gress A, Steinacker J M, Netzer N, Foster C, Gastmann U. Training and overtraining: an overview and experimental results in endurance sports.  J Sports Med Phys Fitness. 1997;  37 7-17
• 5 Friedman J M, Halaas J L. Leptin and the regulation of body weight in mammals.  Nature. 1998;  395 763-770
• 6 Friedman J E, Ferrara C M, Aulak K S, Hatzoglou M, McCune S A, Park S, Sherman W M. Exercise training down-regulates ob gene expression in the genetically obese SHHF/Mcc-fa(cp) rat.  Horm Metab Res. 1997;  29 214-219
• 7 Simsch C, Lormes W, Petersen K G, Baur S, Liu Y, Hackney A C, Lehmann M, Steinacker J M. Training intensity influences leptin and thyroid hormones in highly trained rowers.  Int J Sports Med. 2002;  23 422-427
• 8 Carro E, Seoane L M, Senaris R, Considine R V, Casanueva F F, Dieguez C. Interaction between leptin and neuropeptide Y on in vivo growth hormone secretion.  Neuroendocrinology. 1998;  68 187-191
• 9 Heiman M L, Ahima R S, Craft L S, Schoner B, Stephens T W, Flier J S. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress.  Endocrinology. 1997;  138 3859-3863
• 10 Haddad F, Qin A X, McCue S A, Baldwin K M. Thyroid receptor plasticity in striated muscle types: effects of altered thyroid state.  Am J Physiol. 1998;  274 E1018-E1026
• 11 Kahaly G J, Dillmann W H. Thyroid hormone action in the heart.  Endocr Rev. 2005;  26 704-728
• 12 Clement K, Viguerie N, Diehn M, Alizadeh A, Barbe P, Thalamas C, Storey J D, Brown P O, Barsh G S, Langin D. In vivo regulation of human skeletal muscle gene expression by thyroid hormone.  Genome Res. 2002;  12 281-291
• 13 Haddad F, Bodell P W, McCue S A, Herrick R E, Baldwin K M. Food restriction-induced transformations in cardiac functional and biochemical properties in rats.  J Appl Physiol. 1993;  74 606-612
• 14 Gustafson T A, Markham B E, Morkin E. Effects of thyroid hormone on alpha-actin and myosin heavy chain gene expression in cardiac and skeletal muscles of the rat: measurement of mRNA content using synthetic oligonucleotide probes.  Circ Res. 1986;  59 194-201
• 15 Arruda A P, Da-Silva W S, Carvalho D P, De M L. Hyperthyroidism increases the uncoupled ATPase activity and heat production by the sarcoplasmic reticulum Ca2+-ATPase.  Biochem J. 2003;  375 753-760
• 16 Hackney A C, Feith S, Pozos R, Seale J. Effects of high altitude and cold exposure on resting thyroid hormone concentrations.  Aviat Space Environ Med. 1995;  66 325-329
• 17 Lehmann M, Foster C, Gastmann U, Keizer H A, Steinacker J M. Definition, types, symptoms, findings underlying mechanisms, and frequency of overtraining and overtraining syndrome. In: Lehmann M, Foster C, Gastmann U, Keizer HA, Steinacker JM (eds) Overload, performance incompetence, and regeneration in sport. New York; Kluwer Academic/Plenum Publishers 1999 1: 1-6
• 18 Steinacker J M, Lormes W, Kellmann M, Liu Y, Reissnecker S, Opitz-Gress A, Baller B, Günther K, Petersen K G, Kallus K W, Lehmann M, Altenburg D. Training of Junior Rowers before World Championships. Effects on performance, mood state and selected hormonal and metabolic responses.  J Sports Med Phys Fitness. 2000;  40 327-335
• 19 Steinacker J M, Kellmann M, Böhm B O, Liu Y, Opitz-Gress A, Kallus K W, Lehmann M, Altenburg D, Lormes W. Clinical findings of stress and regeneration in rowers before World Championships. In: Lehmann M, Foster C, Gastmann U, Keizer HA, Steinacker JM (eds) Overload, performance incompetence, and regeneration in sport. New York; Kluwer Academic/Plenum Publishers 1999: 71-80
