
==== Front
BMC Med
BMC Med
BMC Medicine
1741-7015
BioMed Central London

39227921
3595
10.1186/s12916-024-03595-6
Research Article
Time-restricted eating with or without a low-carbohydrate diet improved myocardial status and thyroid function in individuals with metabolic syndrome: secondary analysis of a randomized clinical trial
Zheng Yixuan 1
Wang Jingya 2
Liu Mengmeng 1
Zhou Xingchen 1
Lin Xiaoying 1
Liang Qian 1
Yang Jing 13
Zhang Meng 1
Chen Ziyi 1
Li Meng 1
Wang Yue 1
Sui Jing 4
Qiang Wei 1
Guo Hui 1
Shi Bingyin shibingy@126.com

1
He Mingqian mingqian_he@xjtufh.edu.cn

13
1 https://ror.org/02tbvhh96 grid.452438.c 0000 0004 1760 8119 Department of Endocrinology, the First Affiliated Hospital of Xi’an JiaoTong University, 277 West Yanta Road, Xi’an, Shaanxi 710061 People’s Republic of China
2 grid.452902.8 Department of Gastroenterology, Xi’an Children’s Hospital, Shaanxi Research Institute for Pediatric Diseases, The Affiliated Children’s Hospital of Xi’an JiaoTong University and National Regional Medical Center for Children (Northwest), No 69, Xiju Yuan Lane, Xi’an, Shaanxi 710003 People’s Republic of China
3 https://ror.org/02tbvhh96 grid.452438.c 0000 0004 1760 8119 Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi’an JiaoTong University, 277 West Yanta Road, Xi’an, Shaanxi 710061 People’s Republic of China
4 https://ror.org/02tbvhh96 grid.452438.c 0000 0004 1760 8119 Department of Endocrinology and International Medical Center, the First Affiliated Hospital of Xi’an JiaoTong University, 277 West Yanta Road, Xi’an, Shaanxi 710061 People’s Republic of China
4 9 2024
4 9 2024
2024
22 3622 1 2024
28 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Obesity and metabolic syndrome (MetS) have become urgent worldwide health problems, predisposing patients to unfavorable myocardial status and thyroid dysfunction. Low-carbohydrate diet (LCD) and time-restricted eating (TRE) have been confirmed to be effective methods for weight management and improving MetS, but their effects on the myocardium and thyroid are unclear.

Methods

We conducted a secondary analysis in a randomized clinical diet-induced weight-loss trial. Participants (N = 169) diagnosed with MetS were randomized to the LCD group, the 8 h TRE group, or the combination of the LCD and TRE group for 3 months. Myocardial enzymes and thyroid function were tested before and after the intervention. Pearson’s or Spearman’s correlation was assessed between functions of the myocardium and thyroid and cardiometabolic parameters at baseline.

Results

A total of 162 participants who began the trial were included in the intention-to-treat (ITT) analysis, and 57 participants who adhered to their assigned protocol were involved in the per-protocol (PP) analysis. Relative to baseline, lactate dehydrogenase, creatine kinase MB, hydroxybutyrate dehydrogenase, and free triiodothyronine (FT3) declined, and free thyroxine (FT4) increased after all 3 interventions (both analyses). Creatine kinase (CK) decreased only in the TRE (− 18 [44] U/L, P < 0.001) and combination (− 22 [64] U/L, P = 0.003) groups (PP analysis). Thyrotropin (− 0.24 [0.83] μIU/mL, P = 0.011) and T3 (− 0.10 ± 0.04 ng/mL, P = 0.011) decreased in the combination group (ITT analysis). T4 (0.82 ± 0.39 μg/dL, P = 0.046), thyroglobulin antibodies (TgAb, 2 [1] %, P = 0.021), and thyroid microsomal antibodies (TMAb, 2 [2] %, P < 0.001) increased, while the T3/T4 ratio (− 0.01 ± 0.01, P = 0.020) decreased only in the TRE group (PP analysis). However, no significant difference between groups was observed in either analysis. At baseline, CK was positively correlated with the visceral fat area. FT3 was positively associated with triglycerides and total cholesterol. FT4 was negatively related to insulin and C-peptide levels. TgAb and TMAb were negatively correlated with the waist-to-hip ratio.

Conclusions

TRE with or without LCD confers remarkable metabolic benefits on myocardial status and thyroid function in subjects with MetS.

Trial registration

ClinicalTrials.gov, NCT04475822.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12916-024-03595-6.

Keywords

Metabolic syndrome
Low-carbohydrate diet
Time-restricted eating
Myocardial enzymes
Thyroid function
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Metabolic syndrome (MetS) is a cluster of concomitant conditions, including abdominal obesity, elevated blood pressure, insulin resistance (IR), and hyperglycemia, that predispose individuals to cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and mortality. Along with elevated prevalence rates of obesity [1], MetS affects more than 30% of the population worldwide [2–4]. As critical methods of lifestyle modification, multifarious dietary interventions [5], such as a low-carbohydrate diet (LCD) and time-restricted eating (TRE), are emerging and are well established to cause 5% to 7% weight loss on average. However, no dietary strategy is consistently superior to others for the MetS population.

Compared with individuals without MetS, individuals with MetS are more than twofold more likely to have myocardial infarction (MI) [6, 7], and a dose–response relationship was found between cumulative exposure to MetS components and MI [8]. As indicators of myocardial injury, myocardial enzymes are closely correlated with the risk of obesity and MetS [9, 10], and higher levels of myocardial enzymes have been observed in obese patients and MetS patients [11, 12]. Additionally, MetS is closely related to thyroid dysfunction. Thyroid hormones (THs) play vital roles in maintaining the basal metabolic rate; controlling protein, carbohydrate, and lipid metabolism; and modulating heart rate, body temperature, cardiovascular functions, and weight [13, 14]. An increasing number of studies have shown that subclinical or clinical hypothyroidism in individuals with obesity and MetS is characterized by increased thyrotropin (TSH) and triiodothyronine (T3) levels and decreased thyroxine (T4) levels [15–18], with increasing risks of metabolic disorders, such as dyslipidemia, IR, and nonalcoholic fatty liver disease [19–21]. THs levels and autoantibody titers are associated with MetS components even in euthyroid individuals [22–24].

Despite considerable evidence on the benefits of LCD and TRE for improving MetS [25, 26], whether these interventions also ameliorate myocardial status and thyroid dysfunction in individuals with MetS and which is the superior method are still unclear. Controversial results have been reported regarding THs after LCD or TRE in participants with obesity and MetS. Some studies have shown that THs are altered to varying degrees [27, 28], but some studies have failed to find any changes [29, 30]. In addition, studies on the effects of diet-induced weight loss on thyroid autoantibodies and myocardial enzymes in individuals with MetS are scarce. Furthermore, no study to date has directly compared the effects of LCD, TRE, or their combination on myocardial enzymes and thyroid function in the MetS population.

Therefore, we aimed to evaluate the effects of LCD, TRE, and their combination on the myocardium and thyroid and to determine which is the superior method. We hypothesized that all three interventions could improve thyroid function and myocardial status and that TRE with or without LCD may result in prominent improvements due to additional benefits for weight and cardiometabolic risk factors [31].

Methods

Study design

The detailed protocol is reported elsewhere [31]. Briefly, we conducted a single-center, 3-month, open-label, clinical trial to investigate the effects of LCD, TRE, and their combination on body weight and cardiometabolic risk factors in patients with MetS. We conducted this secondary analysis to explore the effects of LCD, TRE, and their combination on myocardial status and thyroid function. This trial was ethically approved by the Institutional Review Board of the First Affiliated Hospital of Xi’an Jiaotong University, and all participants provided written informed consent. The original study [31] and this secondary analysis followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Participants

Participants were recruited by fliers, posters, and advertisements. Free-living men and women with MetS who met at least 3 out of 5 criteria [32] and were aged 18 to 65 years were eligible for screening. The exclusion criteria included pregnancy or lactation, night shift work, history of major diseases or related diseases, participation in other weight loss trials, consumption of a prescribed diet for special diseases or any drugs that affect appetite, and history of bariatric surgery. The present trial was screened from July 2020 to September 2020 and was completed in January 2021.

