Brown Adipose Tissue Activity and Thyroid Hormone

Obesity Clinical Trial

Official title:

Brown Adipose Tissue Activity and Thyroid Hormone

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02499471
• Other study ID #: NL 39146.068.11
• Status: Completed
• Phase: N/A
• First received: July 6, 2015
• Last updated: July 20, 2015
• Start date: March 2012
• Est. completion date: July 2014

Study information

• Verified date: July 2015
• Source: Maastricht University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

Rationale: During the last decades, research in possible therapies for existing obesity and developmental factors causing obesity has explosively increased. Recently renewed interest aroused for a tissue playing a possible role in both development and therapy for obesity: brown adipose tissue (BAT).

To define the relation between BAT and thyroid hormone, the investigators set up the following research protocol. In this protocol BAT activity will be determined in subjects that underwent thyroidectomy for well-differentiated thyroid carcinoma.

Objective: To study the effect of thyroid hormone and thyroid-stimulating hormone on brown adipose tissue activity.

Study design: Determine BAT activity after thyroidectomy in well-differentiated thyroid carcinoma patients.

Study population: Patients that underwent thyroidectomy for well-differentiated thyroid carcinoma, male and female, aged 18-65 years.

Intervention: FDG-PET-CT-imaging ([18F]fluorodeoxyglucose positron-emission-tomography computed-tomography) of BAT activity will be performed under cold stimulation twice.

For patients clinically withdrawn from thyroid hormone suppletion, the first occasion will be in a hypothyroid state within 4-6 weeks after thyroidectomy and the second measurement will take place in a euthyroid state 4 months after the start of thyroid hormone treatment.

For patients receiving recombinant-thyroid-stimulating-hormone injections, the first occasion will be shortly after the injection in a state of high thyroid-stimulating hormone levels. The second measurement will be in a euthyroid state 4 months after the injection.

Main study parameters/endpoints: The main endpoint of this study is the effect of thyroid hormone and thyroid-stimulating hormone on BAT activity in kBq (kilobecquerel) and SUV (standard uptake value). Secondary endpoints are the effects of thyroid hormone and thyroid-stimulating hormone on energy metabolism, body core temperature, skin surface temperatures and skin perfusion.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The absorbed radiation dose from the FDG PET-CT scan after administration of 74 MBq (megabecquerel) of 18F-FDG is 2.8 mSv (miliSievert).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: July 2014
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Male or postmenopausal females undergoing a total thyroidectomy for well-differentiated thyroid carcinoma

• Age 18-65 years

• Stable physical activity levels for at least six months

• Note: In case of use of anticoagulation, the dose will be adjusted according to plasma thyroid hormone values.

Exclusion Criteria:

• Psychologically unstable subjects (as judged by the treating medical specialist)

• Subjects with mental retardation (as judged by the treating medical specialist)

• Subjects with severe behavior disorders (as judged by the treating medical specialist)

• Pregnant subjects

• The use of the following medication is an exclusion criterium; ß-blockers

• Participation in an intensive weight-loss program or vigorous exercise program during the last year before the start of the study

• Abuse of drugs and/or alcohol

• Severe diabetes which requires application of insulin or patients with diabetes-related complications

Study Design

Allocation: Non-Randomized, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hyperthyroidism
• Hypothyroidism
• Obesity

Intervention

Other:
• Levothyroxine therapy (137.75 ± 23.75 µg/day)
This study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to standard treatment protocol).

