Increased Serum Adipocyte Fatty Acid-Binding Protein Levels Are Associated with Decreased Sensitivity to Thyroid Hormones in the Euthyroid Population

Abstract

Background:

Serum adipocyte fatty acid-binding protein (A-FABP) and thyroid hormones are closely associated with metabolic disorders; however, their relationship remains unknown. We aimed at investigating the associations of serum A-FABP levels with single and composite indices of the thyroid system.

Methods:

The study included 1057 community-based euthyroid participants (age range: 27–81 years) in Shanghai, among whom 601 were women. Serum free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) were measured by electrochemical luminescence immunoassay. The thyroid feedback quantile-based index (TFQI), thyrotropin index (TSHI), and thyrotroph thyroxine resistance index (TT4RI) were calculated to evaluate central sensitivity to thyroid hormones. Peripheral sensitivity to thyroid hormones was evaluated by the fT3 to fT4 ratio (fT3/fT4). Enzyme-linked immunosorbent assay was used to measure serum A-FABP levels.

Results:

Serum A-FABP levels were 6.41 [95% confidence interval: 6.10–6.74] ng/mL among all subjects. Multiple cardiovascular metabolic risk factors were adjusted in the multivariate linear regression analysis and the multinomial logistic regression analysis (nonordinal). In both sexes, serum A-FABP levels were positively associated with fT4 (men: standardized β = 0.150, p = 0.001; women: standardized β = 0.218, p < 0.001), TFQI (men: standardized β = 0.119, p = 0.009; women: standardized β = 0.165, p < 0.001), and TSHI (men: standardized β = 0.108, p = 0.017; women: standardized β = 0.114, p = 0.005); while they were negatively associated with fT3/fT4 (men: standardized β = −0.122, p = 0.008; women: standardized β = −0.129, p = 0.001). Serum A-FABP levels were not associated with fT3, TSH, or TT4RI. Compared with the first quartile group of TFQI, for every 10 ng/mL increase in A-FABP, the odds ratio (OR) for the third quartile group of TFQI was 2.213 in women (p = 0.035); the ORs for the fourth quartile group of TFQI were 2.614 in men (p = 0.022) and 3.425 in women (p = 0.002).

Conclusions:

In a euthyroid population, increased serum A-FABP levels were associated with decreased sensitivity to thyroid hormones, suggesting that A-FABP may mediate the “cross-talk” between adipose tissue and the thyroid system.

Introduction

Metabolic diseases such as obesity and diabetes have become global public health problems (1,2). The pathogenesis of metabolic diseases involves complex dysregulation of various endocrine hormones (3). Thyroid hormones play important roles in the regulation of cellular function and energy metabolism (4). It is well established that overt hyper- or hypothyroidism leads to cardiovascular and metabolic diseases. Variations of thyroid hormones are associated with the development of metabolic disorders, even when within the euthyroid range (5,6). Low normal thyroid function, which is characterized by higher thyrotropin (TSH) or lower free thyroxine (fT4) within the reference range, is positively associated with dyslipidemia (7), insulin resistance (8), obesity (9), and metabolic syndrome (MS) (10).

TSH, fT4, and free triiodothyronine (fT3) are closely regulated and influenced by each other. Compared with a single index, the calculation of composite indices can systematically reflect the regulation of thyroid hormone homeostasis. fT3 is mainly converted from fT4 by deiodinase iodothyronine (DIO) in peripheral tissues, thus the fT3 to fT4 ratio (fT3/fT4) can partly reflect the peripheral sensitivity to thyroid hormones. fT3/fT4 was previously found to be a strong predictor for MS and non-alcoholic fatty liver disease (11,12). Recently, central sensitivity to thyroid hormones that was evaluated based on the interaction between fT4 and TSH was found to be negatively associated with risks of obesity, diabetes, MS, and diabetes-related mortality (13).