Protocol

The detailed methods and procedures have been published previously [31]. In brief, the protocol included a run-in period before the intervention, during which participants were instructed to maintain their habitual diet and physical activity level for 2 weeks to stabilize weight. Participants in the LCD group were required to follow a reduced-carbohydrate diet (carbohydrates < 130 g/day or < 26% total energy) without time limitations. Participants in the TRE group were restrained from eating ad libitum (AL) within 8 h per day and fasted for 16 h. Participants in the combination group were instructed to restrict both carbohydrate intake and the eating window. Participants in the latter two groups voluntarily chose either early TRE (eTRE, eat from 8 AM to 4 PM and fast from 4 PM to 8 AM the next day) or late TRE (lTRE, eat from 12 to 8 PM and fast from 8 to 12 PM the next day) according to their eating habits. All participants were not allowed to change their physical activity habits or dose of medication during the trial.

Dietary guidance was carried out online through a unique and novel application called Zhihui Hao Yiyuan, which was established as a medical assistance platform. All participants were encouraged but not compulsory to write a daily dietary log. Nutrient intake was assessed every other week through an online Food Frequency Questionnaire (FFQ) which also included a 2-week recall of mealtime and days of adherence.

Outcome measurement

Specific processes and approaches to obtaining anthropometric metrics have been described elsewhere [31]. In the original study, the primary outcomes were changes in weight and body fat after 3-month interventions, and the secondary outcomes included changes in blood pressure, blood glucose, blood lipid, and uric acid. This secondary analysis reported additional outcomes including changes in myocardial enzymes and thyroid function after 3-month interventions.

Blood samples were obtained at the First Affiliated Hospital of Xi’an Jiaotong University after a whole-night fast (from 8 PM on) before and after intervention following a standard procedure of blood sample collection and stored at – 80 °C until assessment. The staff who collected and analyzed the outcomes were blinded to the participant assignments. Myocardial enzymes were tested by velocity assays using a LABOSPECT 008AS automatic biochemical analyzer. The laboratory reference ranges of lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase MB (CKMB), and hydroxybutyrate dehydrogenase (HBDH) were 120–250 U/L, 50–210 U/L, 0–24 U/L, and 72–182 U/L, respectively, using standard reagents to the nearest 1 U/L, 1 U/L, 1 U/L, and 1 U/L, respectively. THs were measured by radioimmunoassay using GC-2016 16th automatic sampling change equipment. The laboratory reference ranges of free triiodothyronine (FT3), free thyroxine (FT4), TSH, T3, and T4 were 2.91–9.08 pmol/L, 9.05–25.50 pmol/L, 0.25–5.00 μIU/mL, 0.78–2.20 ng/mL, and 4.20–13.50 μg/dL, respectively, using standard reagents to the nearest 0.01 pmol/L, 0.01 pmol/L, 0.01 μIU/mL, 0.01 ng/mL, and 0.01 μg/dL, respectively. Thyroid autoantibodies were tested by radioimmunoassay using an FM-2000 gamma immune counter, the laboratory reference ranges of thyroglobulin antibodies (TgAb) and thyroid microsomal antibodies (TMAb) were < 30% and < 20% with standard reagents to the nearest 1% and 1%, respectively.

Statistical analysis

Data from participants who started the 3-month intervention were included in this intention-to-treat (ITT) analysis. Missing data were handled by multiple imputations with the use of the Markov chain Monte Carlo method. The per-protocol (PP) analysis included participants who adhered to their assigned protocol. The data are presented as the means ± standard errors of the means (SEMs) for normally distributed variables, medians (interquartile ranges) for abnormally distributed variables, or numbers (percentages) for categorical variables. Comparisons among groups at baseline were assessed using one-way ANOVA for normally distributed variables, the Kruskal–Wallis H test for abnormally distributed variables, or the chi-square test or Fisher’s exact test for categorical variables. Within-group comparisons of outcome variables were performed by paired t tests for normally distributed variables or paired Wilcoxon tests for abnormally distributed variables, and between-group comparisons of changes were performed by independent samples t tests for normally distributed variables or Mann–Whitney U tests for abnormally distributed variables. Statistical significance was considered when two-tailed P < 0.05. Pearson’s correlation for normally distributed variables or Spearman’s correlation for abnormally distributed variables was performed to investigate the correlation between functions of the myocardium and thyroid and cardiometabolic parameters at baseline. All the statistical analyses were performed using R version 4.1.3

Results

Participant characteristics

As Fig. 1 shows, 290 individuals were screened at the beginning of the study, 121 individuals were excluded because they failed to meet the study criteria (n = 77), had scheduling conflicts (n = 20), or declined to participate (n = 24), and 169 individuals were randomly assigned at a 1:1:1 ratio to the LCD group (n = 56), TRE group (n = 57), or combination group (n = 56). Seven participants dropped out before commencing the study, 4 of whom had scheduling conflicts and 3 of whom had adherence concerns. In total, 162 participants started the interventions (55 in the LCD group, 55 in the TRE group, and 52 in the combination group), and 135 completed the interventions (47 in the LCD group, 44 in the TRE group, and 44 in the combination group). Fifty-seven participants (15 in the LCD group, 28 in the TRE group, and 14 in the combination group) who adhered to their assigned protocol were included in the PP analysis (LCD: daily carbohydrate intake < 150 g/day on ≥ 5 days/week for 3 months; TRE: daily eating window ≤ 8 h on ≥ 5 days/week for 3 months; combination treatment: combined criteria of LCD and TRE.)Fig. 1 Participant flow. eTRE, early time-restricted eating; lTRE, late time-restricted eating

The baseline data are outlined in Table 1. The mean ± SEM average body mass index (BMI) was above 28.0 kg/m2 in each group. The majority of participants had normal myocardial and thyroid functions; 33/162 (20.4%) had elevated myocardial enzymes, and 26/162 (16.0%) had thyroid dysfunction. Overall, the baseline characteristics were significantly equal among the three intervention arms and between those who completed the study and those who withdrew (Additional file 1: Table S1). Table 1 Baseline characteristics of participants

	LCD	TRE	Both		
(N = 55)	(N = 55)	(N = 52)	P value	
Male, no. (%)	27 (49.1)	31 (56.4)	31 (59.6)	0.320	
Age (years)	41.8 ± 1.4	42.6 ± 1.5	39.3 ± 1.3	0.252	
Weight (kg)	84.5 ± 2.4	84.6 ± 2.3	85.4 ± 2.0	0.953	
Body mass index (kg/m2)	29.1 ± 0.5	29.3 ± 0.5	29.0 ± 0.5	0.924	
High school education, no. (%)	52 (94.5)	49 (89.1)	46 (88.5)	0.470	
Income of household, no. (%)				0.171	
  < ¥30,000	2 (3.6)	2 (3.6)	0 (0.0)		
 ¥30,000–¥100,000	11 (20.0)	12 (21.8)	18 (34.6)		
 ¥100,000–¥200,000	24 (43.6)	22 (40.0)	15 (28.8)		
 ¥200,000–¥500,000	18 (32.7)	15 (27.3)	18 (34.6)		
  > ¥500,000	0 (0.0)	4 (7.3)	1 (1.9)		
Current smoker, no. (%)	14 (25.5)	16 (29.1)	18 (34.6)	0.602	
Current drinker, no. (%)	14 (25.5)	17 (30.9)	12 (23.1)	0.662	
Myocardial enzymes	
 Lactate dehydrogenase (U/L)	200 ± 6	195 ± 4	187 ± 4	0.228	
 Creatine kinase (CK, U/L)	93 (86)	98 (68)	96 (68)	0.858	
 CKMB (U/L)	13 (4)	12 (5)	13 (4)	0.795	
 HBDH (U/L)	166 ± 4	162 ± 3	155 ± 3	0.319	
Thyroid function	
 Free T3 (FT3, pmol/L)	7.00 ± 0.10	7.02 ± 0.11	6.86 ± 0.11	0.507	
 Free T4 (FT4, pmol/L)	16.68 ± 0.29	16.65 ± 0.32	16.74 ± 0.33	0.977	
 Thyrotropin (μIU/mL)	1.37 (1.35)	1.40 (1.21)	1.54 (1.44)	0.462	
 Triiodothyronine (T3, ng/mL)	1.46 ± 0.03	1.48 ± 0.04	1.48 ± 0.04	0.906	
 Thyroxine (T4, μg/dL)	9.82 ± 0.19	9.24 ± 0.26	9.47 ± 0.22	0.179	
 T3/T4 ratio	0.15 ± 0.00	0.16 ± 0.00	0.16 ± 0.00	0.124	
 Thyroglobulin antibodies (%)	5 (2)	4 (1)	5 (1)	0.526	
 Thyroid microsomal antibodies (%)	4 (2)	4 (1)	4 (1)	0.223	
LCD, low-carbohydrate diet; TRE, time-restricted eating; Both, combination treatment; CKMB, creatine kinase MB; HBDH, hydroxybutyrate dehydrogenase. Unless otherwise indicated, the data are presented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for abnormally distributed variables. Differences among treatment arms (LCD, TRE, and Both) were tested by one-way ANOVA for normally distributed variables, the Kruskal–Wallis H test for abnormally distributed variables, or chi-square tests for categorical variables

