Authors: Patrícia de Fátima dos Santos Teixeira, Patrícia Borges dos Santos, Carmen Cabanelas Pazos-Moura
Categories: Obesity Complications: Challenges and Clinical Impact, blood pressure, hyperthyroidism, hypothyroidism, insulin resistance, lipids, obesity, thyrotropin
Source: Therapeutic Advances in Endocrinology and Metabolism
Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.
Keywords: blood pressure, hyperthyroidism, hypothyroidism, insulin resistance, lipids, obesity, thyrotropin
Patients with both thyroid dysfunction and metabolic syndrome (MetS) are frequently observed in clinical practice. It is estimated that more than 20% of adult people fulfill criteria for MetS in different population studies.^1–4^
MetS is most often associated with obesity and consists of different metabolic risk factors that are associated with higher risk for cardiovascular disease, type 2 diabetes, and mortality.^2–4^ In clinical practice, there are different criteria to define MetS, but the two most common adopted for its diagnosis are based mainly on four main characteristics, as shown in Table 1.^2–4^ The two criteria are those recommended by the IDF (International Diabetes Federation) and by the National Cholesterol Education Program (NCEPT)–Adult Treatment Panel III (ATPIII; NCEPT–ATPIII).^2–4^ The four features present in both criteria are also usually reported in other defining criteria, irrespective of the adopted standard recommendations.^2–4^ Those four major components of MetS consist of different physiological (a) body adiposity, especially central adiposity measured by waist circumference; (b) serum glucose levels that reflect diabetes diagnosis or the risk for its development; (c) lipid abnormalities related to metabolic risk [high serum triglycerides or low, high-density lipoprotein cholesterol (HDL-c)]; and (d) increased blood pressure (BP) levels. The presence of three or more abnormalities, concerning any of the described elements, is needed to define MetS. Additionally, some authors define MetS by the presence of abnormal serum levels of insulin or markers of insulin resistance (IR).^2–4^
At the same time, the prevalence of hypothyroidism in different population surveys has been reported to be just around 8–15%.^5–7^ Additionally, this prevalence increases with age, reaching almost 20% of elderly subjects.^7^ The interest in studying possible associations between these two common disorders has increased. The knowledge that MetS may not necessarily be a consequence of thyroid dysfunction but also that thyroid dysfunction may arise from the effects of MetS has gained attention.^8–14^ Sectional studies have shown that the overlap between both diagnoses is common, justifying a high association between them, as shown in Table 2.^14,15–105^ However, as highly prevalent entities, the cause–consequence effect may not be established in these types of studies. We also observed that some studies applied a predefined criterion to establish the presence or absence of MetS and its associations with thyroid function,^14,16,19,20,24–26,29,30,33,34,38,42,45,47–49,52,54,55,57,62,66–68,73,75–77,79,82,84,92–94,96–98,100–103,106,108^ but the majority just evaluated the presence of one or more specific features related to MetS and not necessarily its diagnosis.
Cohort studies also do not seem to be capable of showing that a unidirectional pathway justifies this association,^17,18,28,34,68,74,76,82,95,99,106–117^ and the hypotheses that both thyroid dysfunction leads to MetS and that this condition also influences thyroid function has gained credibility.^9–13^ THs, and also some of their metabolites, regulate metabolic rate, leading to variations in weight gain and adiposity.^9–11,13^ Additionally, THs also act on central regulation of appetite control and sympathetic activity. In the opposite direction, thyroid function is affected by adiposity, with leptin having important modulatory effects.^9–11,13^ Also, pro-inflammatory cytokines related to obesity and IR may impact thyroid function and perhaps its structure.^9,11–13^ Table 3 summarizes the results of longitudinal studies done over the past decade regarding the association between thyroid function and MetS diagnosis, or even different MetS components. For this purpose, we did not include a detailed analysis of studies focusing on the effect of bariatric surgery on thyroid, even though a recent meta-analysis found that patients who underwent bariatric surgery exhibited a reduction of TSH, free triidothyronine (FT3) and triidothyronine (T3) levels after surgery.^12^
In this review, we will discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS development, and not solely focus on the diagnosis of its complete presentation but also the way in which TH may influence each one of the four main features (or components) of this important syndrome. The consequences of augmenting adiposity, which is a highly prevalent marker of MetS, may also interfere with thyroid function will also be described. Finally, a list of recent studies enrolling humans and intending to evaluate possible associations between thyroid function and MetS will be present. For this purpose, we will focus on research excluding specific populations, like pediatric or elderly subjects, and also patients with other diagnoses, such as polycystic ovary syndrome. Additionally, we do not intend to review data on patients that underwent bariatric surgery.
