Free Thyroxine Levels are Associated with Cold Induced Thermogenesis in Healthy Euthyroid Individuals

Claudia Irene Maushart, Jaël Rut Senn, Rahel Catherina Loeliger, Marius E Kraenzlin, Julian Müller, Anton S Becker, Miroslav Balaz, Christian Wolfrum, Irene A Burger, Matthias Johannes Betz, Claudia Irene Maushart, Jaël Rut Senn, Rahel Catherina Loeliger, Marius E Kraenzlin, Julian Müller, Anton S Becker, Miroslav Balaz, Christian Wolfrum, Irene A Burger, Matthias Johannes Betz

Abstract

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.

Keywords: brown adipose tissue; cold adaptation; cold induced thermogenesis; energy expenditure; thyroid hormone; thyroxine.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Maushart, Senn, Loeliger, Kraenzlin, Müller, Becker, Balaz, Wolfrum, Burger and Betz.

Figures

Figure 1
Figure 1
Comparison of tympanic temperature and skin temperatures before and after mild cold exposure. (A) Tympanic temperature; Skin temperatures: (B) Supraclavicular region; (C) Parasternal region; (D), Umbilicus; (E) Thigh; (F) Non-dominant forearm; (G) Middle finger, non dominant hand; (H) Left lower leg; (I) Left dorsal foot. ****p<0.0001 in Wilcoxon-Signed-Rank Test, ns, p≥0.05.
Figure 2
Figure 2
Free T4 within the reference range was not significantly related to energy expenditure during warm conditions (EEwarm, R2 = 0.03, p=0.12, (A), but to energy expenditure during mild cold exposure (EEcold, R2 = 0.11, p=0.0025, (B) and to relative cold induced thermogenesis (CIT, R2 = 0.13, p=0.0011, (C). Free T3 was significantly associated with EEwarm (R2 = 0.16, p=0.0004, (D), EEcold (R2 = 0.11, p=0.0039, (E), but not with CIT (R2 = 0.00, p=0.90, (F).
Figure 3
Figure 3
Subjects were grouped into tertiles according their levels of free T4 (A). The mean TSH levels of the three groups did not differ significantly (ANOVA p=0.89, (B). In the highest tertile (free T4 17.5 to 21.0 pM) they had mean CIT of 10.2 ± 7.5% of EEwarm while those in the lowest tertile (free T4 10.9 to 15.7 pM) had a mean CIT of 2.3 ± 8.7% (ANOVA p=0.0057, trend p=0.0027, (C). **p<0.01; ****p<0.0001; ns, p≥0.05.
Figure 4
Figure 4
Levels of free T4 were significantly associated with the uptake of fluoro-deoxyglucose (SUVmean) into supraclavicular brown adipose tissue (R2 = 0.21, p=0.018). Diamonds: individual data points from trial 1 NCT03189511 (PET/MRI, BAT stimulation by Mirabegron and cold exposure), Circles: individual data points from trial 2 NCT03269747 (PET/CT, BAT stimulation by cold exposure).

