The Interconnections Between Obesity,Thyroid Function,and Autoimmunity: The Multifold Role of Leptin

Abstract

Background:

There is increasing evidence that changes in thyroid function are associated with obesity, a condition associated with a chronic low-grade state of inflammation. Meanwhile, recent data have disclosed a relation between obesity and thyroid autoimmunity, with the adipocyte hormone leptin appearing to be the key factor linking these two conditions.

Summary:

Leptin has variably been implicated in thyroid function, while recent findings suggest that leptin resistance may mitigate leptin deficiency and enhance autoimmunity in obese subjects via mechanisms operating independently of thyroid function. The development of resistance to the weight-lowering effects of leptin in obesity might well be initiated by activation of inflammatory signaling, which substantially contributes to the derangement of immune response and propagation of autoimmunity in susceptible individuals.

Conclusions:

Regulation of inflammasome-derived cytokines in obesity is an important step in controlling the trigger of thyroid autoimmunity. The clarification of the pathways may offer innovative therapeutic targets in obesity and thyroid autoimmunity.

Introduction

T he term “homeostasis,” formed of the Greek words “homeos” (“similar”) and “stasis” (“stability”), defines an internal condition of relative equilibrium despite changes in the external environment. In complex biological systems, thyroid hormone is of cardinal importance for the maintenance of certain aspects of homeostasis, including stable core temperature, metabolic adaptation in response to variable caloric intake, and various functions of the immune system. With regard to the last, autoimmunity is well established as being a leading cause of morbidity, particularly when it involves the thyroid, where it is the major cause of hypothyroidism and hyperthyroidism, Hashimoto's thyroiditis, and Graves' disease, respectively.

Obesity (defined as a body mass index [BMI] ≥30 kg/m²) results both from the interplay of genetics, which today may be responsible for >60% of BMI increases, as well as from lifestyle choices and environmental factors (1). Exogenous obesity is an increasingly common public health problem, capable of inducing particularly serious consequences, as it aggravates arterial hypertension, dyslipidemia, cardiovascular disease, and type 2 diabetes mellitus, and even heightens the risk of cancer (2 –4). Notably, a pooling of the results of 19 prospective studies including 1.46 million white adults led to the conclusion that any BMI above 24.9 kg/m² is increasingly associated with all-cause mortality (5). It thus appears set to cause increasing mortality in the coming years, either directly or indirectly.

Meanwhile, the prevalence of thyroid disease, including thyroid autoimmunity and thyroid cancer (TC), is also on the rise worldwide. In this context, the multiple associations that are coming to light between the underlying factors and pathophysiology of both thyroid disease and obesity, today present a potential for enhanced clinical management and therapeutic intervention for these afflictions (6,7).

With regard to TC, a recent analysis of two case–control studies from New Caledonia and French Polynesia established an association between increased BMI and TC (8). However, TC in this analysis was related to various anthropometric characteristics, including obesity, indicating the necessity to identify anthropomorphic features when studying metabolic perturbations and possible correlations with thyroid disorders (9).

In December 1994, Zhang et al. (10) identified the plasma protein encoded by what has been designated the “obese gene.” The protein was termed leptin on the basis of the Greek word “leptos,” meaning “thin.” This announcement was a landmark event in the study of appetite regulation and weight homeostasis. Since that time, an additional 20,000 publications have been released pertaining to leptin and its key role in appetite regulation and, increasingly, in other areas of study connecting leptin with thyroid function and certain responses of the immune system (11,12).

This copious literature is intriguing, not only in itself, but also because it raises questions concerning possible interrelationships between thyroid function and obesity, as well as thyroid autoimmunity and obesity, while it also evokes the question whether leptin is the orchestrator of these interrelationships.