Only 3 participants (2 in the LCD group and 1 in the TRE group) had been diagnosed with hypothyroidism and were taking levothyroxine sodium tablets before the intervention; no other medication in addition to cardiovascular medication was taken by any of the participants. All participants maintained their medication dosage and did not change their level of physical activity during the 3-month intervention. The intake of aquatic products was decreased in the TRE group and the intake of phytocomycetes was increased in the combination group (Additional file 1: Table S3).

LCD, TRE, and their combination reduced LDH, CK, CKMB, and HBDH

All three groups exhibited equivalent reductions in LDH, CK, CKMB, and HBDH after the 3-month intervention (P < 0.01). Moreover, there was no significant difference in the reductions in myocardial enzymes among the three groups (Fig. 2A–D and Table 2). Differently, PP analysis revealed that CK levels decreased only in the TRE (− 18 [44] U/L, P < 0.001) and combination (− 22 [64] U/L, P = 0.003) groups, without significant changes in the LCD (− 11 [10] U/L, P = 0.075) group (Fig. 3B and Additional file 1: Table S4); moreover, changes in the other three myocardial enzymes were similar to those observed in the ITT analysis (Fig. 3A, C, and D and Additional file 1: Table S4). No significant difference between the eTRE and lTRE groups was observed for either the TRE or combination group (Additional file 1: Table S6).Fig. 2 Changes in myocardial enzymes and thyroid function among participants. A–D Changes in myocardial enzymes among the three groups after the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), or combination treatment (Both). A Lactate dehydrogenase (LDH), B creatine kinase (CK), C creatine kinase MB (CKMB), and D hydroxybutyrate dehydrogenase (HBDH). E–J Changes in thyroid hormone levels among the three groups after intervention. E Free triiodothyronine (FT3), F free thyroxine (FT4), G thyrotropin (TSH), H triiodothyronine (T3), I thyroxine (T4), and J the T3/T4 ratio. K, L Changes in K thyroglobulin antibodies (TgAb) and L thyroid microsomal antibodies (TMAb) among the three interventions after 3 months. Changes from baseline are presented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for abnormally distributed variables. Analysis was conducted on 162 participants who began interventions (55 in the LCD group, 55 in the TRE group, and 52 in the Both group). *P < 0.05, **P < 0.01, ***P < 0.001: significant differences shown on the x-axis compared with baseline (paired t test for normally distributed variables or paired Wilcoxon test for abnormally distributed variables)

Table 2 Changes in myocardial enzymes and thyroid function after 3 months among participants

	LCD (group A)	TRE (group B)	Both (group C)	P value between-group comparison	
N = 55	P value	N = 55	P value	N = 52	P value	A vs. B	A vs. C	B vs. C	
Myocardial enzymes	
 LDH (U/L)	3 m	176 ± 4		171 ± 3		166 ± 2					
△	 − 24 ± 6	 < 0.001	 − 24 ± 4	 < 0.001	 − 21 ± 3	 < 0.001	0.838	0.665	0.989	
 Creatine kinase (CK, U/L)	3 m	77 (65)		80 (45)		83 (48)					
△	 − 13 (40)	0.002	 − 14 (32)	 < 0.001	 − 18 (47)	0.001	0.713	0.711	0.989	
 CKMB (U/L)	3 m	12 (3)		11 (3)		11 (3)					
△	 − 1 (4)	0.003	 − 2 (3)	 < 0.001	 − 2 (4)	 < 0.001	0.526	0.601	0.974	
 HBDH (U/L)	3 m	152 ± 3		150 ± 3		145 ± 2					
△	 − 13 ± 4	0.001	 − 12 ± 3	0.001	 − 10 ± 3	 < 0.001	0.925	0.839	0.700	
Thyroid function	
 Free T3 (pmol/L)	3 m	5.95 ± 0.09		6.11 ± 0.18		5.93 ± 0.09					
△	 − 1.04 ± 0.15	 < 0.001	 − 0.91 ± 0.20	 < 0.001	 − 0.93 ± 0.12	 < 0.001	0.811	0.472	0.558	
 Free T4 (pmol/L)	3 m	20.21 ± 1.34		18.70 ± 0.36		18.77 ± 0.33					
△	3.53 ± 1.33	 < 0.001	2.05 ± 0.46	 < 0.001	2.03 ± 0.35	 < 0.001	0.656	0.798	0.969	
 Thyrotropin (μIU/mL)	3 m	1.42 (1.11)		1.34 (1.08)		1.31 (0.99)					
△	 − 0.01 (0.65)	0.528	 − 0.13 (1.02)	0.435	 − 0.24 (0.83)	0.011	0.693	0.149	0.233	
 Triiodothyronine (T3, ng/mL)	3 m	1.43 ± 0.04		1.47 ± 0.07		1.38 ± 0.04					
△	 − 0.03 ± 0.04	0.511	 − 0.01 ± 0.08	0.076	 − 0.10 ± 0.04	0.011	0.457	0.220	0.451	
 Thyroxine (T4, μg/dL)	3 m	10.29 ± 0.28		9.94 ± 0.27		9.81 ± 0.27					
△	0.46 ± 0.27	0.087	0.70 ± 0.28	0.013	0.34 ± 0.22	0.121	0.583	0.729	0.437	
 T3/T4 ratio	3 m	0.14 ± 0.01		0.15 ± 0.01		0.15 ± 0.01					
△	 − 0.01 ± 0.00	0.189	 − 0.01 ± 0.01	0.003	 − 0.01 ± 0.00	0.012	0.238	0.300	0.802	
 TgAb (%)	3 m	7 (2)		7 (1)		7 (2)					
△	2 (2)	0.011	2 (2)	0.001	2 (2)	0.001	0.852	0.373	0.472	
 TMAb (%)	3 m	6 (2)		6 (1)		6 (2)					
△	2 (2)	0.003	2 (2)	 < 0.001	2 (2)	 < 0.001	0.371	0.084	0.298	
LCD low-carbohydrate diet, TRE time-restricted eating, Both combination treatment, LDH lactate dehydrogenase, CKMB creatine kinase MB, HBDH hydroxybutyrate dehydrogenase, TgAb thyroglobulin antibodies, TMAb thyroid microsomal antibodies. All the data are presented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for abnormally distributed variables. The outcome variables tested at postintervention are represented by “3 m,” and the variations from baseline to 3 months are represented by “△” in the table. Within-group comparisons of outcome variables between baseline and follow-up were performed by paired t tests for normally distributed variables or paired Wilcoxon tests for abnormally distributed variables, and between-group comparisons (e.g., LCD vs. TRE, LCD vs. Both, and TRE vs. Both) of changes were tested by independent sample t tests for normally distributed variables or Mann–Whitney U tests for abnormally distributed variables. Significant P values are italicized