The pathological mechanisms of metabolic disorders include adipose tissue dysfunction. Adipose tissue not only stores energy but also has important endocrine functions (14). Adipokines act on metabolic target tissues through endocrine and paracrine function. Adipocyte fatty acid-binding protein (A-FABP), also called fatty acid-binding protein 4, is one of the main proteins secreted by mature adipocytes. A-FABP accounts for ∼6% of the total cellular proteins (15). Previous studies have found that A-FABP was positively associated with the risks of diabetes, obesity, non-alcoholic fatty liver disease, and subclinical atherosclerosis (16 –20). Whether A-FABP levels are associated with thyroid hormones remains unknown. We aimed at investigating the associations of serum A-FABP levels with single and composite indices of the thyroid system in a euthyroid population.

Materials and Methods

Subjects

Subjects were recruited from Shanghai communities from October 2015 to July 2016. The details of recruitment were described in our previous study (18). All subjects completed a questionnaire survey, physical examination, and laboratory examination. The inclusion criteria included age ≥20 years, voluntary participation in this study, and the ability to provide the required information. The exclusion criteria included a history of diabetes or cardiovascular diseases; abnormal thyroid function; hormone replacement treatment such as replacement of thyroid hormones or sex hormones; anti-thyroid therapies; severe hepatic or renal dysfunction; use of hypertensive drugs, lipid-regulating drugs, glucocorticoids, lithium, or amiodarone; moderate to severe anemia; cancer; and acute infection. All participants provided informed consent. The study was approved by the Ethics Committee of the Shanghai Jiao Tong University Affiliated Sixth People's Hospital.

Body measurements and laboratory examinations

Height and body weight were measured according to standard methods described in our previous study (18). Body mass index (BMI) = body weight (kg)/height² (m²). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured as the mean of 3 blood pressure measurements taken at 3-minute intervals.

All subjects underwent a 75-g oral glucose tolerance test in the morning after an overnight fast of 10 hours. Fasting plasma glucose (FPG), 2-hour post-load glucose (2hPG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c), fasting insulin (FINS), C-reactive protein (CRP), and creatinine (Cr) were measured by methods as described in our previous study (18). Homeostasis model assessment of insulin resistance (HOMA-IR) was used to evaluate the level of insulin resistance. HOMA-IR = FINS (mU/L) × FPG (mmol/L)/22.5 (21). Serum A-FABP levels were measured by enzyme-linked immunosorbent assay (Antibody and Immunoassay Services, The University of Hong Kong, Hong Kong, China), and details of the method were described in our previous study (18). The fT3, fT4, and TSH were measured by electrochemiluminescence immunoassays (Roche Diagnostics GmbH, Mannheim, Germany) on a Cobas e601 analyzer, and the details of the method were described in our previous study (22).

Composite indices of the thyroid system

The thyroid feedback quantile-based index (TFQI) was calculated according to the equation proposed by Laclaustra et al. (13). First, fT4 and TSH were placed in order from minimum to maximum values. Second, fT4 and TSH were transformed by empirical cumulative distribution function (cdf) and converted into quantiles between 0 and 1. TFQI = cdffT4 – (1 – cdfTSH). The thyrotropin index (TSHI) = lnTSH (mIU/L) +0.1345 × fT4 (pmol/L) (23). The thyrotroph thyroxine resistance index (TT4RI) = fT4 (pmol/L) × TSH (mIU/L) (24).

The TFQI, TSHI, and TT4RI were considered as central indices of thyroid hormone sensitivity to reflect the sensitivity of the hypothalamus-pituitary-thyroid (HPT) axis to the change of circulating fT4. The fT3/fT4 was calculated to reflect peripheral sensitivity to thyroid hormones. The value of TFQI ranged from −1 to 1. For TFQI, negative values indicated that the HPT axis was more sensitive to the change of fT4; positive values indicated that the HPT axis was less sensitive to the change of fT4; and the value of 0 indicated a normal sensitivity of the HPT axis to the change of fT4 (13). For TSHI and TT4RI, the higher the values, the lower the central sensitivity to thyroid hormones. For fT3/fT4, higher values indicated higher peripheral sensitivity to thyroid hormones.

