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ADIPONECTIN AND THYROID
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Juan J. Díez
Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain
Pedro Iglesias
Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain
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Editorial 2009
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The Authors declare no conflict of interest related to this work.
Correspondence
Juan J. Díez
Servicio de Endocrinología
Hospital Ramón y Cajal
Carretera de Colmenar km 9
28046 Madrid
E-mail: jdiez.hrc@salud.madrid.org
ABSTRACT
Available experimental data suggest that adiponectin and thyroid hormone share some biological effects and that may interact each other. Adiponectin may influence thyroid hormone production through interaction with gC1q receptor, whereas changes in the pituitary-thyroid axis may alter serum adiponectin levels through different mechanisms. Thyroid hypofunction in animals and humans did not modify serum adiponectin in most of the studies reported. However, data from experimental hyperthyroidism in animals and from clinical studies in patients with thyroid hyperfunction suggest that excess of thyroid hormone is accompanied by an elevation in circulating adiponectin. A positive association between adiponectin and thyrotropin receptor antibodies has been found in some studies, and it has been speculated that stimulation of these receptors could increase adiponectin production. Although some of these results are encouraging, the participation of adiponectin in pathogenesis of thyroid disorders is merely speculative.
Adipose tissue is the source of a variety of biologically active molecules, including cytokines, growth factors, complements factors, enzymes, and hormones (1). These adipocyte products, acting in autocrine, paracrine and endocrine ways, are capable of influencing not only local adipocyte physiology, but also the function of different organ systems. Among them, adiponectin is a protein specifically produced by the adipose tissue and released in high quantity into the bloodstream, accounting for up to 0.01% of total plasma protein in humans (2). As opposed to other adipocytokines, such as leptin, serum concentrations of adiponectin are decreased in states associated to insulin resistance, such as obesity and type 2 diabetes. Several lines of evidence suggest that adiponectin has a protective role against diabetes and atherosclerosis, and may behave as a cardioprotective factor.
ADIPONECTIN
Adiponectin, the product of the apM1 gene, is a 244 amino acid protein, which is specifically and highly expressed in human adipose cells (9-12). This 30 kDa protein contains an N-terminal signal sequence, a short variable domain, a collagen-like domain, and a C1q-like globular domain at the C-terminal end (9-12). It belongs to the soluble defence collagen superfamily and has structural homology to collagen VIII and X and complement factor C1q. Posttranslational hydroxylation and glycosylation give rise to multiples isoforms of adiponectin (13). In plasma, adiponectin circulates in trimeric, hexameric and high molecular weight (HMW) complexes. The globular domain of adiponectin, a proteolytic cleavage fragment, also circulates and has biological activity (14).
Serum adiponectin concentrations seem to be gender dependent being higher among women than men (15-18). Adiponectin and age are positively associated in both diabetic (19) and nondiabetic persons (16).
trimeric, hexameric and high molecular weight (HMW) complexes. The globular domain of adiponectin, a proteolytic cleavage fragment, also circulates and has biological activity (14).
Serum adiponectin concentrations seem to be gender dependent being higher among women than men (15-18). Adiponectin and age are positively associated in both diabetic (19) and nondiabetic persons (16).
ADIPONECTIN RECEPTORS
Two adiponectin transmembrane receptors (AdipoR) have been cloned. These receptors contain seven transmembrane domains, but are structurally and functionally distinct from G protein-couple receptors. AdipoR1 is expressed abundantly in skeletal muscle and has a preference for binding to globular adiponectin, while AdipoR2 is distributed mainly in liver and has intermediate affinity for both globular and full-length adiponectin (20,21). AdipoR1 acts through the AMP-dependent protein kinase (AMP kinase) signalling pathway, whereas AdipoR2 is associated with the peroxisome proliferator activator receptor (PPAR)-α pathway (22). Recent data from experimental investigation suggest that AdipoR1 and AdipoR2 deficiencies give rise to opposite effects on energy expenditure and spontaneous locomotor activity. In fact, AdipoR1-/- mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. In contrast, AdipoR2-/- mice were lean and resistant to high-fat diet-induced obesity and showed improved glucose tolerance and reduced plasma cholesterol levels (23). Whether additional receptors can mediate these or other biological effects of adiponectin is still a matter of debate.