Fig. 3 Changes in myocardial enzymes and thyroid function according to the PP analysis. A–D Changes in myocardial enzymes among the three groups in the per-protocol (PP) analysis after the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), or combination treatment (Both) interventions. A Lactate dehydrogenase (LDH), B creatine kinase (CK), C creatine kinase MB (CKMB), and D hydroxybutyrate dehydrogenase (HBDH). E–J Changes in thyroid hormone levels among the three groups according to the PP analysis after intervention. E Free triiodothyronine (FT3), F free thyroxine (FT4), G thyrotropin (TSH), H triiodothyronine (T3), I thyroxine (T4), and J the T3/T4 ratio. K, L Changes in K thyroglobulin antibodies (TgAb) and L thyroid microsomal antibodies (TMAb) in the PP analysis among the three interventions after 3 months. Changes from baseline are presented as the mean ± standard error of the mean for normally distributed variables or the median (interquartile range) for abnormally distributed variables. Analysis was conducted on 57 adherent participants (15 in the LCD group, 28 in the TRE group, and 14 in the Both group). *P < 0.05, **P < 0.01, ***P < 0.001: significant differences shown on the x-axis compared with baseline (paired t test for normally distributed variables or paired Wilcoxon test for abnormally distributed variables)

LCD, TRE, and their combination altered FT3 and FT4, while only combination treatment reduced TSH

After 3 months, FT3 levels decreased and FT4 levels increased in all three groups (Fig. 2E and F and Table 2). Reductions in TSH (− 0.24 [0.83] μIU/mL, P = 0.011) and T3 (− 0.10 ± 0.04 ng/mL, P = 0.011) were observed in the combination group (Fig. 2G and H and Table 2). Only the TRE group exhibited an increase in T4 (0.70 ± 0.28 μg/dL, P = 0.013; Fig. 2I and Table 2). The T3/T4 ratio decreased in both the TRE (− 0.01 ± 0.01, P = 0.003) and combination (− 0.01 ± 0.00, P = 0.012) groups (Fig. 2J and Table 2). No significant difference in changes in THs was observed among the three groups. The results from the PP analysis differed moderately from those from the primary analysis. Relative to those at baseline, TSH and T3 levels remained unchanged in all three groups (Fig. 3G and H), and the T3/T4 ratio decreased only in the TRE (− 0.01 ± 0.01, P = 0.020) group (Fig. 3J and Additional file 1: Table S4). The eTRE and lTRE subgroups in both the TRE and combination groups showed comparable improvements in THs (Additional file 1: Table S6).

LCD, TRE, and their combination increased TgAb and TMAb

Compared to baseline, the TgAb and TMAb levels increased in all three groups (Fig. 2K and L and Table 2). The changes in thyroid autoantibodies were not significantly different among the groups (Table 2). PP analysis revealed that TgAb (2 (1) %, P = 0.021) and TMAb (2 (2) %, P < 0.001) increased only in the TRE group (Fig. 3K and L and Additional file 1: Table S4). No significant difference was observed in TgAb or TMAb between the two subgroups (eTRE vs. lTRE) (Additional file 1: Table S6).

Correlation analysis

Pearson’s or Spearman’s correlation was assessed between functions of the myocardium and thyroid and cardiometabolic parameters at baseline (Additional file 1: Fig. S1). CK was positively correlated with visceral fat area (VFA, r = 0.213, P = 0.013). FT3 was positively associated with triglyceride (r = 0.237, P = 0.006) and total cholesterol (r = 0.223, P = 0.009). FT4 was negatively related to fasting insulin (r =  − 0.244, P = 0.004) and C-peptide (r =  − 0.238, P = 0.005). TgAb and TMAb were negatively correlated with the waist-to-hip ratio (WHR, r =  − 0.237, P = 0.006; r =  − 0.245, P = 0.004, respectively).

Discussion

In this study, we observed that all three distinct interventions improved myocardial status and thyroid function, while TRE with or without LCD had apparent beneficial effects on CK, TSH, T3, T4, and the T3/T4 ratio. In the preliminary analysis, eTRE and lTRE had comparable effects on the myocardium and thyroid. Correlations between the functions of the myocardium and thyroid and cardiometabolic risk factors were observed at baseline. In addition, the results of the PP analysis seemed more precise in that only adherent participants were included, which could reflect the real effects of the diverse diet without bias from higher compliance in the TRE group [31]. However, whether the changes in the intake of aquatic products and phytocomycetes indicated that the exact iodine intake changed accordingly was unclear. To our knowledge, the present study is the first to directly compare the effects of LCD and TRE on myocardial status and thyroid function, especially on thyroid autoimmunity, in subjects with MetS.

Although the majority of the patients were within the reference range at baseline, myocardial enzymes, including LDH, CK, CKMB, and HBDH, markedly decreased after all three interventions, without differences among the groups. Our findings are consistent with other studies that showed decreased LDH, CK, and HBDH after weight loss induced by bariatric surgery [33] and reduced LDH after a low-calorie diet [34]. However, the results of existing trials on changes in myocardial enzymes via LCD and TRE are sparse, and further studies are needed to investigate the effects of LCD and TRE on myocardial enzymes in individuals with MetS to verify our findings. Notably, in the PP analysis, CK decreased only in the TRE and combination groups, partially because of decreased VFA in the TRE and combination treatments but not in the LCD group [31], given that CK was positively correlated with VFA (Additional file 1: Fig. S1A). As an ATP-regenerating enzyme, CK regulates energy metabolism, affects cardiovascular hemodynamics [35], and is abundant in type II skeletal muscle fibers, which particularly contribute to IR and obesity. Accordingly, higher levels of serum CK are found in patients with obesity [11, 12]. CK is correlated with multiple MetS components, such as BMI, waist circumference, and blood pressure [9, 10, 36]. Therefore, TRE with or without LCD markedly reduced CK levels and could ameliorate unfavorable myocardial status and cardiovascular risk.

Studies on the effects of LCD and TRE on THs have yielded inconsistent results. As the most sensitive and significant serum biomarker of thyroid function, TSH decreased only in the combination group according to the ITT analysis and showed a decreasing trend but was insignificant in the combination group according to the PP analysis, which is consistent with the findings of several trials that failed to detect any significant changes in TSH after LCD or TRE intervention [26–28]. Nevertheless, studies on the effects of LCD combined with TRE on TSH are scarce, and further larger-scale trials are needed to investigate whether TRE combined with LCD could induce a reduction in TSH levels. Notably, TRE with or without LCD led to a significant reduction in the T3/T4 ratio (an index of deiodinase activity), indicating that the reduction in (F)T3 and increase in (F)T4 may be signals of decreased deiodinase activity and peripheral conversion from T4 to T3. Another explanation for the observed trends toward (F)T3 and (F)T4 is decreased ATP-dependent uptake of T4 into T3-producing tissues, including the liver [37]. (F)T3 activates thermogenesis and induces an increase in energy expenditure and oxygen consumption. Therefore, a reduction in (F)T3 may represent strong self-protection to save energy and decrease resting energy expenditure in response to energy deficits induced by carb restriction or fasting. Our findings of changes in FT3 and FT4 were consistent with the findings of other trials after LCD (15% carbohydrate) [27] or gastric banding [38]. However, our findings were at odds with several trials that showed no significant changes in FT3 or FT4 after LCD [29] or TRE [30]. These differences might be partially attributed to differences in the scales and durations of the study, thyroid function at baseline, or extent of weight loss. Overall, in this study, we found that all three interventions improved FT3 and FT4 levels, while only TRE with or without LCD significantly improved T3, T4, and the T3/T4 ratio.