THs act on several target peripheral tissues via several mechanisms. Briefly, thyroxine (T4), which is the main product of the thyroid gland, is converted to the active hormone, T3, an enzymatic reaction catalyzed by type 1 (D1) or type 2 5′deiodinases (D2). T4 and T3 can be inactivated by type 3 5-deiodinase (D3). T4 and T3 enter cells through specific membrane transporters, and T3, originating from the circulation or from intracellular conversion of T4 to T3, binds to TH receptors, subtypes 1, β1 or β2, located at the nucleus to regulate the transcriptional activity of target genes.^118^ This is the canonical pathway; however, recently, other non-classical pathways have been reported. TH actions may be mediated by cytoplasmic or mitochondrial TH receptors (TR), or through binding to unspecific membrane proteins that activate intracellular signaling cascades.^118–121^ These non-canonical signaling pathways have been reported to be especially important to the cardiometabolic effects of thyroid hormones.^121^ In that elegant study, the authors employed genetically manipulated mice to differentiate between T3 effects mediated by the canonical and non-canonical pathways. They showed that the acute hypoglycemic effect of T3 is dependent on TRβ but does not require deoxyribonucleic acid binding. Its action involves activation of the phosphatidylinositol 3-kinase (PI3K) signaling cascade. The same non-canonical signaling pathway is involved in a T3-lowering effect in serum and hepatic triglycerides. In addition, T3 actions in metabolic rate and energy expenditure, as well as in the exogenous control of heart rate have important contributions of the non-canonical signaling pathways.^121^
It is also important to mention that tissue responsiveness to TH may vary with age and sex, which may be related to tissue-specific alterations in T4 to T3 conversion.^122–124^ The interplay between age and sex are particularly interesting in TH-induced changes in body weight and energy expenditure in mice, with sex modifying the response of TH differently in old males compared with old females.^122–124^
TH may be involved in each one of the four major components of MetS via several mechanisms. This involvement is not necessarily unidirectional, since target tissues of TH may also be involved with thyroid function. TH actions lead to specific effects that influence endpoints regarding body adiposity, glucose or lipid levels, and BP.^11,120,125–127^ In this way, all four features of MetS may be influenced by TH levels as separately described in specific following sections.
In summary, adiposity may be the consequence of the role of THs (or its metabolites) on the regulation of metabolic rate, appetite control or even sympathetic activity.^9,11,13^ This sympathetic stimulus by THs also influences glucose and lipid metabolism as it impacts cardiovascular system regulation.^9,11–13^ Hyperglycemia may be the consequence of reduced glucose uptake in hypothyroidism or the consequence of increased glucose liver production in hyperthyroidism.^128^ Glucose-stimulated insulin secretion and insulin degradation are also regulated by THs.^128^ Dyslipidemia may be related to thyroid function, since THs also act stimulating both lipid synthesis and degradation.^129^ Finally, high BP (HBP) may be the consequence of TH action on the vasculature and in the heart by TR-mediated gene regulation at the nucleus or via other non-classical pathways at the cytoplasmatic and cellular membrane levels.^130^
However, it is notable that the augmentation in adiposity, especially central adiposity, which is one of the hallmarks of MetS, appears to generate an increase in several hormones, cytokines, and other compounds that influence thyroid function via different pathways.^131,132^ The proposed mechanisms involved in these actions will be summarized in the next sections.
Adiposity gain or loss depends primarily on the balance between energy expenditure (EE) and energy intake (EI). Resting EE (REE) is solely used in the cellular process to maintain life.^133^ EE can be stimulated by physical activity or acceleration of different metabolic processes, resulting in heat production (facultative thermogenesis).^134^ The balance between EE and EI depends mainly on satiety control, sympathetic nervous system (SNS) activity, and the endocrine system. THs are strong regulators of the metabolic rate with consequent effects on different outcomes, including adiposity.^135^ However, as previously described, the relationship between TH and adiposity is bidirectional, since TH and also thyroid-stimulating hormone (TSH) levels have effects on adiposity, which in turn may act on thyroid function and perhaps on the structure of this gland.^136,137^ Adiposity leads to production of several hormones, cytokines, and other compounds that influence thyroid function, as described in the next sections.