Discussion

Leptin appetite regulation and obesity

The adipocyte hormone leptin acts tonically as an afferent signal from the adipose tissue to the brain as part of a negative feedback loop regulating energy balance (13), deregulation of this pathway being a marker of changes in energy homeostasis. Leptin regulates appetite by inhibiting food intake and increasing energy expenditure via an interaction with specific leptin receptors located in the arcuate nucleus (ARN), the paraventricular and dorsomedial nuclei and the lateral hypothalamus (13,14). Leptin's action after binding to its receptors is mediated by inducing Janus activating kinase (JAK)-2/signal transducer and activator of transcription (STAT) 3 factor (JAK/STAT) pathway signaling and also modulation of transcription of several target genes in hypothalamic areas that are intrinsically associated with the regulation of food intake (14,15). Thus, in the hypothalamus, leptin, by activating a specific signaling cascade, inhibits the orexigenic neuropeptide Y (NPY), agouti-related peptide (AgRP), proopiomelanocortin, and the anorexigenic cocaine- and amphetamine-regulated transcript (CART) in the ventromedial hypothalamus (15). Concomitantly, it activates melanin-concentrating hormone, which acts on MC4R (melanocortin-4 receptor) and corticotrophin-releasing-hormone and hypocretin/orexin-containing neurons of the lateral hypothalamus (16).

Interestingly, nutrition-induced obesity may be due, in part, to a malfunctioning of the capacity of the leptin receptor caused by a failure to activate the STAT3 within the hypothalamic ARN (14). It was also shown that leptin-sensitive neurons are, together with the suprachiasmatic nuclei, essential for generation of circadian feeding rhythms entrained by light, in contrast to arcuate nuclei that are required for generation of circadian feeding rhythms independent of light (17).

Leptin is a key hormone not only in the regulation of food intake and energy expenditure, but also in the regulation of neuroendocrine, metabolic, and immune function, as has been revealed by studies in humans with congenital or acquired leptin deficiency (18). It has thus been shown that congenital or acquired leptin deficiency is associated with decreased and less pulsatile gonadotropin levels and with thyroid axis abnormalities marked by aberrant levels of thyrotropin (TSH)-releasing hormone (TRH), conditions which may at least partially be attenuated by leptin administration (19). The mechanism is hypothesized to involve energy deprivation signaled to the brain by hypoleptinemia. Similarly, leptin deficiency results in decreased insulin-like growth factor 1 levels and adrenal axis function, though this is observed to be more pronounced in rodents than in humans. In addition, several other conditions, including hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes are associated with leptin deficiency (19).

In obesity, leptin is increased, this being related to the cell size of the adipose tissue, thus indicating leptin resistance to reduce food intake and increase energy expenditure, a crucial component for the development and maintenance of obesity. It should, however, be clearly stressed that hyperleptinemia is necessary for the development of leptin resistance. The latter is exacerbated in peripheral tissues, and especially in the central nervous system, by high fat intake rather than by obesity per se (20).

However, more significantly, although treatment with recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in leptin-deficient states, its ability to bring about weight loss in common obese patients has been unsatisfactory. The latter shows that in patients possessing adequate leptin secretion, mechanisms of leptin resistance and leptin tolerance inhibit r-metHuLeptin from producing any added effects (21).

Leptin and thyroid function

Thyroid hormone levels are subject to major physiologic regulation during nutritional adaptation from the fed to the starved state. It has recently been reported that leptin signaling, which is mediated by the JAK/STAT pathway, is mandatory for maintenance of TRH expression in the hypothalamic PVN and, consequently, for normal production of TSH and thyroid hormones (22). Leptin likely acts on TRH (i) through arcuate neurons projected to TRH neurons and (ii) directly via leptin receptors on TRH neurons (23). Leptin signaling targets the TRH gene promoter and, hence, in the absence of leptin signaling, the feedback loop between thyroxine (T4)/triiodothyronine (T3) and the hypothalamus-pituitary-thyroid system is dampened. Even in the fasting state, when leptin levels are low, serum TSH will increase if the patient is hypothyroid. Moreover, leptin may regulate, at least in euthyroid individuals, TSH pulsatility, and circadian rhythm (23,24). It therefore seems that via this mechanism leptin is linked to the hypothalamic–pituitary thyroid axis (Fig. 1). In agreement with this hypothesis is the fact that the leptin decline during fasting results in a decrease of TRH levels in the TSH-thyroid axis (25), while leptin administration during fasting in rodents reverses many of the abnormalities that occur in the hypothalamic-pituitary-thyroid axis (26). This demonstrates not only the association between changes in leptin and thyroid hormone levels in fasting, but also the fact that the fall in leptin drives the changes in thyroid function. The reduction, during fasting, in TRH mRNA in hypophysiotropic neurons mediated by suppression of alpha-MSH/CART simultaneously with an increase in NPY/AGRP gene expression in ARN neurons contributes to the fall in circulating thyroid hormone levels presumably by increasing the sensitivity of the TRH gene to negative feedback inhibition by thyroid hormone (27).