Furthermore, adiponectin may act by the expansion of subcutaneous adipose tissue with decreased levels of macrophage infiltration, similar to the action of PPARγ agonists (24). Adiponectin is also capable to activate several other signalling pathways such as the production of nitric oxide through phosphatidylinositol-3-kinase-dependent mechanisms (25).
EFFECTS OF ADIPONECTIN
A great number of experimental investigations have shown that adiponectin increases insulin sensitivity and has noteworthy antiatherogenic and anti-inflammatory properties. Adiponectin knockout animals have shown a tendency to develop diet-induced glucose intolerance, insulin resistance (26,27), neointimal thickening, increase in vascular smooth muscle cells proliferation (26,28), and a higher expression and plasma concentrations of tumor necrosis factor-α (TNFα) (27).
In animal models, adiponectin induces the stimulation of glucose uptake in muscle, fatty acid oxidation in muscle and liver, and the inhibition of hepatic glucose production, cholesterol and triglyceride synthesis, and lipogenesis (14,29-31). Increased free fatty acid oxidation in muscle is mediated, at least in part, by increased expression of genes encoding CD36, acyl CoA oxidase, and UCP2, which enhance free fatty acid oxidation, fat combustion, and dissipation, respectively (31). Free fatty acid liver uptake also decreases and this might lead to decreased hepatic triglyceride content, which improves hepatic insulin sensitivity and reduces glucose output and blood glucose levels.
In animal models, adiponectin induces the stimulation of glucose uptake in muscle, fatty acid oxidation in muscle and liver, and the inhibition of hepatic glucose production, cholesterol and triglyceride synthesis, and lipogenesis (14,29-31). Increased free fatty acid oxidation in muscle is mediated, at least in part, by increased expression of genes encoding CD36, acyl CoA oxidase, and UCP2, which enhance free fatty acid oxidation, fat combustion, and dissipation, respectively (31). Free fatty acid liver uptake also decreases and this might lead to decreased hepatic triglyceride content, which improves hepatic insulin sensitivity and reduces glucose output and blood glucose levels.
Adiponectin supplementation in mice not only leads to improved insulin sensitivity, and to inhibition of inflammatory processes above mentioned, but also exerts noteworthy antiatherogenic effects within the vascular wall. This cytokine attenuates proliferation of vascular smooth muscle cells in response to a variety of growth factors and migration induced by heparin-binding-epidermal growth factor or platelet-derived growth factor-BB (28,37). In in vivo studies adiponectin has been reported to accumulate in the injured vessel wall and suppress the development of atherosclerosis in apolipoprotein E-deficient susceptible mice (38). This effect was associated with suppression of the expression of VCAM-1 and class A scavenger receptors (38). Other putative mechanism of the beneficial effect of adiponectin on the vasculature relates to the endothelial nitric oxide (NO) generation. In fact, concentrations of adiponectin similar to those found in serum have been shown to enhance NO production in cultured aortic endothelial cells (25,33). In endothelial cells treated with oxidized low density lipoproteins (LDL), adiponectin inhibited cell proliferation as well as basal and oxidized LDL-induced release of superoxide, and increased NO production by ameliorating the suppression of endothelial NO synthase (eNOS) activity by oxidized LDL (39). Furthermore, adiponectin also exerts inhibitory effects on thrombus formation and platelet aggregation in mouse models (40).
Adiponectin-induced AMP kinase activation may be a potential link between adiponectin and vascular effects of this adipokine (25,41). In fact, AMP kinase activates eNOS in endothelial cells and also ameliorates the increased apoptosis observed in endothelial cells exposed to high glucose, suggesting that this enzyme may mediate endothelial cell growth and differentiation responses (42). Other potential signalling pathways for adiponectin actions in endothelial cells include the activation of Akt, which is linked upstream to phosphatidylinositol 3’-kinase (PI-3K) signalling (25,41). Recently, a stimulating effect of adiponectin on angiogenesis by promoting cross-talk between AMP kinase and Akt signalling has been reported in endothelial cells (41).