THs, especially T3 produced by enzymatic reaction catalyzed by type 1 (D1) or type 2 5′deiodinases (D2), are enrolled in controlling metabolic rate by several mechanisms, as explained in the following sections of this manuscript. In summary, they exert direct effects on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis and have inotropic and chronotropic effects on body. THs also act controlling core body temperature, appetite, and sympathetic activity. Additionally to T4 and T3, other TH metabolites exert similar effects.^138,139^ It has been demonstrated that 3,5 diiodo-L-thyronine (T2) prevents high-fat-diet-induced adiposity by means of increasing EE and promoting anti-adipogenic and anti-lipogenic pathways in white adipose tissue (WAT).^138,139^ Also, studies have demonstrated that decarboxylated TH molecules, termed thyronamines, when given to animals, lead to metabolic effects that generally oppose the direction of T3. Thyronamines are primarily produced in the thyroid, but there is evidence that they may be produced in other tissues.^139–141^ The physiological and clinical relevance of TH metabolites is under intense investigation.^139–141^
The thermogenic effects of TH, especially T3, are well known, and hyperthyroid patients have an increase in heat production and are heat intolerant. Hyperthyroid patients are opposite to hypothyroid patients, who produce less heat and are cold intolerant.^142^ After thyroid hormone administration there is an increase in oxygen consumption in most tissues.^142^ THs cause a direct increase in adenosine triphosphate (ATP) utilization leading to acceleration of anabolic and catabolic pathways in the macronutrient metabolism, such as lipolysis/fatty-acid oxidation and increased protein turnover.^143^ In addition, THs stimulate the sodium/potassium (Na^+^/K^+^) ATPase and the sarco/endoplasmic reticulum Ca^2+^ ATPase (SERCA) that mediate ion transport through membranes, processes that require ATP utilization, leading to increasing of it consumption and contributing to thermogenesis.^144^ Therefore, thyroid hormone increased the utilization of energy reserves, such as lipids from the adipose tissue.
Another mechanism by which TH may increase the REE is related to the hormones’ inotropic and chronotropic effects, exerted in conjunction with the SNS, since it is well known that part of REE is related to cardiac function.^145^
TH actions at the mitochondria are very important in thermogenesis. In addition to promoting mitochondrial biogenesis, THs act to uncouple the synthesis of ATP from heat production in the mitochondria.^142^ This uncoupling is mediated by their action on mitochondrial uncoupling proteins (UCP) that lead to non-shivering thermogenesis via conversion of chemical energy to heat without an increase in ATP production. The presence of this mechanism, in which promoting uncoupling phosphorylation in brown adipose tissue (BAT) is promoted, is one of the markers of evolutionary process of mammals; however, for many years it was thought that BAT was not present in adults. Nevertheless, in the past decade, the presence of active BAT in adult humans has been demonstrated and its amounts are inversely associated with body weight and serum glucose levels.^146,147–152^ The action of TH in this tissue gains attention as additional mechanisms enrolled in MetS.