FIG. 1.

The expanding adipocyte releases leptin which, via Janus activating kinase (JAK)-2/signal transducer and activator of transcription (STAT) 3 factor, stimulates the secretion of thyrotropin-releasing hormone (TRH) and thyrotropin (TSH), which is likely to sustain the secretion of leptin. Leptin may also stimulate the activation of expression in neurons of the suppressor of cytokine signaling-3 (SOCS-3), which might inhibit leptin signaling, this indicating a probable auto-regulatory mechanism. T4, thyroxine; T3, triiodothyronine.

Furthermore, deiodinase type 1 (D1) expression has been reported to be elevated in omental and subcutaneous fat and has additionally been positively associated with leptin in a cohort of obese patients (28). It would therefore appear that the T3 produced via D1 in response to leptin plays a modulatory role in adipose tissue metabolism (28,29).

Alterations of serum leptin levels have been reported in thyroid disease. Serum leptin concentrations were found to be elevated in postmenopausal women with subclinical or overt hypothyroidism (OH). The relationship between thyroid status and serum leptin is further supported by the fact that, by achieving a euthyroid status, L-T4 treatment reduced leptin levels in OH without any effect on BMI (30). These results corroborate those of another recent study investigating serum leptin concentrations in hypo- and hyperthyroidism, both before and after treatment; the results were then compared with those of 20 healthy volunteers (30). Whereas serum leptin levels among hypothyroid patients were observed to be significantly higher than those of controls, hyperthyroid patients displayed statistically significantly lower levels. Moreover, T4 treatment decreased serum leptin levels in hypothyroid patients, whereas in hyperthyroidism, thyrostatic treatment increased leptin levels. In both hypothyroid and hyperthyroid patients, leptin levels were found to be correlated with BMI and TSH (31). Furthermore, in another study, fasting plasma leptin concentrations in obese OH patients were threefold higher than in lean OH, and twofold higher than in obese hyperthyroid patients (32). These findings indicate that leptin levels are increased in obese OH and that leptin is correlated to body fat mass independently of thyroid dysfunction. However, other studies have revealed both low and high and normal levels in hypothyroidism (33 –37).

Thus, it has been suggested that leptin may form a possible link between thyroid function and obesity, although the precise relationship of serum leptin with thyroid function is not fully clarified as of yet (38).

It has recently been reported that acute administration of recombinant TSH induces a rise in leptin proportionate to the adipose mass (39). The results reveal the presence of functional TSH receptors on the surface of adipocytes and, though produced by a pharmacological intervention, suggest the existence of a positive feedback mechanism between leptin and TSH in untreated obesity (Fig. 1). On the other hand, leptin also stimulates the expression of the suppressor of cytokine signaling-3 in neurons, which may inhibit leptin signaling, and thus implies the presence of an autoregulatory mechanism (40).

Leptin and immune function

Obesity induced by nutrient excess is characterized by expanding adipose tissue and chronic low-grade inflammation. Inflammatory pathways in obesity can be ignited by (i) extracellular components, such as proinflammatory cytokines and free fatty acids, and (ii) intracellular stress reflected in the endoplasmatic reticulum and the overgeneration of radical oxygen species by mitochondria (41).