References

    1. Mullur R, Liu YY, Brent GA. Thyroid Hormone Regulation of Metabolism. Physiol Rev (2014) 94(2):355–82 10.1152/physrev.00030.2013
    1. López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al. . Hypothalamic AMPK and Fatty Acid Metabolism Mediate Thyroid Regulation of Energy Balance. Nat Med (2010) 16(9):1001. 10.1038/nm.2207
    1. Comte B, Vidal H, Laville M, Riou J-P. Influence of Thyroid Hormones on Gluconeogenesis From Glycerol in Rat Hepatocytes: A Dose-Response Study. Metabolism (1990) 39(3):259–63. 10.1016/0026-0495(90)90044-D
    1. Hellstroöm L, Wahrenberg H, Reynisdottir S, Arner P. Catecholamine-Induced Adipocyte Lipolysis in Human Hyperthyroidism*. J Clin Endocrinol Metab (1997) 82(1):159–66. 10.1210/jc.82.1.159
    1. Wolf M, Weigert A, Kreymann G. Body Composition and Energy Expenditure in Thyroidectomized Patients During Short-Term Hypothyroidism and Thyrotropin-Suppressive Thyroxine Therapy. Eur J Endocrinol (1996) 134(2):168–73. 10.1530/eje.0.1340168
    1. Wahrenberg H, Wennlund A, Arner P. Adrenergic Regulation of Lipolysis in Fat Cells From Hyperthyroid and Hypothyroid Patients. J Clin Endocrinol Metab (1994) 78(4):898–903. 10.1210/jcem.78.4.8157718
    1. Mcculloch AJ, Johnston DG, Baylis PH, Kendalltaylor P, Clark F, Young ET, et al. . Evidence That Thyroid-Hormones Regulate Gluconeogenesis From Glycerol in Man. Clin Endocrinol (Oxf) (1983) 19(1):67–76. 10.1111/j.1365-2265.1983.tb00744.x
    1. Mehran L, Amouzegar A, Bakhtiyari M, Mansournia MA, Rahimabad PK, Tohidi M, et al. . Variations in Serum Free Thyroxine Concentration Within the Reference Range Predicts the Incidence of Metabolic Syndrome in Non-Obese Adults: A Cohort Study. Thyroid (2017) 27(7):886–93. 10.1089/thy.2016.0557
    1. Jun JE, Jee JH, Bae JC, Jin SM, Hur KY, Lee MK, et al. . Association Between Changes in Thyroid Hormones and Incident Type 2 Diabetes: A Seven-Year Longitudinal Study. Thyroid (2017) 27(1):29–38. 10.1089/thy.2016.0171
    1. Wolffenbuttel BHR, Wouters H, Slagter SN, van Waateringe RP, Muller Kobold AC, van Vliet-Ostaptchouk JV, et al. . Thyroid Function and Metabolic Syndrome in the Population-Based Life Lines Cohort Study. BMC Endocr Disord (2017) 17(1):65. 10.1186/s12902-017-0215-1
    1. Song Q, Chen X, Su Y, Xie Z, Wang S, Cui B. Age and Gender Specific Thyroid Hormones and Their Relationships With Body Mass Index in a Large Chinese Population. Int J Endocrinol Metab (2019) 17(1):e66450–e. 10.5812/ijem.66450
    1. Silva JE. Thermogenic Mechanisms and Their Hormonal Regulation. Physiol Rev (2006) 86(2):435–64. 10.1152/physrev.00009.2005
    1. Betz MJ, Enerback S. Targeting Thermogenesis in Brown Fat and Muscle to Treat Obesity and Metabolic Disease. Nat Rev Endocrinol (2018) 14(2):77–87. 10.1038/nrendo.2017.132
    1. Fedorenko A, Lishko PV, Kirichok Y. Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria. Cell (2012) 151(2):400–13. 10.1016/j.cell.2012.09.010
    1. Kooijman S, Wang Y, Parlevliet ET, Boon MR, Edelschaap D, Snaterse G, et al. . Central GLP-1 Receptor Signalling Accelerates Plasma Clearance of Triacylglycerol and Glucose by Activating Brown Adipose Tissue in Mice. Diabetologia (2015) 58(11):2637–46. 10.1007/s00125-015-3727-0
    1. Hanssen MJ, Hoeks J, Brans B, van der Lans AA, Schaart G, van den Driessche JJ, et al. . Short-Term Cold Acclimation Improves Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus. Nat Med (2015) 21(8):863–5. 10.1038/nm.3891