In BAT, type 1 UCP (UCP1) is the hallmark of thermogenesis. This UCP expression is stimulated by T3, which is locally generated from T4 by intracellular D2. This D2 is positively regulated by beta-adrenergic activity.^152^ THs cause an upregulation of adrenergic receptor expression, leading to an amplified effect on UCP1 expression, which is also activated by the SNS.^152^ Studies have shown that D2 is very important to TH-induced adaptive type of thermogenesis in BAT.^152^ D2 also responds to other thermogenic inductors, as highlighted by a recent study showing that the adipokine, adipocyte fatty-acid-binding protein (A-FABP), requires BAT D2 activity to exert its thermogenic effects.^153^
Another postulated effect of THs in BAT is the stimulation of WAT ‘browning,’ which consists of the acquisition of brown-fat characteristics by a certain group of WAT cells, termed beige cells.^154^ Although it would be an attractive tool in obesity treatment, evidence in humans is still scarce,^152^ and a recent experimental study does not support that TH-induced browning is accompanied by an increase in thermogenesis.^155^ TH also stimulates the expression of other UCPs, such as UCP2 and 3, and the latter is very important to thermogenesis and fatty oxidation in muscle.^156^
In addition to acting on peripheral tissues, THs also have relevant modulatory actions in the central nervous system with respect to core body temperature, satiety control, and activity of the SNS.^157^ The action of T3 on the hypothalamus, more specifically on the ventromedial hypothalamus (VMH), stimulates the SNS that not only stimulates TH production but also acts in combination with THs in those same peripheral tissues that affect the MetS components.^125–127^
Central T3 administration results in increased body temperature, concomitant with reduction of levels of hypothalamic AMP-activated protein kinase (AMPK), increased tone in the sympathetic nerves innervating BAT.^158,159^ Hypothalamic AMPK and fatty-acid metabolism mediate thyroid regulation of energy balance.^158–160^ Those responses involve UCP1, since they were abrogated in UCP1 knockout mice.^161^
Hyperthyroid individuals frequently have hyperphagia even in the presence of weight lost,^157^ which is related in great part to the direct effect of THs on appetite stimulation. In the hypothalamic nucleus arcuate, T3, produced locally by D2, increases the expression of the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP), and decreases the anorexigenic peptide, pro-opiomelanocortin (POMC),^160^ and the reverse events occur in hypothyroid rats.^162^ Acting at the VMH, T3, in low doses, was shown to induce an increase in food intake and potently stimulate the sympathetic activity and BAT thermogenesis.^126,163,164^ In contrast, Hameed and colleagues demonstrated that ablation of the β isoform of the TR only at the VMH of adult rats led to increase in AgRP/NPY and reduction in POMC pathways, with a concurrent augmentation in food intake and weight gain.^165^ This effect was not observed when both isoforms of TR had downregulated functions in the VMH.^160^ Therefore, not only the availability of T3, but also the specific TR isoform, determines the final effect of THs in control of hypothalamic circuits controlling energy homeostasis.
The action of TH in the regulation of EE may be indirect via controlling the action with or without expression of other circulating or local factors. Recently, it has been reported that irisin, a hormone produced in striate muscle after exercise,^166^ induces browning of WAT and shows a possible relation with thyroid function.^167^ However, human studies present conflicting results regarding the association between thyroid function and irisin levels, with some studies demonstrating higher levels in hyperthyroidism^168,169^ and low levels in hypothyroid patients.^170–172^ However, these results were not confirmed in all studies.^173–175^
Altered thyroid function can modify circulating levels of fibroblast growth factor 21 (FGF21), fetuin A, and neuregulin 4 (NgL-4), among others, which modulate EE.^27,48^ NgL-4 is an epidermal growth factor (EGF) family member that is secreted by BAT and promotes augmentation in EE, inhibition of hepatic lipogenesis, and reduction of fat-mass storage.^176^ A study with 129 hyperthyroid patients demonstrated that they had higher levels of NgL-4 than controls, which showed a reduction in these levels after restoring euthyroidism with treatment.^177^ Studies evaluating possible opposite effects, leading to reduction of NgL-4 in hypothyroidism, are still lacking.
In addition to TH, TSH has been shown to act directly in adipose tissue that expresses TSH receptors. In differentiated human adipocytes, TSH induces lipolysis and inhibits insulin signaling through protein kinase B (Akt) phosphorylation,^178^ which might contribute to IR. However, Ma and coworkers showed that TSH appears to stimulate adipocyte differentiation and lipogenesis in the pre-adipocyte cell lineage 3T3-L1 through a mechanism involving peroxisome-proliferated-activator–receptor (PPAR) gamma.^179^ In agreement with a role of TSH as an adipogenic factor, mice that did not express the TSH receptor and were under TH supplementation, exhibited resistance to high-fat-diet-induced obesity.^179^
Leptin is a hormone produced by adipose tissue in direct proportion to the quantity of adipose tissue mass. Leptin acts mainly at hypothalamic neurons to induce satiety and increase EE. Patients with genetic mutations in the leptin gene or leptin receptor are obese, and chronic reposition of leptin caused normalization of their body weight. However, most obese patients have hyperleptinemia but are resistant to the anorexigenic central action of leptin.^180,181^
In addition, leptin was shown to regulate the production of neurohormones in the medio-basal hypothalamus, among them, thyrotropin-releasing hormone (TRH) neurons of the periventricular nucleus.^181,182^ In another study, leptin activated TRH neurons both directly and indirectly, acting through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway.^182,183^ The increase in TRH release was shown to lead to higher pituitary secretion of TSH,^182–184^ which in turn, stimulates thyroid function and proliferation.