Statistical analyses

The Kolmogorov–Smirnov test was used to evaluate the normal distribution of variables. Variables with a normal distribution were expressed as means ± standard deviations. Lognormally distributed variables were expressed as means [95% confidence intervals (CIs)]. Skewed distributed variables were expressed as medians [interquartile ranges (IQRs)]. For normally distributed variables and lognormally distributed variables (log-transformed), the independent-samples t-test was used for comparison. For variables with skewed distributions, the Mann–Whitney U-test was used for comparison. In this study, A-FABP and fT3/fT4 had lognormal distributions; while fT3, TSH, TSHI, and TT4RI had skewed distributions. These variables were all log-transformed in the statistical analysis. After adjusting for age, BMI, DBP, FPG, HDL-c, TG, Cr, and CRP, multivariate linear regression analysis and multinomial logistic regression analysis (non-ordinal) were used to explore the associations of A-FABP with indices of the thyroid system and TFQI quartiles, respectively. The results of linear regression analysis were expressed as standardized coefficient β and t value. The results of logistic regression analysis were expressed as odds ratio (OR) and CI. All data analyses were performed by using SPSS version 22.0 (SPSS, Inc., Chicago, IL) statistical software. A two-tailed p-value <0.05 was considered statistically significant.

Results

Clinical characteristics of subjects

The study included 1057 participants (age: 58 ± 8 years, range: 27–81 years), among whom 456 were men and 601 were women. The A-FABP among all subjects was 6.41 [CI 6.10–6.74] ng/mL. The fT3, fT4, and TSH were 4.93 (IQR: 4.60–5.30) pmol/L, 16.53 ± 1.78 pmol/L, and 2.17 (IQR: 1.55–2.86) mIU/L, respectively. The TFQI, TSHI, TT4RI, and fT3/fT4 were 0.00 ± 0.38, 3.00 (IQR: 2.65–3.26), 35.77 (IQR: 26.18–46.87), and 0.300 [CI 0.298–0.302], respectively. Women had higher HbA1c (p = 0.009), TC (p < 0.001), HDL-c (p < 0.001), LDL-c (p < 0.001), A-FABP (p < 0.001), TSH (p < 0.001), and TT4RI (p = 0.001) than men. Age (p = 0.003), BMI (p < 0.001), SBP (p < 0.001), DBP (p < 0.001), TG (p < 0.001), Cr (p < 0.001), fT3 (p < 0.001), fT4 (p < 0.001), and fT3/fT4 (p < 0.001) were lower in women than in men. No difference was found in FPG, 2hPG, HOMA-IR, CRP, TFQI, or TSHI by sex (Table 1).

Table 1.