• 20 Baskin D G, Breininger J F, Schwartz M W. Leptin Receptor mRNA identifies a subpopulation of Neuropeptide Y neurons activated by fasting in rat hypothalamus.  Diabetes. 1999;  48 828-833
• 21 Wittert G A, Livesey J H, Espiner E A, Donald R A. Adaptation of the hypothalamopituitary adrenal axis to chronic exercise stress in humans.  Med Sci Sports Exerc. 1996;  28 1015-1019
• 22 Kirwan J P, Jing M. Modulation of insulin signaling in human skeletal muscle in response to exercise.  Exerc Sport Sci Rev. 2002;  30 85-90
• 23 Drenth J P, Van Uum S H, Van Deuren M, Pesman G J, Van der Ven-Jongekrijg J, van der Meer J W. Endurance run increases circulating IL-6 and IL-1ra but downregulates ex vivo TNF-alpha and IL-1 beta production.  J Appl Physiol. 1995;  79 1497-1503
• 24 Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen B K. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans.  J Physiol (Lond). 1999;  515 287-291
• 25 Nehlsen-Cannarella S L, Fagoaga O R, Nieman D C, Henson D A, Butterworth D E, Schmitt R L, Bailey E M, Warren B J, Utter A, Davis J M. Carbohydrate and the cytokine response to 2.5 h of running.  J Appl Physiol. 1997;  82 1662-1667
• 26 Steensberg A, Febbraio M A, Osada T, Schjerling P, van Hall G, Saltin B, Pedersen B K. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content.  J Physiol. 2001;  537 633-639
• 27 Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen B K, Neufer P D. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content.  FASEB J. 2001;  15 2748-2750
• 28 Starkie R L, Arkinstall M J, Koukoulas I, Hawley J A, Febbraio M A. Carbohydrate ingestion attenuates the increase in plasma interleukin-6, but not skeletal muscle interleukin-6 mRNA, during exercise in humans.  J Physiol (Lond). 2001;  533 585-591
• 29 Pedersen B K, Steensberg A, Fischer C, Keller C, Ostrowski K, Schjerling P. Exercise and cytokines with particular focus on muscle derived IL-6.  Exerc Immunol Rev. 2001;  7 18-31
• 30 Path G, Bornstein S R, Gurniak M, Chrousos G P, Scherbaum W A, Hauner H. 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. 2001;  86 2281-2288
• 31 Mohamed-Ali V, Flower L, Sethi J, Hotamisligil G, Gray R, Humphries S E, York D A, Pinkney J. Beta-Adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies.  J Clin Endocrinol Metab. 2001;  86 5864-5869
• 32 Shizuya K, Komori T, Fujiwara R, Miyahara S, Ohmori M, Nomura J. The expressions of mRNAs for interleukin-6 (IL-6) and the IL-6 receptor (IL-6R) in the rat hypothalamus and midbrain during restraint stress.  Life Sci. 1998;  62 2315-2320
• 33 Mastorakos G, Chrousos G P, Weber J S. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans.  J Clin Endocrinol Metab. 1993;  77 1690-1694
• 34 Mantzoros C S, Moschos S, Avramopoulos I, Kaklamani V, Liolios A, Doulgerakis D E, Griveas I, Katsilambros N, Flier J S. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans.  J Clin Endocrinol Metab. 1997;  82 3408-3413
• 35 Halle M, Berg A, Northoff H, Keul J. Importance of TNF-alpha and leptin in obesity and insulin resistance: a hypothesis on the impact of physical exercise.  Exerc Immunol Rev. 1998;  4 77-94