Besides acting as a stimulatory agent for TRH secretion, the overall response of the thyroid axis to leptin is controversial among species and depends on nutritional status.^185^ Both rodents and humans subject to fasting show suppression of TH function, with concomitant decreases in serum levels of leptin, and replacement of leptin partially restored normal concentrations of thyroid hormones.^186–189^ Therefore, during caloric deprivation, the reduction in leptin seems to contribute to an integrated response to fasting, including thyroid-function suppression. However, in conditions with hyperleptinemia or at physiological levels, the role of leptin in thyroid function is less clear and may also reflect other leptin actions in the pituitary, thyroid, and peripheral tissues. Leptin receptors have been found in the anterior pituitary and thyroid gland, and direct inhibitory actions on TSH secretion and on the expressions of the Na^+^/I^–^ symporter (NIS) and thyroglobulin messenger ribonucleic acid (mRNA) in thyroid cell lines have been reported.^184,190^ Additionally, there is experimental evidence from rodent studies that thyroid hormone metabolism may be modulated by leptin. Exogenous leptin administration caused an increase in D1 activity in the liver and pituitary, while causing a reduction in D2 activity at the hypothalamus and in BAT. Therefore, leptin may modulate thyroid hormone actions in target tissues, but collectively, these studies indicate that nutritional status and thyroid state clearly modify the responses to leptin.^191–194^
Another postulated mechanism of the way in which obesity is related to thyroid disfunction concerns chronic low-grade inflammation in adipose tissue that secretes cytokines and may affect thyroid function. It has been demonstrated that tumor necrosis factor alpha (TNF-α) and interleukins 1 and 6 (IL-1 and -6) inhibit the mRNA expression of the NIS.^195^ Additionally, pro-inflammatory cytokines have been associated with inhibition of D1 in HepG2 hepatocarcinoma cells^196^ and induction of D3,^197^ resulting in a decrease in serum T3, one feature of the low T3 syndrome associated with chronic diseases.^198^
Finally, IR, in conjunction with leptin levels, appears to be related to obesity and leads to augmentation of serum TSH levels.^199,200^ Recent studies give support to this hypothesis, showing that metformin, a drug used to improve insulin sensitivity, may cause a reduction in serum TSH levels.^201,202^ Different mechanisms have been proposed and the activation of the AMP-activated protein kinase (AMPK) pathway may be enrolled.^158,159,203,204^
Hypothyroidism is associated with peripheral IR due to a reduction in glucose uptake, and on the other hand, hyperthyroidism increases glycemia due to an increase in liver production.^205–207^ T3 acts directly on the liver through TRβ, regulating genes involved in hepatic gluconeogenesis, glycogen metabolism, and insulin signaling.^205,206^ In addition, TH also acts centrally on the hypothalamus to increase sympathetic flow to the liver.^126^ As a consequence, in the liver, there is a decrease in glycogen synthesis and increase in gluconeogenesis and glucogenolysis,^126,207^ leading to an increase in glucose output.^208^ T3 increases the translocation of the glucose transport 4 (GLUT 4) to the plasma membrane in skeletal muscle and adipose tissue, which is associated with better glucose tolerance.^208–215^ T2 administration has also been associated with better glucose tolerance in animal models. It induces inhibition of hepatic gluconeogenesis gene expression^216–218^ by means of modulation of microRNA,^217^ and regulation of the activity of the protein kinase mammalian target of rapamycin complexes 1 (mTORC1) and 2 (mTORC2).^218^
Although THs play a role in islet trophic state maintenance,^219^ hyperthyroidism impairs glucose-stimulated insulin secretion and accelerates insulin degradation.^220^ In the insulin-producing cell line, INS-1 cells, at high concentrations, T3 induced B-cell apoptosis and death.^221^ Also, T2, at high concentrations, is able to decrease the glucose-induced insulin secretion, even though both T2 and T3 have a stimulatory effect at low concentrations.^222^ The importance of maintaining low levels of T3 in pancreatic β cells was shown in mice with specific β-cell pancreatic deletion of D3 that showed a decrease in pancreatic islet area, insulin-gene expression, and glucose-stimulated insulin secretion, even though the mice were euthyroid.^223^