Hyperleptinemia has been linked to an increased susceptibility to autoimmune disease and, by stimulating proinflammatory cytokines and macrophages, shifts the T helper balance toward a Th1 phenotype (42). In contrast, leptin deficiency could heighten susceptibility to infection by reducing T helper cells (43). Thus, leptin has pluripotent effects on both the innate and adaptive immune mechanisms, though the mechanisms linking leptin with thyroid autoimmunity are variable and remain elusive.

High fat intake promotes inflammation by affecting neuronal expression of MyD88, the signaling adaptor of toll-like receptors (TLRs) (44). TLRs comprise a family of pattern recognition receptors that function as key mediators in innate immunity, while also playing an important part in adaptive immunity by promoting proinflammatory cytokines and upregulating stimulation of antigen-presenting cells (44,45). Thus, adipose tissue in obesity is infiltrated by T lymphocytes and macrophages, regulated by TLRs, whose dysregulation in signaling triggers autoimmunity.

Involvement of leptin in the regulation of the suppressive function of T-regulatory (Treg) cells and immune response has of late been identified (46). Treg cells, a subpopulation of CD(+) T-cells, which are induced depending on local cytokines, reside in abundance in adipose tissue and control metabolic parameters. Activated Treg cells inhibit IFN-γ transcription, but not Th1 programming. Since it has been established that leptin controls self-tolerance by inhibiting Treg cells, thus altering immune response and causing defects in CD4(+) and CD25(+) T-cells (47), there is a strong likelihood that leptin could act as a negative signal for the proliferation of human, naturally occurring CD4(+)CD25(+) Treg cells (48). In addition, a recent report showed an impairment of dendritic cells (DCs), which are involved in T-lymphocyte programming, in ob/ob mice characterized by functional leptin deficiency (49). The DCs were found disturbed in their steady-state number and less efficient in stimulation of allogenic T-cells. Accordingly, DCs, due to their sensitivity to metabolic disturbances, could well be implicated in immunodeficiency associated with obesity (50).

To conclude, leptin deficiency has been associated with reduced numbers of circulating T-lymphocytes as well as an impaired cell proliferation and cytokine release pattern. Therefore, in nutrient excess-induced obesity, the resistance to leptin-mediated weight reduction may mitigate leptin deficiency and propagate autoimmunity. Though these mechanisms have not been confirmed in humans as of yet, they represent a valuable road-map for research and point the way to innovative therapeutic targets in obesity and thyroid autoimmunity.

Thyroid hormones and obesity

Thyroid hormones were linked to obesity when, more than a century ago, obesity was reported to be linked with hypothyroidism. The report issued by the Committee of the Clinical Society of London in 1888 that “in myxedema an increase in bulk and weight is a nearly constant finding” was accompanied by the Society's proposal that obesity should be a criterion in the diagnosis of hypothyroidism (51). Although Plummer concluded in 1940 that the concept that hypothyroid persons are invariably overweight was a bold assumption (52), the ensuing discovery that thyroid hormones control thermogenesis and, by interacting with other implicated peptides and hormones, regulate food intake, energy expenditure, and body weight, intensified scientific interest in the associations between thyroid hormones and obesity.

A number of studies have reported changes in thyroid hormones in obesity (53 –55). An analysis of the association between thyroid function and obesity in a recent population-based prospective study, at baseline and 6 years later, has revealed that changes in thyroid hormones are side effects of increasing body weight (BW) rather than the cause (56). These findings are supported by the observation that treatment of severe hypothyroidism leads to a BW reduction of <10%, indicating that severe obesity is usually not secondary to hypothyroidism (57). It is thus apparent that the induction of obesity appears to modify the pituitary–thyroid secretory pattern.

Thyroid hormone increases obligatory as well as facultative thermogenesis via numerous metabolic pathways and interactions with the sympathetic nervous system, respectively (58). Pioneering studies in the 1970s revealed significant alterations of thyroid hormone by overfeeding, principally evidenced by increased serum T3, this being the result of an elevated production rate via stimulated type I deiodination (59). Increasing calorie intake leads to a higher overall plasma disposal rate of T3 without, however, modifying the percentage of T3 metabolized by the type I deiodination pathway (60). Overeating alters complementary factors to the outer ring monodeiodination pathways of thyroid hormone metabolism, as was indicated by the increased plasma clearance rate of 3,-5-T2 during high calorie intake (61). In contrast, fasting is characterized by a marked decrease of serum T3 and increase of serum reverse T3 (62).