• 36 Kraemer R R, Kraemer G R, Acevedo E O, Hebert E P, Temple E, Bates M, Etie A, Haltom R, Quinn S, Castracane V D. Effects of aerobic exercise on serum leptin levels in obese women.  Eur J Appl Physiol. 1999;  80 154-158
• 37 Perusse L, Collier G, Gagnon J, Leon A S, Rao D C, Skinner J S, Wilmore J H, Nadeau A, Zimmet P Z, Bouchard C. Acute and chronic effects of exercise on leptin levels in humans.  J Appl Physiol. 1997;  83 5-10
• 38 Hickey M S, Considine R V, Israel R G, Mahar T L, McCammon M R, Tyndall G L, Houmard J A, Caro J F. Leptin is related to body fat content in male distance runners.  Am J Physiol. 1996;  271 E938-E940
• 39 Ahima R S, Kelly J, Elmquist J K, Flier J S. Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia.  Endocrinology. 1999;  140 4923-4931
• 40 Gaillard R C, Spinedi E, Chautard T, Pralong F P. Cytokines, leptin, and the hypothalamo-pituitary-adrenal axis.  Ann N Y Acad Sci. 2000;  917 647-657
• 41 Nara M, Kanda T, Tsukui S, Inukai T, Shimomura Y, Inoue S, Kobayashi I. Running exercise increases tumor necrosis factor-alpha secreting from mesenteric fat in insulin-resistant rats.  Life Sci. 1999;  65 237-244
• 42 Hotamisligil G S. Mechanisms of TNF-alpha-induced insulin resistance.  Exp Clin Endocrinol Diabetes. 1999;  107 119-125
• 43 Mantzoros C S, Qu D, Frederich R C, Susulic V S, Lowell B B, Maratos-Flier E, Flier J S. Activation of beta(3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice.  Diabetes. 1996;  45 909-914
• 44 Nedvidkova J, Smitka K, Kopsky V, Hainer V. Adiponectin, an adipocyte-derived protein.  Physiol Res. 2004;  54 133-140
• 45 Elias C F, Aschkenasi C, Lee C, Kelly J, Ahima R S, Bjorbaek C, Flier J S, Saper C B, Elmquist J K. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area.  Neuron. 1999;  23 775-786
• 46 Luckman S M, Rosenzweig I, Dickson S L. Activation of Arcuate Nucleus Neurons by Systemic Administration of Leptin and Growth Hormone-Releasing Peptide-6 in Normal and Fasted Rats.  Neuroendocrinology. 1999;  70 93-100
• 47 Schwartz M W, Seeley R J, Campfield L A, Burn P, Baskin D G. Identification of targets of leptin action in rat hypothalamus.  J Clin Invest. 1996;  98 1101-1106
• 48 Houghton A R, Harrison M, Perry A J, Evans A J, Cowley A J. Endogenous insulin and insulin sensitivity. An important determinant of skeletal muscle blood flow in chronic heart failure?.  Eur Heart J. 1998;  19 476-480
• 49 Ahima R S, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier J S. Role of leptin in the neuroendocrine response to fasting.  Nature. 1999;  382 250-252
• 50 Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects.  J Clin Endocrinol Metab. 1996;  81 3419-3423
• 51 Baylor L S, Hackney A C. Resting thyroid and leptin hormone changes in women following intense, prolonged exercise training.  Eur J Appl Physiol. 2003;  88 480-484
• 52 Wesche M F, Wiersinga W M. Relation between lean body mass and thyroid volume in competition rowers before and during intensive physical training.  Horm Metab Res. 2001;  33 423-427
• 53 Tremblay A, Poehlman E T, Despres J P, Theriault G, Danforth E, Bouchard C. Endurance training with constant energy intake in identical twins: changes over time in energy expenditure and related hormones.  Metabolism. 1997;  46 499-503