The lipid abnormalities related to MetS are hypertriglyceridemia and low serum HDL-c levels. These abnormalities will be the focus of the present revision despite a high number of studies evaluating several other alterations in lipid profile associated with thyroid function.^224,225^
THs have effects throughout the whole body, stimulating both lipid synthesis and degradation, but in the hyperthyroid condition, there is a predominant increase in lipolysis from fat stores.^142^ In the liver, THs stimulate the re-esterification of free fatty acids into triacylglycerol and also induce de novo lipogenesis from glucose metabolism.^226^ However, THs also concurrently stimulate fatty-acid oxidation, and, under physiological conditions, the result is a balance that does not increase hepatic triacylglycerol levels.^226^ The mechanisms of TH action involve direct regulation of the transcription rate of specific lipogenic/oxidative genes, in addition to alterations in the concentrations of metabolites, energy state of the cells, and post-translational modifications of proteins involved in the liver lipid metabolism.^117,226^
TH increases cholesterol clearance because even though they stimulate endogenous cholesterol synthesis, they potently increase hepatic cholesterol uptake and excretion as bile acids.^227^ Low-density lipoprotein (LDL)-c accumulates in the serum of hypothyroid patients since the LDL-receptor and the sterol regulatory element-binding protein 2 (SREBP2) are under-expressed in hypothyroidism. LDL-receptors mediate liver uptake of cholesterol that comes from peripheral tissues. SREBP2 is a key transcription factor that induces the expression of lipogenic-related genes, including Ldlr.^227^ Levels of very-low-density lipoprotein (VLDL) in the liver and in serum are influenced by lipoprotein lipases that are up-regulated by thyroid hormones, a mechanism that may contribute to the high serum triglycerides in hypothyroidism.^228^ In addition, ApoB100 levels are reduced by THs contributing to the increase in VLDL and LDL production observed in the liver during hypothyroidism.^229^
An increase in serum HDL-c has been reported in hypothyroid patients; this finding appears to be related to a decrease in activity of the cholesterol ester transfer protein (CEPT).^228^ CEPT, which is positively regulated by THs, mediates the exchange of cholesteryl-ester between HDL-c and VLDL and also has a pro-atherogenic role. Higher expression of CEPT would lead to higher cardiovascular risk, related to augmentation of serum levels of VLDL and reduction of HDL-c. However, as serum levels of HLD-c are also influenced by several other mechanisms, and are reduced in states of IR and obesity, there are disagreements with respect to the results of human studies regarding thyroid function and serum HDL-c, as shown in Table 2. HDL-c levels in hypothyroid patients might also be reduced when obesity diagnosis is present with marked reduction of insulin sensitivity or MetS.
Additionally, administration of T2 in rodents has hypolipemic action, affecting the hepatic lipid metabolism.^129^ It has been demonstrated that T2 is able to increase hepatic lipid oxidation and contrary to T3, does not stimulate the lipogenic pathway in animals fed a high-fat diet,^230^ which potentially contributes to the important effect reported in avoiding lipid accumulation in the liver of those animals. Despite the evidence in rodents, the physiological role of T2 in human metabolism, and potential therapeutic use, need further clarification.^231,232^ Serum levels of 3,5-T2 have been associated with several clinical conditions, like impaired renal function, sepsis, and oral LT4 (levothyroxine) supplementation;^232^ however, further studies are necessary to evaluate causative effects between the found associations. These studies may benefit from a recently developed method to measure 3,5-T2 in human serum by mass spectrometry, which, interestingly, showed correlation with T2 isomer 3,3'-T2, but not with serum T3 or T4.^233^ Likewise, other methods to measure 3,5-T2 by mass spectrometry have been tested.^234–236^
THs act on the vasculature and in the heart by TR-mediated gene regulation in the nucleus and also via other non-classical pathways at the cytoplasmatic and cellular membrane levels.^130,237^
In myocytes, and also in vasculature, THs, especially T3 with greater affinity, bind to TH nuclear receptors in its two isoforms, TRα and TRβ. Thereafter, the complex formed by TH response elements at the promoter regions of specific responsive genes lead to positive or negative regulation of several genes enrolled in cardiac function and vascular resistance. The sarcoplasmic reticulum calcium ATPase (SERCA2), the myosine-have chains-α (αMHC), the Na^+^/K^+^ ATPase, the voltage-gated K^+^ channels, the adenine nucleotide translocase (ANT1) and the β-adrenergic receptor are positively regulated by THs. In opposite, the myosine-have chains-β (βMHC), the phospholamban, the Na^+^/Ca^2+^ exchanger (NCX1), the TRα1, adenylyl cyclase (types V, VI) and TH transporters 8 and 10 are negatively regulated by THs.^130,237^