Clinical Characteristics of Subjects

Variables	Total	Men	Women	p^c
N	1057	456	601	—
Age, years	59 (54–64)	59 (55–65)	59 (54–63)	0.003
BMI (kg/m²)^a	23.07 (22.88–23.25)	23.45 (23.17–23.74)	22.78 (22.53–23.02)	<0.001
SBP (mmHg)	128 (116–140)	132 (122–143)	124 (113–137)	<0.001
DBP (mmHg)	77 (70–84)	80 (74–87)	75 (69–82)	<0.001
FPG (mmol/L)	5.68 (5.34–6.07)	5.69 (5.37–6.13)	5.67 (5.31–6.03)	0.255
2hPG (mmol/L)	7.06 (5.76–8.67)	7.20 (5.79–8.72)	7.02 (5.72–8.61)	0.449
HbA1c (%)	5.70 (5.40–5.90)	5.60 (5.40–5.90)	5.70 (5.40–6.00)	0.009
HOMA-IR^a	2.14 (2.07–2.21)	2.06 (1.95–2.18)	2.20 (2.11–2.30)	0.076
TC (mmol/L)^b	5.44 ± 0.97	5.18 ± 0.88	5.63 ± 0.99	<0.001
TG (mmol/L)	1.32 (0.94–1.95)	1.46 (1.00–2.22)	1.24 (0.89–1.73)	<0.001
HDL-c (mmol/L)	1.40 (1.18–1.67)	1.25 (1.08–1.49)	1.54 (1.30–1.79)	<0.001
LDL-c (mmol/L)^b	3.30 ± 0.83	3.16 ± 0.76	3.41 ± 0.86	<0.001
CRP (mg/L)	0.85 (0.39–1.61)	0.82 (0.38–1.62)	0.89 (0.41–1.60)	0.647
Cr (μmol/L)	63 (54–74)	76 (68–84)	55 (51–62)	<0.001
A-FABP (ng/mL)^a	6.41 (6.10–6.74)	4.94 (4.58–5.33)	7.82 (7.34–8.32)	<0.001
fT3 (pmol/L)	4.93 (4.60–5.30)	5.19 (4.87–5.48)	4.75 (4.48–5.08)	<0.001
fT4 (pmol/L)^b	16.53 ± 1.78	16.79 ± 1.82	16.34 ± 1.73	<0.001
TSH (mIU/L)	2.17 (1.55–2.86)	2.04 (1.47–2.71)	2.27 (1.64–2.99)	<0.001
fT3/fT4^a	0.300 (0.298–0.302)	0.310 (0.306–0.313)	0.293 (0.290–0.296)	<0.001
TFQI^b	0.00 ± 0.38	0.02 ± 0.38	−0.01 ± 0.39	0.344
TSHI	3.00 (2.65–3.26)	2.97 (2.60–3.25)	3.02 (2.70–3.28)	0.072
TT4RI	35.77 (26.18–46.87)	33.96 (24.56–45.02)	37.26 (27.01–48.00)	0.001

Lognormally distributed variables are expressed as means (CIs). Other skewed distributed variables are expressed as medians (interquartile ranges).

Normally distributed variables are expressed as means ± standard deviation.

Women compared with men.

2hPG, 2-hour post-load glucose; A-FABP, adipocyte fatty acid-binding protein; BMI, body mass index; CIs, confidence intervals; Cr, creatinine; CRP, C-reactive protein; DBP, diastolic blood pressure; FPG, fasting plasma glucose; fT3, free triiodothyronine; fT3/fT4, free triiodothyronine to free thyroxine ratio; fT4, free thyroxine; HbA1c, glycated hemoglobin; HDL-c, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-c, low-density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; TFQI, thyroid feedback quantile-based index; TG, triglyceride; TSH, thyrotropin; TSHI, thyrotropin index; TT4RI, thyrotroph thyroxine resistance index.

Multivariate linear regression analysis between A-FABP and indices of the thyroid system

Multivariate linear regression analysis was further used to explore the associations between A-FABP and indices of the thyroid system after adjusting for confounding factors (Table 2). In men, A-FABP was positively associated with fT4 (standardized β = 0.150, p = 0.001), TFQI (standardized β = 0.119, p = 0.009), and TSHI (standardized β = 0.108, p = 0.017), while it was negatively associated with fT3/fT4 (standardized β = −0.122, p = 0.008). In women, A-FABP was also positively associated with fT4 (standardized β = 0.218, p < 0.001), TFQI (standardized β = 0.165, p < 0.001), and TSHI (standardized β = 0.114, p = 0.005), but it was negatively associated with fT3/fT4 (standardized β = −0.129, p = 0.001). In both sexes, A-FABP was not associated with fT3, TSH, or TT4RI.

Table 2.

Multivariate Linear Regression Analysis for the Associations of Adipocyte Fatty Acid-Binding Protein and Indices of the Thyroid System

Dependent variables	Men		Women
Dependent variables	Standardized β (t)	p	Standardized β (t)	p
fT3	0.016 (0.331)	0.741	0.076 (1.907)	0.057
fT4	0.150 (3.302)	0.001	0.218 (5.606)	<0.001
TSH	0.037 (0.800)	0.424	0.011 (0.273)	0.785
fT3/fT4	−0.122 (−2.645)	0.008	−0.129 (−3.241)	0.001
TFQI	0.119 (2.618)	0.009	0.165 (4.151)	<0.001
TSHI	0.108 (2.396)	0.017	0.114 (2.842)	0.005
TT4RI	0.074 (1.636)	0.103	0.066 (1.650)	0.099

Age, BMI, DBP, FPG, HDL-c, TG, Cr, and CRP were adjusted.