    1. Maushart CI, Loeliger R, Gashi G, Christ-Crain M, Betz MJ. Resolution of Hypothyroidism Restores Cold-Induced Thermogenesis in Humans. Thyroid (2019) 29(4):493–501. 10.1089/thy.2018.0436
    1. Gashi G, Madoerin P, Maushart CI, Michel R, Senn JR, Bieri O, et al. . Mri Characteristics of Supraclavicular Brown Adipose Tissue in Relation to Cold-Induced Thermogenesis in Healthy Human Adults. J Magn Reson Imaging (2019) 50(4):1060–1068. 10.1002/jmri.26733
    1. Balaz M, Becker AS, Balazova L, Straub L, Muller J, Gashi G, et al. . Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation. Cell Metab (2019) 29(4):901–16.e8. 10.1016/j.cmet.2018.11.017
    1. R-Core-Team . R: A Language and Environment for Statistical Computing. 3.4.1 ed. Vienna, Austria: R Foundation for Statistical Computing; (2017)
    1. Senn JR, Maushart CI, Gashi G, Michel R, Lalive d’Epinay M, Vogt R, et al. . Outdoor Temperature Influences Cold Induced Thermogenesis in Humans. Front Physiol (2018) 9:1184. 10.3389/fphys.2018.01184
    1. van Marken Lichtenbelt WD, Schrauwen P, van De Kerckhove S, Westerterp-Plantenga MS. Individual Variation in Body Temperature and Energy Expenditure in Response to Mild Cold. Am J Physiol Endocrinol Metab (2002) 282(5):E1077–83. 10.1152/ajpendo.00020.2001
    1. Andersen S, Kleinschmidt K, Hvingel B, Laurberg P. Thyroid Hyperactivity With High Thyroglobulin in Serum Despite Sufficient Iodine Intake in Chronic Cold Adaptation in An Arctic Inuit Hunter Population. Eur J Endocrinol (2012) 166(3):433–40. 10.1530/EJE-11-0888
    1. Do NV, Mino L, Merriam GR, LeMar H, Case HS, Palinkas LA, et al. . Elevation in Serum Thyroglobulin During Prolonged Antarctic Residence: Effect of Thyroxine Supplement in the Polar 3,5,3’-Triiodothyronine Syndrome. J Clin Endocrinol Metab (2004) 89(4):1529–33. 10.1210/jc.2003-031747
    1. Wilke TJ. Influence of Age and Sex on the Concentration of Free Thyroxin in Serum and on the Free Thyroxin: Total Thyroxin Ratio. Clin Chem (1983) 29(7):1428–30. 10.1093/clinchem/29.7.1428
    1. Meier CA, Maisey MN, Lowry A, Muller J, Smith MA. Interindividual Differences in the Pituitary-Thyroid Axis Influence the Interpretation of Thyroid Function Tests. Clin Endocrinol (Oxf) (1993) 39(1):101–7. 10.1111/j.1365-2265.1993.tb01758.x
    1. Hoermann R, Eckl W, Hoermann C, Larisch R. Complex Relationship Between Free Thyroxine and TSH in the Regulation of Thyroid Function. Eur J Endocrinol (2010) 162(6):1123–9. 10.1530/EJE-10-0106
    1. Broeders EP, Vijgen GH, Havekes B, Bouvy ND, Mottaghy FM, Kars M, et al. . Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis–A Cohort Study in A Group of Thyroid Carcinoma Patients. PLoS One (2016) 11(1):e0145049. 10.1371/journal.pone.0145049
    1. Spadafranca A, Cappelletti C, Leone A, Vignati L, Battezzati A, Bedogni G, et al. . Relationship Between Thyroid Hormones, Resting Energy Expenditure and Cardiometabolic Risk Factors in Euthyroid Subjects. Clin Nutr (2015) 34(4):674–8. 10.1016/j.clnu.2014.07.014
    1. Roef GL, Rietzschel ER, Van Daele CM, Taes YE, De Buyzere ML, Gillebert TC, et al. . Triiodothyronine and Free Thyroxine Levels Are Differentially Associated With Metabolic Profile and Adiposity-Related Cardiovascular Risk Markers in Euthyroid Middle-Aged Subjects. Thyroid (2014) 24(2):223–31. 10.1089/thy.2013.0314
    1. Gereben BZ, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. . Cellular and Molecular Basis of Deiodinase-Regulated Thyroid Hormone Signaling1. Endocr Rev (2008) 29(7):898–938. 10.1210/er.2008-0019
