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      Metabolic effects of brown fat in transitioning from hyperthyroidism to euthyroidism

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          Abstract

          Objective

          Brown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status.

          Design

          Participants with newly diagnosed Graves’ disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose ( 18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity.

          Results

          Twenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean ( r = 0.58, P = 0.01) and resting metabolic rate (RMR) ( P < 0.01).

          Conclusion

          Hyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.

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          Most cited references56

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          User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability.

          Active contour segmentation and its robust implementation using level set methods are well-established theoretical approaches that have been studied thoroughly in the image analysis literature. Despite the existence of these powerful segmentation methods, the needs of clinical research continue to be fulfilled, to a large extent, using slice-by-slice manual tracing. To bridge the gap between methodological advances and clinical routine, we developed an open source application called ITK-SNAP, which is intended to make level set segmentation easily accessible to a wide range of users, including those with little or no mathematical expertise. This paper describes the methods and software engineering philosophy behind this new tool and provides the results of validation experiments performed in the context of an ongoing child autism neuroimaging study. The validation establishes SNAP intrarater and interrater reliability and overlap error statistics for the caudate nucleus and finds that SNAP is a highly reliable and efficient alternative to manual tracing. Analogous results for lateral ventricle segmentation are provided.
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            Thyroid hormone regulation of metabolism.

            Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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              Identification and Importance of Brown Adipose Tissue in Adult Humans

              Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism. 2009 Massachusetts Medical Society

                Author and article information

                Journal
                Eur J Endocrinol
                Eur J Endocrinol
                EJE
                European Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                0804-4643
                1479-683X
                03 August 2021
                01 October 2021
                : 185
                : 4
                : 553-563
                Affiliations
                [1 ]Singapore Institute for Clinical Sciences , Agency for Science, Technology and Research (A*STAR), Singapore
                [2 ]Institute of Bioengineering and Bioimaging , Agency for Science, Technology and Research (A*STAR), Singapore
                [3 ]Singapore Institute of Food and Biotechnology Innovation , Agency for Science, Technology and Research (A*STAR), Singapore
                [4 ]Department of Biochemistry , Yong Loo Lin School of Medicine
                [5 ]Departments of Physiology & Medicine , National University of Singapore (NUS), Singapore
                [6 ]Lee Kong Chian School of Medicine , Nanyang Technological University (NTU), Singapore
                [7 ]Department of Endocrinology , Tan Tock Seng Hospital (TTSH), Singapore
                [8 ]Yong Loo Lin School of Medicine , National University of Singapore, Singapore
                [9 ]Cardiovascular and Metabolic Disorders Program , Duke-NUS Medical School, Singapore
                Author notes
                Correspondence should be addressed to M K Leow Email melvin_leow@ 123456sics.a-star.edu.sg
                Article
                EJE-21-0366
                10.1530/EJE-21-0366
                8428075
                34342595
                dc6b3656-d56c-4ee5-a8c9-7a7bf34d0f7a
                © The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 08 April 2021
                : 03 August 2021
                Categories
                Clinical Study

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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