Locations

Country	Name	City	State
Netherlands	Maastricht UMC	Maastricht	Limburg

Sponsors (1)

Lead Sponsor	Collaborator
Maastricht University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (35)

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 Mar;166(3):433-40. doi: 10.1530/EJE-11-0888. Epub 2011 Dec 14. — View Citation

BARKER SB, KLITGAARD HM. Metabolism of tissues excised from thyroxine-injected rats. Am J Physiol. 1952 Jul;170(1):81-6. — View Citation

Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglycer — View Citation

Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002 Feb;23(1):38-89. Review. — View Citation

Bilezikian JP, Loeb JN. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness. Endocr Rev. 1983 Fall;4(4):378-88. Review. — View Citation

Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004 Jan;84(1):277-359. Review. — View Citation

Cannon B, Nedergaard J. Thyroid hormones: igniting brown fat via the brain. Nat Med. 2010 Sep;16(9):965-7. doi: 10.1038/nm0910-965. — View Citation

Castillo M, Hall JA, Correa-Medina M, Ueta C, Kang HW, Cohen DE, Bianco AC. Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes. 2011 Ap — View Citation

Danforth E Jr, Burger A. The role of thyroid hormones in the control of energy expenditure. Clin Endocrinol Metab. 1984 Nov;13(3):581-95. Review. — View Citation

de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, Larsen PR, Bianco AC. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest. 2001 Nov;108(9):1379-85. — View Citation

Endo T, Kobayashi T. Thyroid-stimulating hormone receptor in brown adipose tissue is involved in the regulation of thermogenesis. Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E514-8. doi: 10.1152/ajpendo.90433.2008. Epub 2008 Jun 17. — View Citation

Gagnon A, Antunes TT, Ly T, Pongsuwan P, Gavin C, Lochnan HA, Sorisky A. Thyroid-stimulating hormone stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo. Metabolism. 2010 Apr;59(4):547-53. doi: 10.1016/j.metabol.2 — View Citation

Goglia F, Silvestri E, Lanni A. Thyroid hormones and mitochondria. Biosci Rep. 2002 Feb;22(1):17-32. Review. — View Citation

Johannsen DL, Galgani JE, Johannsen NM, Zhang Z, Covington JD, Ravussin E. Effect of short-term thyroxine administration on energy metabolism and mitochondrial efficiency in humans. PLoS One. 2012;7(7):e40837. doi: 10.1371/journal.pone.0040837. Epub 2012 Jul 26. — View Citation

Kim MS, Hu HH, Aggabao PC, Geffner ME, Gilsanz V. Presence of brown adipose tissue in an adolescent with severe primary hypothyroidism. J Clin Endocrinol Metab. 2014 Sep;99(9):E1686-90. doi: 10.1210/jc.2014-1343. Epub 2014 Jun 10. — View Citation

Kingma BR, Frijns AJ, Saris WH, van Steenhoven AA, Lichtenbelt WD. Increased systolic blood pressure after mild cold and rewarming: relation to cold-induced thermogenesis and age. Acta Physiol (Oxf). 2011 Dec;203(4):419-27. doi: 10.1111/j.1748-1716.2011.02336.x. Epub 2011 Aug 12. — View Citation

Lahesmaa M, Orava J, Schalin-Jäntti C, Soinio M, Hannukainen JC, Noponen T, Kirjavainen A, Iida H, Kudomi N, Enerbäck S, Virtanen KA, Nuutila P. Hyperthyroidism increases brown fat metabolism in humans. J Clin Endocrinol Metab. 2014 Jan;99(1):E28-35. doi: 10.1210/jc.2013-2312. Epub 2013 Dec 20. — View Citation

Lee JY, Takahashi N, Yasubuchi M, Kim YI, Hashizaki H, Kim MJ, Sakamoto T, Goto T, Kawada T. Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Physiol Cell Physiol. 2012 Jan 15;302(2):C463-72. doi: 10.1152/ajpcell.00010.2011. Epub 2011 Nov 9. — View Citation

Liu D, Jiang F, Shan Z, Wang B, Wang J, Lai Y, Chen Y, Li M, Liu H, Li C, Xue H, Li N, Yu J, Shi L, Bai X, Hou X, Zhu L, Lu L, Wang S, Xing Q, Teng W. A cross-sectional survey of relationship between serum TSH level and blood pressure. J Hum Hypertens. 20 — View Citation