Consistent with previous findings [39, 40], we also observed that THs were closely associated with the lipid profile and insulin sensitivity (Additional file 1: Fig. S1B and S1C), which are not only MetS components but also risk factors for multiple chronic diseases, revealing the mechanism of correlation between thyroid dysfunction and chronic endocrine disorders. Recently, several TH analogs or thyromimetics have been developed to modulate lipid and glucose levels based on the possibility that THs control multiple signaling pathways involved in related metabolism [41–43].

Our results showed that TgAb and TMAb levels increased after all three interventions in the ITT analysis but increased only in the TRE group after the PP analysis. For participants with negative baseline thyroid autoantibodies, TgAb and TMAb levels increased after all three interventions in both the ITT and PP analyses (Additional file 1: Fig. S2). Elevated thyroid autoantibodies are common not only in patients with autoimmune thyroid disease but also in individuals without evident thyroid dysfunction. The percentage of patients with a positive serum TgAb concentration is estimated to be 12.6% in the Chinese general population [44]. Negative correlations have been observed between TgAb levels and BMI [45], prevalence of impaired fasting glucose, hypertriglyceridemia, and metabolic dysfunction-associated fatty liver disease [23, 46]. We found that TgAb and TMAb levels were negatively correlated with the WHR (Additional file 1: Fig. S1D), which was recently identified as a stronger adiposity surrogate associated with mortality than BMI [47]. However, several studies have reported a correlation between positivity or higher titers of TgAb and MetS components [48–50]. These inconsistencies might be partly due to altered thyroid function and differences in the specificity and sensitivity of the antibody detection methods. To date, no study has investigated the effects of LCD or TRE on thyroid autoimmunity, and whether increased thyroid autoantibody levels, even within the normal range, adversely impair thyroid function is unclear. Further studies are warranted to elucidate the effects of LCD and TRE on thyroid autoimmunity and explore the underlying mechanism involved.

Following circadian rhythms, eTRE was previously suggested to be superior to lTRE [51]. We observed that eTRE and lTRE improved myocardial enzymes and thyroid function comparably, which indicated that people could choose freely following preferences. Indeed, studies comparing the effects of eTRE and lTRE on the myocardium and thyroid are scarce. Zhang et al. reported that TSH levels were significantly lower in the eTRE group than in the lTRE group after 4 but not 8 weeks [52]. Although our early or late TRE method involves self-selection but not randomization, the outcomes could still be used to tentatively explore the effects of eTRE and lTRE on the myocardium and thyroid. Further randomized controlled trials with longer durations and larger scales are needed to verify our findings.

This analysis has several limitations. First, the lack of an AL control group limits the exploration of the effects of TRE alone and LCD alone, although we conducted a comparison between pre- and postintervention data. Second, in line with the findings of other TRE trials [51, 53, 54], participants in the TRE group spontaneously reduced their daily carbohydrate intake by approximately 4.6%, and the exact daily iodine intake of all participants was obscure. Third, to enhance adherence, eTRE and lTRE were not randomized but rather self-selected, which impaired the reliability of the analytical results to some extent. Further randomized trials are warranted to compare the effects of eTRE and lTRE on the thyroid and myocardium. Moreover, a limited number of participants in the LCD and combination groups were included in the PP analysis, and further larger-scale and strict follow-up trials are warranted to verify our findings. Finally, thyroid antibodies are influenced by multiple factors, and the results vary depending on the testing methods used; additional trials are needed to verify our results.

Conclusions

Taken together, LCD, TRE, and their combination all improved functions of the myocardium and thyroid even though the majority were within the reference range at baseline, and TRE with or without LCD conferred substantial benefits regarding CK, TSH, T3, T4, and the T3/T4 ratio, suggesting that TRE with or without LCD can serve as effective dietary strategy for ameliorating the myocardial status and thyroid function in patients with MetS.

Supplementary Information

Additional file 1: Fig. S1. Correlations between myocardial and thyroid functions and cardiometabolic risk factors at baseline. Fig. S2. Changes in TgAb and TMAb after 3 months in participants with negative baseline thyroid autoimmunity. Table S1. Baseline characteristics of all, completed, and dropout participants. Table S2. Baseline characteristics of adherent participants. Table S3. Intake of food containing high iodine among completed participants. Table S4. Changes in myocardial enzymes and thyroid function after 3-month intervention among adherent participants. Table S5. Baseline characteristics of the early TRE and late TRE subgroups. Table S6. Changes in myocardial enzymes and thyroid function after 3-month intervention between early TRE and late TRE subgroups.

Abbreviations

MetS Metabolic syndrome

LCD Low-carbohydrate diet

TRE Time-restricted eating

LDH Lactate dehydrogenase

CK Creatine kinase

CKMB Creatine kinase MB

HBDH Hydroxybutyrate dehydrogenase

THs Thyroid hormones

FT3 Free triiodothyronine

FT4 Free thyroxine

TSH Thyrotropin

TgAb Thyroglobulin antibodies

TMAb Thyroid microsomal antibodies

Acknowledgements

We sincerely thank the patients who participated in the research. We thank Mrs. Alice Chung for helping with dietary instruction.

Authors’ contributions

YZ and MH conducted the clinical trial, analyzed the data, and wrote the manuscript. BS designed the research and revised the manuscript. ML1, XZ, and XL assisted with the data analysis. JW, QL, JY, MZ, ZC, ML2, YW, JS, WQ, and HG assisted with the conduction of the clinical trial. All authors read and approved the final manuscript.

Funding

This study was supported by the Natural Science Foundation Program of Shaanxi (No. 2024JC-YBQN-0828), the Key Research and Development Program of Shaanxi (No. 2023-ZDLSF-40), and Natural Science Foundation Program of Shaanxi (No. 2023-JC-QN-0927).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files. All data reported in this paper and any additional information required to reanalyze the data reported in this paper will be shared by the lead contact upon reasonable request.

Declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Board of the First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF2020LSK-003). Participants provided written informed consent and received no compensation.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Chew NWS Ng CH Tan DJH Kong G Lin C Chin YH The global burden of metabolic disease: data from 2000 to 2019 Cell Metab 2023 35 3 414 28.e3 10.1016/j.cmet.2023.02.003 36889281
Chew NWS, Ng CH, Tan DJH, Kong G, Lin C, Chin YH, et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. 2023;35(3):414–28.e3.36889281 10.1016/j.cmet.2023.02.003
2. Cohen RV Drager LF Petry TBZ Santos RD Metabolic health in Brazil: trends and challenges Lancet Diabetes Endocrinol 2020 8 12 937 938 10.1016/S2213-8587(20)30370-3 33156997
Cohen RV, Drager LF, Petry TBZ, Santos RD. Metabolic health in Brazil: trends and challenges. Lancet Diabetes Endocrinol. 2020;8(12):937–8.33156997 10.1016/S2213-8587(20)30370-3
3. Aguilar M Bhuket T Torres S Liu B Wong RJ Prevalence of the metabolic syndrome in the United States, 2003–2012 JAMA 2015 313 19 1973 1974 10.1001/jama.2015.4260 25988468
Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003–2012. JAMA. 2015;313(19):1973–4.25988468 10.1001/jama.2015.4260
4. Zuo H Shi Z Hu X Wu M Guo Z Hussain A Prevalence of metabolic syndrome and factors associated with its components in Chinese adults Metabolism 2009 58 8 1102 1108 10.1016/j.metabol.2009.04.008 19481771
Zuo H, Shi Z, Hu X, Wu M, Guo Z, Hussain A. Prevalence of metabolic syndrome and factors associated with its components in Chinese adults. Metabolism. 2009;58(8):1102–8.19481771 10.1016/j.metabol.2009.04.008
5. Bray GA Ryan DH Evidence-based weight loss interventions: individualized treatment options to maximize patient outcomes Diabetes Obes Metab 2021 23 Suppl 1 50 62 10.1111/dom.14200 32969147
Bray GA, Ryan DH. Evidence-based weight loss interventions: individualized treatment options to maximize patient outcomes. Diabetes Obes Metab. 2021;23(Suppl 1):50–62.32969147 10.1111/dom.14200
6. Ninomiya JK L’Italien G Criqui MH Whyte JL Gamst A Chen RS Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey Circulation 2004 109 1 42 46 10.1161/01.CIR.0000108926.04022.0C 14676144
Ninomiya JK, L’Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109(1):42–6.14676144 10.1161/01.CIR.0000108926.04022.0C
7. Mente A Yusuf S Islam S McQueen MJ Tanomsup S Onen CL Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries J Am Coll Cardiol 2010 55 21 2390 2398 10.1016/j.jacc.2009.12.053 20488312
Mente A, Yusuf S, Islam S, McQueen MJ, Tanomsup S, Onen CL, et al. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. J Am Coll Cardiol. 2010;55(21):2390–8.20488312 10.1016/j.jacc.2009.12.053
8. Lee EY Han K Kim DH Park YM Kwon HS Yoon KH Exposure-weighted scoring for metabolic syndrome and the risk of myocardial infarction and stroke: a nationwide population-based study Cardiovasc Diabetol 2020 19 1 153 10.1186/s12933-020-01129-x 32993664
Lee EY, Han K, Kim DH, Park YM, Kwon HS, Yoon KH, et al. Exposure-weighted scoring for metabolic syndrome and the risk of myocardial infarction and stroke: a nationwide population-based study. Cardiovasc Diabetol. 2020;19(1):153.32993664 10.1186/s12933-020-01129-x
9. Haan YC Oudman I Diemer FS Karamat FA van Valkengoed IG van Montfrans GA Creatine kinase as a marker of obesity in a multi-ethnic population Mol Cell Endocrinol 2017 442 24 31 10.1016/j.mce.2016.11.022 27894867
Haan YC, Oudman I, Diemer FS, Karamat FA, van Valkengoed IG, van Montfrans GA, et al. Creatine kinase as a marker of obesity in a multi-ethnic population. Mol Cell Endocrinol. 2017;442:24–31.27894867 10.1016/j.mce.2016.11.022
10. Al-Hail N Butler AE Dargham SR Abou Seif A Atkin SL Creatine kinase is a marker of metabolic syndrome in Qatari women with and without polycystic ovarian syndrome Front Endocrinol (Lausanne) 2019 10 659 10.3389/fendo.2019.00659 31608014
Al-Hail N, Butler AE, Dargham SR, Abou Seif A, Atkin SL. Creatine kinase is a marker of metabolic syndrome in Qatari women with and without polycystic ovarian syndrome. Front Endocrinol (Lausanne). 2019;10:659.31608014 10.3389/fendo.2019.00659
11. Sun J Wang L Lin Y Liu Y Liu F Liu X Anthropometric parameters of obesity can be alternative biomarkers for the potential cardiac dysfunction in obese children Front Cardiovasc Med 2022 9 850071 10.3389/fcvm.2022.850071 36061547
Sun J, Wang L, Lin Y, Liu Y, Liu F, Liu X, et al. Anthropometric parameters of obesity can be alternative biomarkers for the potential cardiac dysfunction in obese children. Front Cardiovasc Med. 2022;9:850071.36061547 10.3389/fcvm.2022.850071
12. George MD McGill NK Baker JF Creatine kinase in the U.S. population: impact of demographics, comorbidities, and body composition on the normal range Medicine (Baltimore). 2016 95 33 e4344 10.1097/MD.0000000000004344 27537560
George MD, McGill NK, Baker JF. Creatine kinase in the U.S. population: impact of demographics, comorbidities, and body composition on the normal range. Medicine (Baltimore). 2016;95(33):e4344.27537560 10.1097/MD.0000000000004344
13. Mondal S Raja K Schweizer U Mugesh G Chemistry and biology in the biosynthesis and action of thyroid hormones Angew Chem Int Ed Engl 2016 55 27 7606 7630 10.1002/anie.201601116 27226395
Mondal S, Raja K, Schweizer U, Mugesh G. Chemistry and biology in the biosynthesis and action of thyroid hormones. Angew Chem Int Ed Engl. 2016;55(27):7606–30.27226395 10.1002/anie.201601116
14. Mullur R Liu YY Brent GA Thyroid hormone regulation of metabolism Physiol Rev 2014 94 2 355 382 10.1152/physrev.00030.2013 24692351
Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355–82.24692351 10.1152/physrev.00030.2013
15. Amouzegar A Kazemian E Abdi H Mansournia MA Bakhtiyari M Hosseini MS Association between thyroid function and development of different obesity phenotypes in euthyroid adults: a nine-year follow-up Thyroid 2018 28 4 458 464 10.1089/thy.2017.0454 29620968
Amouzegar A, Kazemian E, Abdi H, Mansournia MA, Bakhtiyari M, Hosseini MS, et al. Association between thyroid function and development of different obesity phenotypes in euthyroid adults: a nine-year follow-up. Thyroid. 2018;28(4):458–64.29620968 10.1089/thy.2017.0454
16. Abiri B Ahmadi AR Mahdavi M Amouzegar A Valizadeh M Association between thyroid function and obesity phenotypes in healthy euthyroid individuals: an investigation based on Tehran Thyroid Study Eur J Med Res 2023 28 1 179 10.1186/s40001-023-01135-1 37248529
Abiri B, Ahmadi AR, Mahdavi M, Amouzegar A, Valizadeh M. Association between thyroid function and obesity phenotypes in healthy euthyroid individuals: an investigation based on Tehran Thyroid Study. Eur J Med Res. 2023;28(1):179.37248529 10.1186/s40001-023-01135-1
17. Nie X Ma X Xu Y Shen Y Wang Y Bao Y Characteristics of serum thyroid hormones in different metabolic phenotypes of obesity Front Endocrinol (Lausanne) 2020 11 68 10.3389/fendo.2020.00068 32184757
Nie X, Ma X, Xu Y, Shen Y, Wang Y, Bao Y. Characteristics of serum thyroid hormones in different metabolic phenotypes of obesity. Front Endocrinol (Lausanne). 2020;11:68.32184757 10.3389/fendo.2020.00068
18. Lass N Barth A Reinehr T Thyroid volume and thyroid function parameters are independently associated with weight status in overweight children Horm Res Paediatr 2020 93 5 279 286 10.1159/000509786 33040066
Lass N, Barth A, Reinehr T. Thyroid volume and thyroid function parameters are independently associated with weight status in overweight children. Horm Res Paediatr. 2020;93(5):279–86.33040066 10.1159/000509786