• 54 Evason M D, Carr A P, Taylor S M, Waldner C L. Alterations in thyroid hormone concentrations in healthy sled dogs before and after athletic conditioning.  Am J Vet Res. 2004;  65 333-337
• 55 Tsuboyama-Kasaoka N, Tsunoda N, Maruyama K, Takahashi M, Kim H, Ikemoto S, Ezaki O. Up-regulation of uncoupling protein 3 (UCP3) mRNA by exercise training and down-regulation of UCP3 by denervation in skeletal muscles.  Biochem Biophys Res Commun. 1998;  247 498-503
• 56 Cunningham O, McElligott A M, Carroll A M, Breen E, Reguenga C, Oliveira M E, Azevedo J E, Porter R K. Selective detection of UCP 3 expression in skeletal muscle: effect of thyroid status and temperature acclimation.  Biochim Biophys Acta. 2003;  1604 170-179
• 57 Schrauwen P, Hesselink M. Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited.  Proc Nutr Soc. 2003;  62 635-643
• 58 Gong D W, Monemdjou S, Gavrilova O, Leon L R, Marcus-Samuels B, Chou C J, Everett C, Kozak L P, Li C, Deng C, Harper M E, Reitman M L. Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.  J Biol Chem. 2000;  275 16 251-16 257
• 59 Schuler M J, Buhler S, Pette D. Effects of contractile activity and hypothyroidism on nuclear hormone receptor mRNA isoforms in rat skeletal muscle.  Eur J Biochem. 1999;  264 982-988
• 60 Viguerie N, Millet L, Avizou S, Vidal H, Larrouy D, Langin D. Regulation of human adipocyte gene expression by thyroid hormone.  J Clin Endocrinol Metab. 2002;  87 630-634
• 61 Booth F W, Baldwin K M. Muscle plasticity: energy demand and supply processes. In: Rowell LB, Shepherd JT (eds) Handbook of Physiology. New York, Oxford; Oxford University Press 1996 1: 1075-1123
• 62 Pette D, Staron R S. Mammalian skeletal muscle fiber type transitions.  Int Rev Cytol. 1997;  170 143-223
• 63 Haddad F, Qin A X, McCue S A, Baldwin K M. Thyroid receptor plasticity in striated muscle types: effects of altered thyroid state.  Am J Physiol. 1998;  274 E1018-E1026
• 64 Wahrmann J P, Fulla Y, Rieu M, Kahn A, Dinh-Xuan A T. Altered myosin isoform expression in rat skeletal muscles induced by a changed thyroid state.  Acta Physiol Scand. 2002;  176 233-243
• 65 Muscat G E, Mynett-Johnson L, Dowhan D, Downes M, Griggs R. Activation of myoD gene transcription by 3,5,3'-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors.  Nucleic Acids Res. 1994;  22 583-591
• 66 Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart.  Endocrinology. 2000;  141 2139-2144
• 67 Wang Y, Tonouchi M, Miskovic D, Hatta H, Bonen A. T3 increases lactate transport and the expression of MCT4, but not MCT1, in rat skeletal muscle.  Am J Physiol Endocrinol Metab. 2003;  285 E622-E628
• 68 Fehmann H C, Peiser C, Bode H P, Stamm M, Staats P, Hedetoft C, Lang R E, Goke B. Leptin: a potent inhibitor of insulin secretion.  Peptides. 1997;  18 1267-1273
• 69 Minokoshi Y, Kim Y B, Peroni O D, Fryer L G, Muller C, Carling D, Kahn B B. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.  Nature. 2002;  415 339-343
• 70 Coppack S W. Pro-inflammatory cytokines and adipose tissue.  Proc Nutr Soc. 2001;  60 349-356
• 71 Borghouts L B, Keizer H A. Exercise and insulin sensitivity: A review.  Int J Sports Med. 2000;  21 1-12
• 72 Haas H S, Schauenstein K. Neuroimmunomodulation via limbic structures - the neuroanatomy of psychoimmunology.  Prog Neurobiol. 1997;  51 195-222
• 73 Spinedi E, Gaillard R C. A regulatory loop between the hypothalamo-pituitary-adrenal (HPA) axis and circulating leptin: a physiological role of ACTH.  Endocrinology. 1998;  139 4016-4020