López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, Martínez de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Oresic M, Chatterjee K, Saha AK, Rahmouni K, Diéguez C, Vidal-Puig A. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med. 2010 Sep;16(9):1001-8. doi: 10.1038/nm.2207. Epub 2010 Aug 29. — View Citation

Louzada RA, Santos MC, Cavalcanti-de-Albuquerque JP, Rangel IF, Ferreira AC, Galina A, Werneck-de-Castro JP, Carvalho DP. Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure. Am J Physiol Endocrinol Metab. 2014 Dec 1;307(11):E1020-9. doi: 10.1152/ajpendo.00637.2013. Epub 2014 Oct 7. — View Citation

Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004 Mar 10;291(10):1238-45. Review. Erratum in: JAMA. 2005 Jan 19;293(3):298. JAMA. 2005 Jan 19;293(3):293-4. — View Citation

Nedergaard J, Golozoubova V, Matthias A, Asadi A, Jacobsson A, Cannon B. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency. Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106. Review. — View Citation

Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen KA. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011 Aug 3;14(2):272-9. doi: 10.1016/j.cmet.2011.06.012. — View Citation

Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009 Jul;58(7):1526-31. doi: 10.2337/db09-0530. Epub 2009 Apr 28. — View Citation

Silva JE, Bianco SD. Thyroid-adrenergic interactions: physiological and clinical implications. Thyroid. 2008 Feb;18(2):157-65. doi: 10.1089/thy.2007.0252. Review. — View Citation

Skarulis MC, Celi FS, Mueller E, Zemskova M, Malek R, Hugendubler L, Cochran C, Solomon J, Chen C, Gorden P. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab. 2 — View Citation

TATA JR, ERNSTER L, LINDBERG O. Control of basal metabolic rate by thyroid hormones and cellular function. Nature. 1962 Mar 17;193:1058-60. — View Citation

Thrush AB, Gagnon A, Sorisky A. PKC activation is required for TSH-mediated lipolysis via perilipin activation. Horm Metab Res. 2012 Oct;44(11):825-31. doi: 10.1055/s-0032-1316332. Epub 2012 Jun 22. — View Citation

van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jörgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013 Aug;123(8):3395-403. doi: 10.1172/JCI68993. Epub 2013 Jul 15. — View Citation

van Marken Lichtenbelt WD, Daanen HA, Wouters L, Fronczek R, Raymann RJ, Severens NM, Van Someren EJ. Evaluation of wireless determination of skin temperature using iButtons. Physiol Behav. 2006 Jul 30;88(4-5):489-97. Epub 2006 Jun 23. — View Citation

van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009 Apr 9;360(15):1500-8. doi: 10.1056/NEJMoa0808718. Erratum in: N Engl J Med. 2009 Apr 30;360(18):1917. — View Citation

Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009 Apr 9;360(15):1518-25. doi: 10.1056/NEJMoa0808949. Erratum in: N Engl J Med. 2009 Sep 10;361(11):1123. — View Citation

Völzke H, Alte D, Dörr M, Wallaschofski H, John U, Felix SB, Rettig R. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J Hypertens. 2006 Oct;24(10):1947-53. — View Citation

Vosselman MJ, van der Lans AA, Brans B, Wierts R, van Baak MA, Schrauwen P, van Marken Lichtenbelt WD. Systemic ß-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes. 2012 Dec;61(12):3106-13. doi: 10.2337/db12-0288. Epub 2012 Aug 7. — View Citation

* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cold-induced brown adipose tissue activity	Measured with 18FDG PET/CT scan after personalised cooling protocol	1 day	No
Secondary	Energy expenditure	Energy expenditure measured with ventilated hood system	1 day	No
Secondary	Body core temperature	Body core temperature measured with CorTemp telemetric pill	1 day	No
Secondary	Skin temperatures	Skin temperatures measured with iButton wireless dataloggers at 14 ISO-defined positions on the skin	1 day	No
Secondary	Skin perfusion	Skin perfusion measured with laser-doppler flowmetry on hand and forearm	1 day	No