It is also noteworthy that the food composition may variably affect energy expenditure. Thus, a high fat diet leads not only to a significant decrease of serum T3 levels and of the free thyroid hormone index, but also to a significant diminishment of total energy expenditure, as compared to a high carbohydrate diet (63). Furthermore, by modulating thyroid hormones, for instance, by rendering individuals subclinically thyrotoxic, an increase in energy expenditure can be achieved both during exercise and in the resting metabolic rate (+6%), without this qualitatively affecting the impact of exercise on the thermic effects of food (64). It has very recently been reported that environmental temperature influences the effects of thyroid hormone on metabolism; thus, the phenomenon of global warming might also be contributing to the present day obesity pandemic. Accordingly, people who live in what is known as thermoneutrality, that is, a consistently maintained ambient temperature of 30°C, due to central heating, clothing, and the like, may exhibit decreased thyroid hormone effects on metabolism (65). The adaptive metabolic response to thermoneutrality, as this was investigated in an experimental study, showed that in the state of hypothyroidism only acclimatization to 30°C decreased energy expenditure, while a high-fat diet induced obesity and liver steatosis (65).

The first trials administrating triidothyronine (T3) or thyroid hormone analogs as a treatment modality for obesity were conducted in the late 1960s to 1970s (66,67). This mode of treatment, especially when combined with a low calorie diet, was relatively effective in terms of weight loss, but not of fat loss (65). Moreover, the considerable side effects that occurred, due to the fairly high doses of T3 applied, rendered the treatment obsolete and unsatisfactory in euthyroid obese patients. Of note, a classical study conducted with 150 μg or with 225 μg T3 daily, placebo-controlled, led to weight loss that was primarily (80%) due to protein catabolism and extracellular fluid loss (68). Meanwhile, since a slightly increased heart rate (6 beats/min) and serum T3 levels clearly above the normal range were registered, it is clear that we should abstain from prescribing T3 therapy in euthyroid obese patients for weight loss purposes.

Interesting data revealing that even small variations, within the reference range, of thyroid hormones may favor weight gain appear to point to thyroid function as a major factor in determining body weight (69). In a cross-sectional study (the Dan Thyr Study) that included 4082 subjects, FT4 levels were negatively associated with BMI, whereas serum TSH levels were positively, and independently of hypothyroidism, associated with BMI (70). It is noteworthy that a positive association between TSH and BW was observed to be significant at 5 years of follow-up, but not at 6 months.

A positive association between TSH and BMI was also registered in another large study from Norway in both nonsmokers and smokers, though it was stronger among current smokers (71). In a cross-sectional and longitudinal evaluation of the Framingham Study participants, baseline mean BW increased progressively from the lowest to highest TSH quartile, while a rise in TSH during the 3.5 years of follow-up was associated with a BW gain in both women and men (72).

In another study analyzing the 24 hours plasma TSH concentration in obese women by sampling at 10 minute intervals, as well as the 24 hours TSH secretion rate, it was shown that circadian TSH is elevated in obese women as compared to controls (69). Long-term calorie restriction-induced BW reduction resulted in a significant diminishment of TSH release, which was related to BMI and BW loss, and in a decline of FT3 and also of 24 hour leptin serum concentrations (73). These adaptations to diet and BW, on the other hand, blunt energy expenditure, thereby often contributing to the unsuccessful attempts of many obese individuals to lose more weight.

Subclinical hypothyroidism (SCH) in obese patients lowers resting energy expenditure (REE) in those who exhibit a serum TSH above 5.7 mU/L, which represents three SD above the mean of TSH levels in euthyroid obese patients. The latter observation strongly suggests that when assessment of REE in obese patients is required, evaluation of TSH is mandatory (74).