• 74 Lehmann M, Gastmann U, Baur S, Liu Y, Lormes W, Opitz-Gress A, Reissnecker S, Simsch C, Steinacker J M. Selected parameters and mechanisms of peripheral and central fatigue and regeneration in overtrained athletes. In: Lehmann M, Foster C, Gastmann U, Keizer HA, Steinacker JM (eds) Overload, performance incompetence and regeneration in sport. New York; Kluwer Academic/Plenum Pubishers 1999: 7-26
• 75 Steinacker J M, Lormes W, Kellmann M, Liu Y, Reissnecker S, Opitz-Gress A, Baller B, Gunther K, Petersen K G, Kallus K W, Lehmann M, Altenburg D. Training of junior rowers before world championships. Effects on performance, mood state and selected hormonal and metabolic responses.  J Sports Med Phys Fitness. 2000;  40 327-335
• 76 Lehmann M, Jakob E, Spori U, Bergdolt E, Keul J. Free and conjugated plasma catecholamines, lactate behavior and oxygen uptake at rest and in staged physical exertion as well as alpha receptor density in intact thrombocytes in trained athletes.  Z Kardiol. 1985;  74 32-38
• 77 Fry A C, Kraemer W J. Resistance exercise overtraining and overreaching. Neuroendocrine responses.  Sports Med. 1997;  23 106-129
• 78 Urhausen A, Gabriel H H, Kindermann W. Impaired pituitary hormonal response to exhaustive exercise in overtrained endurance athletes.  Med Sci Sports Exerc. 1998;  30 407-414
• 79 Barron J L, Noakes T D, Levy W, Smith C, Millar R P. Hypothalamic dysfunction in overtrained athletes.  J Clin Endocrinol Metab. 1985;  60 803-806
• 80 Lehmann M, Knizia K, Gastmann U, Petersen K G, Khalaf A N, Bauer S, Kerp L, Keul J. Influence of 6-week, 6 days per week, training on pituitary function in recreational athletes.  Br J Sports Med. 1993;  27 186-192
• 81 Brüning J C, Gautam D, Burks D J, Gillette J, Schubert M, Orban P C, Klein R, Krone W, Müller-Wieland D, Kahn C R. Role of brain insulin receptor in control of body weight and reproduction.  Science. 2000;  289 2122-2125
• 82 Ribeiro M O, Carvalho S D, Schultz J J, Chiellini G, Scanlan T S, Bianco A C, Brent G A. Thyroid hormone-sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform-specific.  J Clin Invest. 2001;  108 97-105
• 83 Ennion S, Sant’ana P J, Sargeant A J, Young A, Goldspink G. Characterization of human skeletal muscle fibres according to the myosin heavy chains they express.  J Muscle Res Cell Motil. 1995;  16 35-43
• 84 Adams G R, Haddad F. The relationships among IGF-I, DNA content, and protein accumulation during skeletal muscle hypertrophy.  J Appl Physiol. 1996;  81 2509-2516
• 85 Eisenberg B R, Goldspink P H, Wenderoth M P. Distribution of myosin heavy chain mRNA in normal and hyperthyroid heart.  J Mol Cell Cardiol. 1991;  23 287-296
• 86 Williams N I, Helmreich D L, Parfitt D B, Caston-Balderrama A, Cameron J L. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training.  J Clin Endocrinol Metab. 2001;  86 5184-5193
• 87 Atalay M, Seene T, Hanninen O, Sen C K. Skeletal muscle and heart antioxidant defences in response to sprint training.  Acta Physiol Scand. 1996;  158 129-134
• 88 Liu Y, Lormes W, Reissnecker S, Steinacker J M. Effects of high intensity resistance and low intensity endurance training on myosin heavy chain isoform expression in highly trained rowers.  Int J Sports Med. 2003;  24 264-270