Additionally to genomic effects of TH on cardiac myocytes, and also on vasculature, there are important and faster non-genomic actions, like those related to direct modulation of membrane ion channels.^130^
THs have important inotropic and chronotropic effects on the heart and concomitantly, they cause vasodilatation in the systemic circulation, leading to a decrease in systemic vascular resistance. Hyperthyroid patients exhibit tachycardia, increased heart contractility, and decreased cardiac after-load, resulting in increased cardiac output, which leads to systolic hypertension. Hypothyroid patients may exhibit diastolic hypertension, associated with impaired endothelial-dependent vasodilatation.^238^ Alterations in the microcirculation of hypothyroid patients have also been reported, such as a decrease in blood-flow velocity and impaired vasodilation after a short period of ischemia.^239^ The mechanism involves TH stimulation of nitric oxide production and regulation of other local regulatory factors, resulting in a decrease in vascular smooth muscular tone.^239–242^
In addition, TH actions in the central nervous system have an influence on autonomic regulation of BP. Recently, a group of parvalbuminergic neurons at the anterior hypothalamus, which act to decrease BP, was described, and their development appears to be dependent on TRα signaling.^243^ This finding may explain the hypotension present in patients with TRα mutations.^244^ Different from peripheral systemic vasculature, the pulmonary vasculature does not respond to the vasodilator effect of TH and may explain reversible pulmonary hypertension related to hyperthyroidism.^245^
Table 2 summarizes the results of different cross-sectional studies of the association between MetS and thyroid function that have been published in the last decade through July 2019. We excluded studies focusing on pediatric patients, elderly patients, and patients with a secondary diagnosis, such as polycystic ovary syndrome. Different criteria for defining MetS were adopted for these studies. However, the NCEPT/ATPIII was the most commonly applied criteria for diagnosis.^14,16,19,25,26,38,48,54,68,69,73,77,92,94,97,98,102^ Other authors used the IDF criteria,^42,47,55,56,75,81,93^ the World Health Organization or American Heart Association criteria,^45,62,79^ or even local/regional or pre-established criteria defined by a joint interim statement.^29,45,52,76,96^ Finally, some studies defined MetS by the presence of IR according to an abnormal Homeostatic Model Assessment of Insulin Resistance index (HOMA-IR) or euglycemic clamp result.^24,49,57,71,82,84,96,100^ As previously reported, not all studies evaluated the MetS diagnosis. However, the number of MetS components, or the presence of one or more of its features, were considered in many of the studies.
Almost all studies evaluated thyroid function through the assessment of serum TSH. Some studies combined assessments of serum TSH levels with the measurement of FT4. Serum FT3 or total T3 were also evaluated in some studies.^15,16,22,27,33,35–38,45–47,49,54,57,60,73,74,77–79,81,82,85,86,89,93,96,101,105–110^
When there was an observed association between serum TSH and the diagnosis of MetS, this association was commonly related to higher TSH levels.^19,25,29,30,42,55,67,71,76,79,91,92,98,100,102,105^ In some instances, it was detected among euthyroid subjects even in the presence of normal TSH levels.^19,29,30,42,55,71,79,102^ The association between serum FT4 and MetS diagnosis was not always found. However, when this association occurred, it was reported as positive (with higher serum FT4 levels) in some studies,^38,53,102^ while negative in others.^24,54,95^ Higher levels of serum FT3 related to MetS were also detected in some studies.^38,82,96,105^
As previously reported, obesity is commonly associated with high serum TSH level and with increment of deiodinases’ activities, converting T4 to T3. Thus, this hormonal profile (high TSH and FT3 levels and low serum FT4, even in its respective reference ranges) might be associated with MetS via mechanisms previously described that mediate the interaction between thyroid function and clinical components of metabolic syndrome.