Multinomial logistic regression analysis between A-FABP and TFQI quartiles

Multinomial logistic regression analysis (non-ordinal) was used to investigate associations between A-FABP and TFQI quartiles after adjusting for confounding factors (Table 3). Both men and women were divided into 4 groups according to the TFQI quartiles (Q1: ≥ −1 and < −0.25; Q2: ≥ −0.25 and <0; Q3: ≥ 0 and <0.25; Q4: ≥ 0.25 and ≤1). The lowest quartile group (Q1) of TFQI was set to be the reference group. For every 1 unit increase in A-FABP (corresponding to actual value of 10 ng/mL), the OR for the third quartile group (Q3) of TFQI was 2.213 ([CI 1.057–4.633], p = 0.035) in women; the ORs for the highest quartile group (Q4) of TFQI were 2.614 ([CI 1.152–5.934], p = 0.022) in men and 3.425 ([CI 1.601–7.326], p = 0.002) in women.

Table 3.

Multinomial Logistic Regression Analysis for the Association of Adipocyte Fatty Acid-Binding Protein and Thyroid Feedback Quantile-Based Index Quartiles

TFQI quartiles	Men		Women
TFQI quartiles	ORs [CIs]	p	ORs [CIs]	p
Q1 (≥ −1 and < −0.25)	Reference [1.000]	—	Reference [1.000]	—
Q2 (≥ −0.25 and <0)	1.678 [0.746–3.772]	0.210	1.315 [0.633–2.733]	0.463
Q3 (≥0 and <0.25)	1.743 [0.777–3.910]	0.178	2.213 [1.057–4.633]	0.035
Q4 (≥0.25 and ≤1)	2.614 [1.152–5.934]	0.022	3.425 [1.601–7.326]	0.002

Age, BMI, DBP, FPG, HDL-c, TG, Cr, and CRP were adjusted.

ORs, odds ratios.

Discussion

In this study, we investigated the associations of serum A-FABP levels with single and composite indices of the thyroid system in euthyroid subjects from communities in China. We found that A-FABP was positively associated with fT4, TFQI, and TSHI, while it was negatively associated with fT3/fT4, suggesting that increased serum A-FABP levels were associated with decreased sensitivity to thyroid hormones.

Under physiological conditions, circulating thyroid hormones are tightly regulated by the HPT axis through a negative feedback regulation mechanism (25). Thyroid hormones are mainly secreted in the form of thyroxine. Thyroxine is catalyzed by DIO in the peripheral tissues to form the bioactive triiodothyronine (26), and triiodothyronine further exerts physiological effects by binding to the thyroid hormone receptor (THR). Therefore, circulating thyroid hormones are also influenced by THR and DIO.

The set point of the HPT axis and peripheral sensitivity to thyroid hormones may change with the development of metabolic dysfunction. Even in euthyroid subjects, thyroid hormones were closely associated with the development of type 2 diabetes, obesity, and MS (5,6,27). Laclaustra et al. found that impaired sensitivity to thyroid hormones was associated with increased risks of diabetes and MS (13). The expressions of DIO, THR, and TSH receptors changed in metabolic disorders. Kurylowicz et al. found that the expressions of THRα, THRβ and DIO2 were significantly lower in the subcutaneous adipose tissues of obese patients than those of normal weight individuals (28). Nannipieri et al. (29) found that the expressions of THR and TSH receptors were reduced by 33% and 67%, respectively, in the subcutaneous fat of obese participants. After weight loss, the expressions of THR and TSH receptors were significantly increased (29). In diet-induced obese mice, selective agonists of THRβ failed to accelerate energy expenditure (30), suggesting that impaired sensitivity to thyroid hormones may exist in metabolic disorders. In addition, some adipokines may also mediate the associations between metabolic disease and thyroid hormone dysregulation. Previous studies mainly focused on leptin, which was found to influence thyroid hormone homeostasis by upregulating the expressions of DIO1 in white adipose tissue and TSH-releasing hormone in hypothalamus (31,32). The associations between other adipokines and thyroid hormone homeostasis have been rarely reported.

