Palmitic acid (C16:0, PA) is the principal saturated fatty acid (SFA) of palm oil (PO) (1) and is also the most common plasma fatty acid (FA) in the human body (2, 3), representing 28%–32% of the total FAs in serum (4, 5). With increasing concerns about the relationship between nutrition and human health (6), there is growing evidence demonstrating that PA is much more than an energy source. The normal PA concentration is the basic guarantee for the multiple fundamental biological functions (3), whereas the overaccumulation of PA may result in adverse effects on human health (4). Emerging studies have linked elevated PA to multiple diseases (4), including cancers (7–10), diabetes (2, 11), metabolic syndrome (5, 12), cardiovascular diseases (CVDs) (13), autoimmune diseases (14), and neurodegenerative diseases (15, 16).

As is well known, thyroid hormones play a crucial role in regulating energy metabolism and cellular function (17). On the other hand, it is widely believed that lipotoxicity may lead to chronic cellular dysfunction and injury, with the thyroid gland considered to be the victim (18, 19). In a study by Araujo et al. (20), a high-fat diet could contribute to elevated serum thyroid-stimulating hormone (TSH) levels and increased systemic oxygen consumption. Shao et al. (21) reported that, in parallel with increased TSH levels, excess dietary high-fat lard intake could also induce decreased serum-free thyroxine (FT4) and total T4 (TT4) levels, as well as abnormal morphology in rats, which might be a long-term course. In addition, lipotoxicity was also correlated with the risk of subclinical hypothyroidism (SCH) (22). Furthermore, Zhao et al. (23) indicated that PA could downregulate the expressions and activity of the key molecules of thyroid hormone synthesis, including thyroglobulin (Tg), sodium iodide symporter (NIS), and thyroperoxidase (TPO). Moreover, lipotoxicity was also reported to be a significant risk factor in predicting extrathyroidal extension (ETE) of papillary thyroid microcarcinoma (PTMC) (24).

Although the excess intake of dietary fat is closely related to adverse health events, research investigating the association between serum PA (sPA) and thyroid function remains sparse. The current study aimed to examine the cross-sectional association between PA and thyroid parameters in a nationally representative sample of adults from the United States (US) using the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2012.

The present retrospective investigation aimed to assess the relationship between sPA and thyroid function in a nationally representative sample of the population in the USA. In the 737 adult participants (age ≥18), we noted a significant association between sPA and FT4, and the FT3/FT4 ratio throughout multiple analyses. Subgroup analysis stratified by gender and BMI category indicated that the FT4 level and the FT3/FT4 ratio decreased and increased prominently in male and obese participants with higher sPA, respectively. Furthermore, interaction terms suggested that gender might influence the aforementioned associations.

In recent years, there has been an emerging focus on the effect of a high-fat diet (HFD) on human diseases, which could promote the disorders of lipid metabolism and triglyceride accumulation in non-adipose tissues (7, 35). In addition, increasing evidence has demonstrated the close relationship between lipid metabolism disorder and thyroid dysfunction, especially hypothyroidism or SCH (7, 35). In a cohort of 24,100 Chinese subjects with similar and stable iodine nutrition status, Zhao et al. (22) illustrated the significant positive association between the elevation of serum triglyceride levels and the risk for SCH. Similarly, Lai et al. (36) and Kota et al. (37) observed higher TSH levels in the participants with hypertriglyceridemia, which further suggested that the thyroid gland might be the victim of lipotoxicity. Primary thyroid hypofunction was also reported in diet-induced obese (DIO) mice, as well as the increased expression levels of the key molecules in the thyroid gland such as the TSH receptor, TPO, NIS, and Tg (38). However, in the experiments about the effect of short-term and long-term HFD feeding on obesity-prone (OP) and obesity-resistant (OR) mice, Xia et al. (39) illustrated suppressed NIS, TPO, and Tg mRNA levels in OP mice, and contradictory observations might be speculated to the upregulated TSH level (23). As shown in Table 1, this work also observed a slightly increased TSH level within the normal range in elevated ln sPA tertile; however, the statistical difference was insignificant (p = 0.081). On the other hand, the significant negative association between sPA and FT4 was considered to support the close correlation between lipotoxicity and hypothyroidism or SCH, and the hypothesis is desired in future studies.

As a representative SFA, PA has been widely applied in experiments investigating the underlying mechanisms of lipotoxicity on cellular damage (40). The present work showed that the elevated sPA level was significantly related to decreased FT4 (p < 0.001) and increased FT3/FT4 ratio (p = 0.001) after adjusting covariates, and the potential mechanism could be elucidated in some other studies. For instance, in human thyrocytes, Zhao et al. (23) demonstrated that PA could suppress NIS, TPO, and Tg mRNA levels, as well as promote intracellular lipid accumulation. Several studies have illustrated that endoplasmic reticulum (ER) stress could inhibit the expression of the three key molecules and their regulators in the thyrocytes (41, 42). In addition, ER stress was also observed in HFD rats and PA-treated thyrocytes, along with the increased degradation rate of Tg, which further indicated that the effect of ER stress on HFD-induced hypothyroidism might contribute to a decrease in the production of Tg (35).

As demonstrated in Tables 1, 3, the subjects with elevated sPA level were more likely to have larger BMI and waist circumference, and the relationship between sPA and thyroid dysfunction was more significant in obese and male participants; several investigations might provide some implications to the underlying mechanism. As is well known, obesity results from an imbalance between caloric intake and caloric expenditure (43), and thyroid hormones (THs) play a pivotal role in modulating the energy balance, appetite, basal metabolic rate (BMR), and lipid metabolism (44). Changes in THs in obese subjects have been reported in various epidemiological studies, and Walczak et al. (44) further observe that obesity through lipotoxicity may lead to thyroid dysfunction and promote the development of SCH. Moreover, in the contralateral lobe of thyroid tissue derived from patients with PTMC, Lee et al. (38) observed the expansion of interfollicular adipose (IFA) depot and steatosis in thyroid follicular cells (thyroid steatosis, TS) in the majority of obese patients (BMI ≥25.0 kg/m²). Furthermore, SCH and morphological changes in the thyroid tissue were also documented in the male obese mice, which could not be remitted by peroxisome proliferator-activated receptor γ (PPARγ) agonist administration (38).

The findings of the present work should be interpreted cautiously because of some limitations. First, for the cross-sectional design of NHANES, the causal relationships between sPA and thyroid parameters could not be established. Hence, a cohort study with long observation periods and a larger sample size is desired in the future study. Second, the information on medical history, SES, marital status, tobacco consumption, and alcohol use was self-reported data obtained from questionnaires; thus, recall bias and several other errors could not be ruled out. Subsequently, we excluded children and pregnant participants on account of the uncertain influence on thyroid function, and further research is needed on these populations.

In conclusion, we demonstrated the significant negative and positive relationship between sPA and FT4, and the FT3/FT4 ratio, respectively, in a representative population in the US. These results did not change on multiple imputations. In the subgroup analyses, the aforementioned associations were more remarkable in male and obese subjects. Our findings supported the close relationship between lipotoxicity and hypothyroidism or SCH, and further studies are needed to confirm this deduction. In addition, further studies are needed to verify the causal association between PA and thyroid function.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

This work was supported by grants from the Natural Science Foundation of Jiangsu Province (BK20181506) and Project of Jiangsu Province Hospital of Chinese Medicine (Y21024).

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

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