19. Garduño-Garcia Jde J Alvirde-Garcia U López-Carrasco G Padilla Mendoza ME Mehta R Arellano-Campos O TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects Eur J Endocrinol 2010 163 2 273 278 10.1530/EJE-10-0312 20516204
Garduño-Garcia Jde J, Alvirde-Garcia U, López-Carrasco G, Padilla Mendoza ME, Mehta R, Arellano-Campos O, et al. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. Eur J Endocrinol. 2010;163(2):273–8.20516204 10.1530/EJE-10-0312
20. Borges-Canha M Neves JS Mendonça F Silva MM Costa C Cabral PM Thyroid function and the risk of non-alcoholic fatty liver disease in morbid obesity Front Endocrinol (Lausanne) 2020 11 572128 10.3389/fendo.2020.572128 33193088
Borges-Canha M, Neves JS, Mendonça F, Silva MM, Costa C, Cabral PM, et al. Thyroid function and the risk of non-alcoholic fatty liver disease in morbid obesity. Front Endocrinol (Lausanne). 2020;11:572128.33193088 10.3389/fendo.2020.572128
21. van den Berg EH van Tienhoven-Wind LJ Amini M Schreuder TC Faber KN Blokzijl H Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study Metabolism 2017 67 62 71 10.1016/j.metabol.2016.11.002 28081779
van den Berg EH, van Tienhoven-Wind LJ, Amini M, Schreuder TC, Faber KN, Blokzijl H, et al. Higher free triiodothyronine is associated with non-alcoholic fatty liver disease in euthyroid subjects: the Lifelines Cohort Study. Metabolism. 2017;67:62–71.28081779 10.1016/j.metabol.2016.11.002
22. Amouzegar A Kazemian E Gharibzadeh S Mehran L Tohidi M Azizi F Association between thyroid hormones, thyroid antibodies and insulin resistance in euthyroid individuals: a population-based cohort Diabetes Metab 2015 41 6 480 488 10.1016/j.diabet.2015.04.004 26049821
Amouzegar A, Kazemian E, Gharibzadeh S, Mehran L, Tohidi M, Azizi F. Association between thyroid hormones, thyroid antibodies and insulin resistance in euthyroid individuals: a population-based cohort. Diabetes Metab. 2015;41(6):480–8.26049821 10.1016/j.diabet.2015.04.004
23. Zhang J Gao Y Li Y Teng D Xue Y Yan L The presence of serum TgAb suggests lower risks for glucose and lipid metabolic disorders in euthyroid general population from a national survey Front Endocrinol (Lausanne) 2020 11 139 10.3389/fendo.2020.00139 32256451
Zhang J, Gao Y, Li Y, Teng D, Xue Y, Yan L, et al. The presence of serum TgAb suggests lower risks for glucose and lipid metabolic disorders in euthyroid general population from a national survey. Front Endocrinol (Lausanne). 2020;11:139.32256451 10.3389/fendo.2020.00139
24. Le TN Celi FS Wickham EP 3rd Thyrotropin levels are associated with cardiometabolic risk factors in euthyroid adolescents Thyroid 2016 26 10 1441 1449 10.1089/thy.2016.0055 27599541
Le TN, Celi FS, Wickham EP 3rd. Thyrotropin levels are associated with cardiometabolic risk factors in euthyroid adolescents. Thyroid. 2016;26(10):1441–9.27599541 10.1089/thy.2016.0055
25 Hyde PN Sapper TN Crabtree CD LaFountain RA Bowling ML Buga A Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss JCI Insight. 2019 4 12 e128308 10.1172/jci.insight.128308 31217353
Hyde PN, Sapper TN, Crabtree CD, LaFountain RA, Bowling ML, Buga A, et al. Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI Insight. 2019;4(12):e128308.31217353 10.1172/jci.insight.128308
26. Wilkinson MJ Manoogian ENC Zadourian A Lo H Fakhouri S Shoghi A Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome Cell Metab 2020 31 1 92 104.e5 10.1016/j.cmet.2019.11.004 31813824
Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 2020;31(1):92–104.e5.31813824 10.1016/j.cmet.2019.11.004
27. Iacovides S Maloney SK Bhana S Angamia Z Meiring RM Could the ketogenic diet induce a shift in thyroid function and support a metabolic advantage in healthy participants? A pilot randomized-controlled-crossover trial PLoS One 2022 17 6 e0269440 10.1371/journal.pone.0269440 35658056
Iacovides S, Maloney SK, Bhana S, Angamia Z, Meiring RM. Could the ketogenic diet induce a shift in thyroid function and support a metabolic advantage in healthy participants? A pilot randomized-controlled-crossover trial. PLoS One. 2022;17(6):e0269440.35658056 10.1371/journal.pone.0269440
28. Moro T Tinsley G Bianco A Marcolin G Pacelli QF Battaglia G Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males J Transl Med 2016 14 1 290 10.1186/s12967-016-1044-0 27737674
Moro T, Tinsley G, Bianco A, Marcolin G, Pacelli QF, Battaglia G, et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med. 2016;14(1):290.27737674 10.1186/s12967-016-1044-0
29. Nuttall FQ Gannon MC The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 diabetes mellitus Metabolism 2006 55 2 243 251 10.1016/j.metabol.2005.08.027 16423633
Nuttall FQ, Gannon MC. The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 diabetes mellitus. Metabolism. 2006;55(2):243–51.16423633 10.1016/j.metabol.2005.08.027
30. Schroder JD Falqueto H Mânica A Zanini D de Oliveira T de Sá CA Effects of time-restricted feeding in weight loss, metabolic syndrome and cardiovascular risk in obese women J Transl Med 2021 19 1 3 10.1186/s12967-020-02687-0 33407612
Schroder JD, Falqueto H, Mânica A, Zanini D, de Oliveira T, de Sá CA, et al. Effects of time-restricted feeding in weight loss, metabolic syndrome and cardiovascular risk in obese women. J Transl Med. 2021;19(1):3.33407612 10.1186/s12967-020-02687-0
31. He M Wang J Liang Q Li M Guo H Wang Y Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: a randomized trial Cell Rep Med 2022 3 10 100777 10.1016/j.xcrm.2022.100777 36220069
He M, Wang J, Liang Q, Li M, Guo H, Wang Y, et al. Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: a randomized trial. Cell Rep Med. 2022;3(10):100777.36220069 10.1016/j.xcrm.2022.100777
32. Alberti KG Eckel RH Grundy SM Zimmet PZ Cleeman JI Donato KA Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity Circulation 2009 120 16 1640 1645 10.1161/CIRCULATIONAHA.109.192644 19805654
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–5.19805654 10.1161/CIRCULATIONAHA.109.192644
33. Guan B Chen Y Chong TH Peng J Mak TK Wang C Effect of bariatric surgery on serum enzyme status in obese patients Obes Surg 2020 30 7 2700 2707 10.1007/s11695-020-04554-9 32180113
Guan B, Chen Y, Chong TH, Peng J, Mak TK, Wang C, et al. Effect of bariatric surgery on serum enzyme status in obese patients. Obes Surg. 2020;30(7):2700–7.32180113 10.1007/s11695-020-04554-9
34. Greco M Chiefari E Montalcini T Accattato F Costanzo FS Pujia A Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals Mediators Inflamm 2014 2014 750860 10.1155/2014/750860 24729662
Greco M, Chiefari E, Montalcini T, Accattato F, Costanzo FS, Pujia A, et al. Early effects of a hypocaloric, Mediterranean diet on laboratory parameters in obese individuals. Mediators Inflamm. 2014;2014:750860.24729662 10.1155/2014/750860
35. Brewster LM Haan YC Zwinderman AH van den Born BJ van Montfrans GA CK (creatine kinase) is associated with cardiovascular hemodynamics: the HELIUS study Hypertension 2020 76 2 373 380 10.1161/HYPERTENSIONAHA.120.14675 32594803
Brewster LM, Haan YC, Zwinderman AH, van den Born BJ, van Montfrans GA. CK (creatine kinase) is associated with cardiovascular hemodynamics: the HELIUS study. Hypertension. 2020;76(2):373–80.32594803 10.1161/HYPERTENSIONAHA.120.14675
36. Brewster LM Creatine kinase, energy reserve, and hypertension: from bench to bedside Ann Transl Med 2018 6 15 292 10.21037/atm.2018.07.15 30211180
Brewster LM. Creatine kinase, energy reserve, and hypertension: from bench to bedside. Ann Transl Med. 2018;6(15):292.30211180 10.21037/atm.2018.07.15
37. Hennemann G Krenning EP The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation Best Pract Res Clin Endocrinol Metab 2007 21 2 323 338 10.1016/j.beem.2007.03.007 17574011