The A-FABP is one of the most important proteins secreted by adipocytes. Previous studies have found that A-FABP mediates obesity-related cardiovascular metabolic diseases by enhancing lipid-induced inflammation and inhibiting myocardial contraction (15). Whether A-FABP is associated with thyroid hormone dysregulation remains unknown and deserves further investigation. However, no previous studies have reported such a link. For the first time, our study investigated the association between A-FABP and thyroid hormone sensitivity. We found that increased serum A-FABP levels were associated with decreased sensitivity to thyroid hormones in the euthyroid population. In one previous study, Tseng et al. recruited 30 patients with hyperthyroidism who underwent anti-thyroid therapy and 30 euthyroid controls to explore the association between A-FABP and fT4. They found that A-FABP was positively associated with fT4 (33). Although this earlier study did not assess thyroid hormone sensitivity, their findings also supported a close association between A-FABP and thyroid hormone homeostasis. Elevated serum A-FABP levels are products of adipose tissue dysfunction and may further mediate the moderately decreased sensitivity to thyroid hormones associated with metabolic disorders.

A few studies have explored the mechanisms underlying the associations between A-FABP and thyroid hormone homeostasis. Liver X receptors (LXRs) are key nuclear receptors involved in regulating glucose and lipid metabolism. The LXRs influence paraventricular nucleus of hypothalamus and subcutaneous adipose tissue; promote the secretion of TSH-releasing hormone, TSH, and thyroxines; and activate thyroid hormone signals in peripheral tissues (34). Previous studies found that A-FABP inhibited the activity of LXRα in macrophages and brown adipose tissue (35,36). Whether A-FABP regulates thyroid hormone sensitivity by inhibiting LXRs activity remains unknown. Moreover, THRβ is expressed in adipose tissue and the hypothalamus (37,38), and it plays an important role in the negative feedback regulation of the HPT axis and the peripheral sensitivity of thyroid hormones. Whether A-FABP affects thyroid hormone sensitivity by regulating the expression of THRβ in the hypothalamus and peripheral tissues also needs to be explored in future studies.

Our study has two main limitations. One is that due to the cross-sectional study design, we could not assess causality between A-FABP and thyroid hormone sensitivity; future prospective studies are needed. The other limitation is that thyroid-related antibodies were not measured in the study; thus, potential confounding factors from thyroid autoimmunity cannot be excluded.

In conclusion, we found that increased serum A-FABP levels were associated with decreased central and peripheral sensitivity to thyroid hormones in a euthyroid population, suggesting an association of A-FABP in the “cross-talk” between adipose tissue and thyroid.

Footnotes

Author Disclosure Statement

The authors declare no conflict of interest.

Funding Information

This work was funded by the National Key R&D Program of China (Grant No. 2016YFA0502003).

References

NCD Risk Factor Collaboration (NCD-RisC). 2017. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet, 390:2627–2642.

Ogurtsova

, da Rocha Fernandes

, Huang

, Linnenkamp

, Guariguata

, Cho

, Cavan

, Shaw

, Makaroff

. 2017. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract, 128:40–50.

Cao

. 2014. Adipocytokines in obesity and metabolic disease. J Endocrinol, 220:T47–T59.

van den Beld

, Kaufman

J-M

, Zillikens

, Lamberts

SWJ

, Egan

, van der Lely

. 2018. The physiology of endocrine systems with ageing. Lancet Diabetes Endocrinol, 6:647–658.