In an investigation including 206 children and adolescents, TSH was found to be high normal in up to 52% of the subjects, though no correlation with BW, BMI, or body fat was observed. During BW reduction, TSH diminished, accompanied by a predicted improvement in fasting insulin and insulin sensitivity as determined by homeostasis model assessment (75). These findings point to high TSH as a therapeutic target during diet-induced BW reduction carried out with the aim of enhancing insulin sensitivity. Nevertheless, it needs to be stressed that inhibition of a high normal TSH should be achieved either by diet plus exercise to reduce BW, but by no means through using thyroid hormones. In the future, thyroid hormone analogs may be discovered that can be effectively and safely used to treat obesity without causing unacceptable side effects.

There is adequate evidence that a TSH change within the normal range is associated with an increased BMI. In a recent analysis of 29 studies, 18 showed a positive relationship between adiposity and TSH. Nevertheless, the fact that only 2 out of 18 were longitudinal studies reflects the need for further investigation to clarify the association and the underlying mechanisms (76).

Obesity, thyroid dysfunction, thyroid autoimmunity, and leptin

There is a steadily growing number of peer-reviewed publications dealing with obesity, thyroid disease, autoimmunity, and leptin (77 –79). In a recent cohort analysis of 778 euthyroid subjects, TSH levels in the upper tertile displayed a BMI value higher than in those with lower TSH; however, the relationship was abolished when subjects without thyroid autoimmunity were selected (80). This is partially in line with other studies that did not find any relation between TSH and BMI, even in morbidly obese patients, when no stratification of autoimmune and nonautoimmune patients was undertaken (81,82). As hypothyroidism is an established cause of mild to moderate weight increase, autoimmune thyroiditis could presumably be more frequent in obese patients who do not achieve extreme degrees of adiposity (83). Thus, it may be hypothesized that autoimmunity is the factor determining an association between TSH and BMI.

On the other hand, the fact that treatment with T4 decreases leptin levels in both OH and SCH, as mentioned earlier (30), without affecting BMI, strongly indicates an association between leptin and thyroid status. Interestingly, in a cross-sectional study including 78 otherwise healthy obese women (mean BMI: 40.1 kg/m²), TSH was found to be higher in those with a BMI>40 kg/m² as compared to those with a BMI<40 kg/m², while it was positively associated with leptin and leptin/BMI ratio and negatively with adiponectin (84). These findings thus suggest that TSH and leptin are sensitive markers of impaired energy balance in obese women. Similarly, leptin, T3, and TSH have been reported to be increased in obese/overweight women, while the values significantly decreased following an energy deficit of 20%–50% (85).

In light of the above, it is of interest that a recent cross-sectional study has reported a higher prevalence of hypothyroidism and thyroid peroxidase antibodies in obese patients (86). According to the authors, obesity appears to increase susceptibility to autoimmunity: in this context, leptin is likely to play a pivotal role, since it is related to autoimmunity (87), is positively associated with serum TSH and inversely with FT4 levels and, together with the female sex, might well be a predictor of autoimmune thyroiditis.

Thus, in states of hyperleptinemia and/or hyperleptinemia-induced leptin resistance, the actions of leptin are quite probably connected to metabolic changes and alterations in immunologic tolerance thereby triggering autoimmunity, though the specific mechanisms connecting leptin to thyroid autoimmunity remain to be determined. Chronically high central leptin may diminish hypothalamic leptin receptor expression and impair leptin signaling, leading to leptin resistance that enhances susceptibility to diet-induced obesity (85). Consequently, the elevated leptin accompanying obesity heightens leptin resistance, which further sustains obesity, resulting in a vicious cycle of escalating metabolic derangement (85). The development of resistance to leptin's weight-lowering effects in obesity might be initiated by activation of inflammatory signaling, which substantially contributes to the impairment of immune response and propagation of autoimmunity in susceptible individuals. Regulation of inflammasome-derived cytokines in obesity constitutes an important step in controlling the trigger of thyroid autoimmunity. Clarification of these mechanisms will provide valuable insight into the pathogenesis of autoimmunity in obesity and, thereby, additionally open the way to innovative therapeutic targets in obesity and thyroid autoimmunity.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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