Hennemann G, Krenning EP. The kinetics of thyroid hormone transporters and their role in non-thyroidal illness and starvation. Best Pract Res Clin Endocrinol Metab. 2007;21(2):323–38.17574011 10.1016/j.beem.2007.03.007
38 Dall’Asta C Paganelli M Morabito A Vedani P Barbieri M Paolisso G Weight loss through gastric banding: effects on TSH and thyroid hormones in obese subjects with normal thyroid function Obesity (Silver Spring). 2010 18 4 854 7 10.1038/oby.2009.320 19834461
Dall’Asta C, Paganelli M, Morabito A, Vedani P, Barbieri M, Paolisso G, et al. Weight loss through gastric banding: effects on TSH and thyroid hormones in obese subjects with normal thyroid function. Obesity (Silver Spring). 2010;18(4):854–7.19834461 10.1038/oby.2009.320
39. Mehran L Amouzegar A Tohidi M Moayedi M Azizi F Serum free thyroxine concentration is associated with metabolic syndrome in euthyroid subjects Thyroid 2014 24 11 1566 1574 10.1089/thy.2014.0103 25069017
Mehran L, Amouzegar A, Tohidi M, Moayedi M, Azizi F. Serum free thyroxine concentration is associated with metabolic syndrome in euthyroid subjects. Thyroid. 2014;24(11):1566–74.25069017 10.1089/thy.2014.0103
40. Roos A Bakker SJ Links TP Gans RO Wolffenbuttel BH Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects J Clin Endocrinol Metab 2007 92 2 491 496 10.1210/jc.2006-1718 17090642
Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007;92(2):491–6.17090642 10.1210/jc.2006-1718
41. Erion MD Cable EE Ito BR Jiang H Fujitaki JM Finn PD Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index Proc Natl Acad Sci U S A 2007 104 39 15490 15495 10.1073/pnas.0702759104 17878314
Erion MD, Cable EE, Ito BR, Jiang H, Fujitaki JM, Finn PD, et al. Targeting thyroid hormone receptor-beta agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index. Proc Natl Acad Sci U S A. 2007;104(39):15490–5.17878314 10.1073/pnas.0702759104
42. Ladenson PW Kristensen JD Ridgway EC Olsson AG Carlsson B Klein I Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia N Engl J Med 2010 362 10 906 916 10.1056/NEJMoa0905633 20220185
Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med. 2010;362(10):906–16.20220185 10.1056/NEJMoa0905633
43. Bryzgalova G Effendic S Khan A Rehnmark S Barbounis P Boulet J Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141 J Steroid Biochem Mol Biol 2008 111 3–5 262 267 10.1016/j.jsbmb.2008.06.010 18621127
Bryzgalova G, Effendic S, Khan A, Rehnmark S, Barbounis P, Boulet J, et al. Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141. J Steroid Biochem Mol Biol. 2008;111(3–5):262–7.18621127 10.1016/j.jsbmb.2008.06.010
44. Shan Z Chen L Lian X Liu C Shi B Shi L Iodine status and prevalence of thyroid disorders after introduction of mandatory universal salt iodization for 16 years in China: a cross-sectional study in 10 cities Thyroid 2016 26 8 1125 1130 10.1089/thy.2015.0613 27370068
Shan Z, Chen L, Lian X, Liu C, Shi B, Shi L, et al. Iodine status and prevalence of thyroid disorders after introduction of mandatory universal salt iodization for 16 years in China: a cross-sectional study in 10 cities. Thyroid. 2016;26(8):1125–30.27370068 10.1089/thy.2015.0613
45. Wang B Song R He W Yao Q Li Q Jia X Sex differences in the associations of obesity with hypothyroidism and thyroid autoimmunity among Chinese adults Front Physiol 2018 9 1397 10.3389/fphys.2018.01397 30337885
Wang B, Song R, He W, Yao Q, Li Q, Jia X, et al. Sex differences in the associations of obesity with hypothyroidism and thyroid autoimmunity among Chinese adults. Front Physiol. 2018;9:1397.30337885 10.3389/fphys.2018.01397
46. Zhang X Li R Chen Y Dai Y Chen L Qin L The role of thyroid hormones and autoantibodies in metabolic dysfunction associated fatty liver disease: TgAb may be a potential protective factor Front Endocrinol (Lausanne) 2020 11 598836 10.3389/fendo.2020.598836 33363517
Zhang X, Li R, Chen Y, Dai Y, Chen L, Qin L, et al. The role of thyroid hormones and autoantibodies in metabolic dysfunction associated fatty liver disease: TgAb may be a potential protective factor. Front Endocrinol (Lausanne). 2020;11:598836.33363517 10.3389/fendo.2020.598836
47. Khan I Chong M Le A Mohammadi-Shemirani P Morton R Brinza C Surrogate adiposity markers and mortality JAMA Netw Open 2023 6 9 e2334836 10.1001/jamanetworkopen.2023.34836 37728925
Khan I, Chong M, Le A, Mohammadi-Shemirani P, Morton R, Brinza C, et al. Surrogate adiposity markers and mortality. JAMA Netw Open. 2023;6(9):e2334836.37728925 10.1001/jamanetworkopen.2023.34836
48. Wu Y Shi X Tang X Li Y Tong N Wang G The correlation between metabolic disorders and Tpoab/Tgab: a cross-sectional population-based study Endocr Pract 2020 26 8 869 882 10.4158/EP-2020-0008 33471678
Wu Y, Shi X, Tang X, Li Y, Tong N, Wang G, et al. The correlation between metabolic disorders and Tpoab/Tgab: a cross-sectional population-based study. Endocr Pract. 2020;26(8):869–82.33471678 10.4158/EP-2020-0008
49. Chen Y Zhu C Chen Y Wang N Li Q Han B Are Thyroid autoimmune diseases associated with cardiometabolic risks in a population with normal thyroid-stimulating hormone? Mediators Inflamm 2018 2018 1856137 10.1155/2018/1856137 30405316
Chen Y, Zhu C, Chen Y, Wang N, Li Q, Han B, et al. Are Thyroid autoimmune diseases associated with cardiometabolic risks in a population with normal thyroid-stimulating hormone? Mediators Inflamm. 2018;2018:1856137.30405316 10.1155/2018/1856137
50. Özcabı B Tarçın G Şengenç E TahmiscioğluBucak F Ercan O Bolayırlı İM Is waist-height ratio associated with thyroid antibody levels in children with obesity? J Clin Res Pediatr Endocrinol 2021 13 2 152 159 10.4274/jcrpe.galenos.2020.2020.0170 33006550
Özcabı B, Tarçın G, Şengenç E, TahmiscioğluBucak F, Ercan O, Bolayırlı İM, et al. Is waist-height ratio associated with thyroid antibody levels in children with obesity? J Clin Res Pediatr Endocrinol. 2021;13(2):152–9.33006550 10.4274/jcrpe.galenos.2020.2020.0170
51. Xie Z Sun Y Ye Y Hu D Zhang H He Z Randomized controlled trial for time-restricted eating in healthy volunteers without obesity Nat Commun 2022 13 1 1003 10.1038/s41467-022-28662-5 35194047
Xie Z, Sun Y, Ye Y, Hu D, Zhang H, He Z, et al. Randomized controlled trial for time-restricted eating in healthy volunteers without obesity. Nat Commun. 2022;13(1):1003.35194047 10.1038/s41467-022-28662-5
52 Zhang LM Liu Z Wang JQ Li RQ Ren JY Gao X Randomized controlled trial for time-restricted eating in overweight and obese young adults iScience. 2022 25 9 104870 10.1016/j.isci.2022.104870 36034217
Zhang LM, Liu Z, Wang JQ, Li RQ, Ren JY, Gao X, et al. Randomized controlled trial for time-restricted eating in overweight and obese young adults. iScience. 2022;25(9):104870.36034217 10.1016/j.isci.2022.104870
53. Moro T Tinsley G Pacelli FQ Marcolin G Bianco A Paoli A Twelve months of time-restricted eating and resistance training improves inflammatory markers and cardiometabolic risk factors Med Sci Sports Exerc 2021 53 12 2577 2585 10.1249/MSS.0000000000002738 34649266
Moro T, Tinsley G, Pacelli FQ, Marcolin G, Bianco A, Paoli A. Twelve months of time-restricted eating and resistance training improves inflammatory markers and cardiometabolic risk factors. Med Sci Sports Exerc. 2021;53(12):2577–85.34649266 10.1249/MSS.0000000000002738
54. Haganes KL Silva CP Eyjólfsdóttir SK Steen S Grindberg M Lydersen S Time-restricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: a randomized controlled trial Cell Metab 2022 34 10 1457 71.e4 10.1016/j.cmet.2022.09.003 36198292
Haganes KL, Silva CP, Eyjólfsdóttir SK, Steen S, Grindberg M, Lydersen S, et al. Time-restricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: a randomized controlled trial. Cell Metab. 2022;34(10):1457–71.e4.36198292 10.1016/j.cmet.2022.09.003