Jun

, Jee

, Bae

, Jin

, Hur

, Lee

, Kim

. 2017. Association between changes in thyroid hormones and incident type 2 diabetes: a seven-year longitudinal study. Thyroid, 27:29–38.

Mehran

, Amouzegar

, Bakhtiyari

, Mansournia

, Rahimabad

, Tohidi

, Azizi

. 2017. Variations in serum free thyroxine concentration within the reference range predicts the incidence of metabolic syndrome in non-obese adults: a cohort study. Thyroid, 27:886–893.

Lee

, Pedley

, Marqusee

, Sutherland

, Hoffmann

, Massaro

, Fox

. 2016. Thyroid function and cardiovascular disease risk factors in euthyroid adults: a cross-sectional and longitudinal study. Clin Endocrinol (Oxf), 85:932–941.

van Tienhoven-Wind

LJN

, Dullaart

RPF

. 2015. Low-normal thyroid function and novel cardiometabolic biomarkers. Nutrients, 7:1352–1377.

Motamed

, Eftekharzadeh

, Hosseinpanah

, Tohidi

, Hasheminia

, Azizi

. 2016. The relation between changes in thyroid function and anthropometric indices during long-term follow-up of euthyroid subjects: the Tehran Thyroid Study (TTS). Eur J Endocrinol, 175:247–253.

10.

Roos

, Bakker

, Links

, Gans

, Wolffenbuttel

. 2007. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab, 92:491–496.

11.

van den Berg

, van Tienhoven-Wind

, Amini

, Schreuder

, Faber

, Blokzijl

, Dullaart

. 2017. Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study. Metabolism, 67:62–71.

12.

Park

, Park

, Jung

, Jin

, Park

, Ahn

, Lee

. 2017. Free triiodothyronine/free thyroxine ratio rather than thyrotropin is more associated with metabolic parameters in healthy euthyroid adult subjects. Clin Endocrinol (Oxf), 87:87–96.

13.

Laclaustra

, Moreno-Franco

, Lou-Bonafonte

, Mateo-Gallego

, Casasnovas

, Guallar-Castillon

, Cenarro

, Civeira

. 2019. Impaired sensitivity to thyroid hormones is associated with diabetes and metabolic syndrome. Diabetes Care, 42:303–310.

14.

Schwartz

, Seeley

, Zeltser

, Drewnowski

, Ravussin

, Redman

, Leibel

. 2017. Obesity pathogenesis: an endocrine society scientific statement. Endocr Rev, 38:267–296.

15.

, Vanhoutte

. 2012. Adiponectin and adipocyte fatty acid binding protein in the pathogenesis of cardiovascular disease. Am J Physiol Heart Circ Physiol, 302:H1231–H1240.

16.

Furuhashi

. 2019. Fatty acid-binding protein 4 in cardiovascular and metabolic diseases. J Atheroscler Thromb, 26:216–232.

17.

Tso

, Xu

, Sham

, Wat

, Wang

, Fong

, Cheung

, Janus

, Lam

. 2007. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort. Diabetes Care, 30:2667–2672.

18.

, Ma

, Pan

, He

, Wang

, Bao

. 2019. Serum adipocyte fatty acid-binding protein levels: an indicator of non-alcoholic fatty liver disease in Chinese individuals. Liver Int, 39:568–574.

19.

Hao

, Ma

, Luo

, Shen

, Dou

, Pan

, Bao

, Jia

. 2014. Serum adipocyte fatty acid binding protein levels are positively associated with subclinical atherosclerosis in Chinese pre- and postmenopausal women with normal glucose tolerance. J Clin Endocrinol Metab, 99:4321–4327.

20.

, Wang

, Xu

, Stejskal

, Tam

, Zhang

, Wat

, Wong

, Lam

. 2006. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin Chem, 52:405–413.

21.

Matthews

, Hosker

, Rudenski

, Naylor

, Treacher

, Turner

. 1985. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28:412–419.

22.

Nie

, Xu

, Ma

, Shen

, Wang

, Bao

. 2019. Trunk fat and leg fat in relation to free triiodothyronine in euthyroid postmenopausal women. Endocr Connect, 8:1425–1432.