    1. de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, et al. . The Type 2 Iodothyronine Deiodinase Is Essential for Adaptive Thermogenesis in Brown Adipose Tissue. J Clin Invest (2001) 108(9):1379–85. 10.1172/JCI200113803
    1. Louzada RA, Santos MC, Cavalcanti-de-Albuquerque JP, Rangel IF, Ferreira AC, Galina A, et al. . Type 2 Iodothyronine Deiodinase Is Upregulated in Rat Slow- and Fast-Twitch Skeletal Muscle During Cold Exposure. Am J Physiol Endocrinol Metab (2014) 307(11):E1020–9. 10.1152/ajpendo.00637.2013
    1. Martínez-Sánchez N, Moreno-Navarrete JM, Contreras C, Rial-Pensado E, Fernø J, Nogueiras R, et al. . Thyroid Hormones Induce Browning of White Fat. J Endocrinol (2016) 232(2):351–62. 10.1530/JOE-16-0425
    1. Yoneshiro T, Matsushita M, Nakae S, Kameya T, Sugie H, Tanaka S, et al. . Brown Adipose Tissue is Involved in the Seasonal Variation of Cold-Induced Thermogenesis in Humans. Am J Physiol Regul Integr Comp Physiol (2016) 310(10):R999–1009. 10.1152/ajpregu.00057.2015
    1. van Ooijen AM, van Marken Lichtenbelt WD, van Steenhoven AA, Westerterp KR. Seasonal Changes in Metabolic and Temperature Responses to Cold Air in Humans. Physiol Behav (2004) 82(2-3):545–53. 10.1016/j.physbeh.2004.05.001
    1. Zaninovich AA, Raices M, Rebagliati I, Ricci C, Hagmuller K. Brown Fat Thermogenesis in Cold-Acclimated Rats Is Not Abolished by the Suppression of Thyroid Function. Am J Physiol Endocrinol Metab (2002) 283(3):E496–502. 10.1152/ajpendo.00540.2001
    1. Hollstein T, Heinitz S, Ando T, Rodzevik TL, Basolo A, Walter M, et al. . Metabolic Responses to 24-Hour Fasting and Mild Cold Exposure in Overweight Individuals Are Correlated and Accompanied by Changes in FGF21 Concentration. Diabetes (2020) 69(7):1382–8. 10.2337/db20-0153
    1. Guerra C, Koza RA, Yamashita H, Walsh K, 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(2):412–20. 10.1172/JCI3155
    1. Bakker LE, Boon MR, van der Linden RA, Arias-Bouda LP, van Klinken JB, Smit F, et al. . Brown Adipose Tissue Volume in Healthy Lean South Asian Adults Compared With White Caucasians: A Prospective, Case-Controlled Observational Study. Lancet Diabetes Endocrinol (2014) 2(3):210–7. 10.1016/S2213-8587(13)70156-6
    1. Claussnitzer M, Dankel SN, Kim K-H, Quon G, Meuleman W, Haugen C, et al. . FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med (2015) 373(10):895–907. 10.1056/NEJMoa1502214
    1. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, et al. . Recruited Brown Adipose Tissue as An Antiobesity Agent in Humans. J Clin Invest (2013) 123(8):3404–8. 10.1172/JCI67803
    1. Andersen S, Bruun NH, Pedersen KM, Laurberg P. Biologic Variation Is Important for Interpretation of Thyroid Function Tests. Thyroid (2003) 13(11):1069–78. 10.1089/105072503770867237
    1. Smals A, Ross H, Kloppenborg P. Seasonal Variation in Serum T3 and T4 Levels in Man. J Clin Endocrinol Metab (1977) 44(5):998–1001. 10.1210/jcem-44-5-998
    1. Wang D, Cheng X, Yu S, Qiu L, Lian X, Guo X, et al. . Data Mining: Seasonal and Temperature Fluctuations in Thyroid-Stimulating Hormone. Clin Biochem (2018) 60:59–63. 10.1016/j.clinbiochem.2018.08.008
    1. De Grande LA, Goossens K, Van Uytfanghe K, Halsall I, Yoshimura Noh J, Hens K, et al. . Using “Big Data” to Describe the Effect of Seasonal Variation in Thyroid-Stimulating Hormone. Clin Chem Lab Med (2017) 55(2):e34–6. 10.1515/cclm-2016-0500

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