As demonstrated in Table 2, glycemia or glycosylated hemoglobin might be positively^37,46,62,75,93,94,100,153^ or negatively^33,66,76^ associated with serum TSH levels. A positive association between TSH levels (or reduced thyroid function) and abnormal glucose metabolism may be related to the importance of the action of TH in different pathways related to glucose transport, especially those related to the expression of GLUT 4, as previously described. This hypothesis is supported by longitudinal studies that found a higher risk for diabetes mellitus (DM) development in patients with low thyroid function or higher levels of serum TSH.^34,115^
In fact, a positive association between fasting plasmatic insulin or HOMA-IR index and TSH levels has been described in some cross-sectional studies,^16,24,25,59,66,70,82,84,94,100^ which was confirmed in a cohort analysis of 5998 subjects.^34^ However, the increase in serum TSH levels may be an effect of weight gain based on several previously described mechanisms. Consequently, it may be solely a biomarker for MetS and not necessarily a causative effect of the studied endpoints related to MetS. Since patients diagnosed with MetS concomitant with IR may demonstrate lower levels of serum FT4 due to conversion of FT4 to T3, the absence of a correlation between glycemia or HOMA-IR and FT4 has been observed in a large number of studies, especially those examining euthyroid subjects (Table 2).
The adverse effects of glucose metabolism are not only associated with the reduction of thyroid function or higher serum TSH levels in humans, but the adverse effects are also associated with higher serum TH levels. Longitudinal studies found a higher risk for DM development correlated with higher levels of serum FT4.^82,110,114^ In fact, overt and subclinical (SC) hyperthyroidism were associated with fasting glycemia or abnormal glucose metabolism in different studies.^27,59,76,114^ However, the association between serum FT4 levels in the upper reference range and serum glucose was not consistently observed in all human studies (Table 2). Finally, a cohort analysis involving 38,200 individuals revealed a higher risk for DM development in patients with either hypothyroidism or hyperthyroidism. It seems reasonable to attribute a U-shaped pattern of risk to THs and glucose metabolism abnormalities.
Despite the lack of a consistent association between THs and HDL-c levels, a reduction in thyroid function and consequently, elevation of serum TSH levels, were shown to be associated with higher levels of serum TG in almost all human studies (Table 2). It is important to remember that a possible elevation of serum TSH levels as a consequence of obesity may be caused by both hormonal and metabolic abnormalities related to weight gain. Attributing this increase in serum TSH levels merely to reduced primary thyroid function may underestimate the effects of weight gain on thyroid function and overestimate hypothyroidism diagnostics, leading to possible overtreatment of conditions that should be first addressed by dietary modifications.
Not all human studies have demonstrated a correlation between TH levels and BP. However, a positive association between FT4 levels (even those levels in the reference range) and BP has been reported.^20,22,34,38,63,76,98^ However, the opposite results have also been found.^26^ Furthermore, associations between SC hypothyroidism^58,89,90,100^ or SC hyperthyroidism^97^ and higher BP have also been reported in some studies (Table 2).
Some longitudinal studies (Table 3) have shown that weight reduction is associated with lowering levels of serum TSH and FT3.^28^ Similarly, MetS development^34,95,113^ and weight gain^74,116^ have been found to be positively associated with TSH-level changes. However, these results have not been validated in other studies.^17,67,69,110^ Some researches only found this positive association for MetS development and not for changes in body mass index.^34,113^
The interaction between thyroid hormone levels and all components of MetS is complex. The potential role of T2 and novel factors, like irisin, FGF21, fetuin A and NgL-4, have been identified in recent studies that contribute to this multifaceted interaction. Researchers of human studies evaluating this association need to consider all confounding variables. Of note, longitudinal studies controlling each of those potential variables are still needed in order to assess this intriguing association, with special attention to age-, sex- and tissue-specific effects of THs.
Patrícia de Fátima dos Santos Teixeira, Endocrine Clinic, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Rocco, 255 – Cidade Universitária, Rio de Janeiro, RJ 21941-617, Brazil.
Patrícia Borges dos Santos, Research Fellow, Medicine School, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; Endocrinologist, Instituto Estadual de Endocrinologia Luiz Capriglione, Rio de Janeiro, Brazil.
Carmen Cabanelas Pazos-Moura, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro-Brazil.