23.

Jostel

, Ryder

, Shalet

. 2009. The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index. Clin Endocrinol (Oxf), 71:529–534.

24.

Yagi

, Pohlenz

, Hayashi

, Sakurai

, Refetoff

. 1997. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab, 82:1608–1614.

25.

Mullur

, Liu

, Brent

. 2014. Thyroid hormone regulation of metabolism. Physiol Rev, 94:355–382.

26.

Mendoza

, Hollenberg

. 2017. New insights into thyroid hormone action. Pharmacol Ther, 173:135–145.

27.

Amouzegar

, Kazemian

, Abdi

, Mansournia

, Bakhtiyari

, Hosseini

, Azizi

. 2018. Association between thyroid function and development of different obesity phenotypes in euthyroid adults: a nine-year follow-up. Thyroid, 28:458–464.

28.

Kurylowicz

, Jonas

, Lisik

, Jonas

, Wicik

, Wierzbicki

, Chmura

, Puzianowska-Kuznicka

. 2015. Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues. J Transl Med, 13:31.

29.

Nannipieri

, Cecchetti

, Anselmino

, Camastra

, Niccolini

, Lamacchia

, Rossi

, Iervasi

, Ferrannini

. 2009. Expression of thyrotropin and thyroid hormone receptors in adipose tissue of patients with morbid obesity and/or type 2 diabetes: effects of weight loss. Int J Obes, 33:1001–1006.

30.

Castillo

, Freitas

, Rosene

, Drigo

, Grozovsky

, Maciel

, Patti

, Ribeiro

, Bianco

. 2010. Impaired metabolic effects of a thyroid hormone receptor beta-selective agonist in a mouse model of diet-induced obesity. Thyroid, 20:545–553.

31.

Macek Jilkova

, Pavelka

, Flachs

, Hensler

, Kus

, Kopecky

. 2010. Modulation of type I iodothyronine 5'-deiodinase activity in white adipose tissue by nutrition: possible involvement of leptin. Physiol Res, 59:561–569.

32.

Huo

, Munzberg

, Nillni

, Bjorbaek

. 2004. Role of signal transducer and activator of transcription 3 in regulation of hypothalamic trh gene expression by leptin. Endocrinology, 145:2516–2523.

33.

Tseng

, Chen

, Chi

, Shih

, Wang

, Chen

, Yang

. 2015. Association between serum levels of adipocyte fatty acid-binding protein and free thyroxine. Medicine (Baltim), 94:e1798.

34.

Miao

, Wu

, Dai

, Maneix

, Huang

, Warner

, Gustafsson

J-A

. 2015. Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue. Proc Natl Acad Sci USA, 112:14006–14011.

35.

Shu

, Hoo

, Wu

, Pan

, Lee

, Cheong

, Bornstein

, Rong

, Guo

, Xu

. 2017. A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes. Nat Commun, 8:14147.

36.

Erbay

, Babaev

, Mayers

, Makowski

, Charles

, Snitow

, Fazio

, Wiest

, Watkins

, Linton

, Hotamisligil

. 2009. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med, 15:1383–1391.

37.

Lin

, Martagón

, Cimini

, Gonzalez

, Tinkey

, Biter

, Baxter

, Webb

, Gustafsson

J-Å

, Hartig

, Phillips

. 2015. Pharmacological activation of thyroid hormone receptors elicits a functional conversion of white to brown fat. Cell Rep, 13:1528–1537.

38.

Hameed

, Patterson

, Dhillo

, Rahman

, Ma

, Holton

, Gogakos

, Yeo

GSH

, Lam

BYH

, Polex-Wolf

, Fenske

, Bell

, Anastasovska

, Samarut

, Bloom

, Bassett

JHD

, Williams

, Gardiner

. 2017. Thyroid hormone receptor beta in the ventromedial hypothalamus is essential for the physiological regulation of food intake and body weight. Cell Rep, 19:2202–2209.