INFLUENCE OF ADIPONECTIN IN THYROID HORMONE HOMEOSTASIS
Adiponectin might participate in the regulation of thyroid hormone production. The C-terminal globular structure of adiponectin can use the gC1q receptor, a molecule with broad tissue distribution that includes liver, smooth muscle, endothelium, immune cells and thyroid (43). Some authors have suggested that adiponectin, via this receptor found in the mitochondria of the thyroid cells, may be a regulator of thyroid hormone production (9,44).
In agreement with this hypothesis, human studies have shown that healthy subjects with high adiponectin levels had higher serum free T4 levels (45), and free T4 was found to be a predictive variable for adiponectin concentrations in humans. However, discordant results have been obtained by other investigators. The recent study by Malyszko et al. (46), performed in healthy subjects and patients with chronic kidney disease, but without a history of thyroid diseases, reported a negative correlation between adiponectin and free T3 both in healthy subjects and in patients with chronic renal failure and with kidney allograft (46). On the other hand, in hemodialysis patients adiponectin correlated negatively with free thyroxine (T4) and positively with thyrotropin (TSH). Multiple regression analysis in this study showed that, in kidney transplant recipients, adiponectin was independently related to free triiodothyronine (T3), whereas in hemodialysis patients adiponectin was independently related to free T4 (46). Lastly, in a study performed in severe obese women, TSH was inversely related with adiponectin concentrations (47).
INFLUENCE OF THYROID HORMONES IN ADIPONECTIN PRODUCTION
Rat adipose tissue has been found to express TSH receptor mRNA in amounts approaching those in the thyroid. The function of TSH receptor in rats seems to be indistinguishable from that in the thyroid and some authors have suggested that the interaction of autoantibodies with this TSH receptor plays an important role in the pathogenesis of the extrathyroidal manifestation of Graves’ disease (48). Therefore, it has been suggested that, in patients with autoimmune hyperthyroidism, TSH receptor antibodies may cross-react with TSH receptor in adipose tissue to affect adiponectin production.
This finding suggests that changes in the pituitary-thyroid axis may alter serum adipocytokine levels, including adiponectin. Fujimoto et al. (49) found that, in cultures of brown adipose tissue, thyroid hormone presented a small stimulatory effect on adiponectin messenger RNA expression and on hormone secretion. However, T3 treatment did not have any effect on adiponectin gene expression in 3T3-L1 adipocytes (50).
On the other hand, thyroid hormone might stimulate adiponectin production through the PPAR pathway. It has been reported that thyroid hormone can induce the expression of PPARγ in hepatocytes (51), and PPARγ stimulation increases serum adiponectin by transcriptional induction in adipose tissue because there is a functional PPAR-responsive element in human adiponectin promoter (52). It has also been shown that, in hepatocytes, thyroid hormone stimulates an increase in the mature sterol regulatory element-binding protein-1 (SREBP-1), a protein that binds the promoter regions of several lipogenic genes (53), and that the adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element-binding protein 1c transcription factor (ADD1/SREBP1c) controls adiponectin gene expression in differentiated adipocytes (54). Therefore, it is likely that thyroid hormone increases transcriptional induction of adiponectin through PPARγ or SREBP stimulation.
ADIPONECTIN AND HYPOTHYROIDISM
Hypothyroidism is accompanied by reduction in oxygen consumption, heat production and basal metabolic rate (55). A reduction in lipolysis and an increase in serum lipids are also characteristics of thyroid hormone deficiency (56). In rats with propylthiouracil-induced hypothyroidism serum adiponectin levels were significantly increased as compared to untreated rats (57). However, experimental hypothyroidism induced by methimazole treatment in rats was not accompanied by any significant change in serum adiponectin concentrations (58).
Serum adiponectin concentrations have been studied in patients with hypothyroidism before and after normalization of thyroid hormone levels with levothyroxine therapy. Most of the authors have reported that adiponectin levels remain unmodified in patients with thyroid hypofunction in comparison with euthyroid subjects (59-65). However, a few number of studies have found low adiponectin levels in hypothyroid subjects (44,66). A summary of clinical studies on adiponectin levels in hypothyroid patients is shown in Table 1.
In a group of 20 hypothyroid subjects we found that restoration of normal thyroid hormone levels after levothyroxine therapy was not accompanied by significant changes in circulating adiponectin levels (59). This finding was confirmed in a further study (61). Studies in humans have also demonstrated that the negative correlation between adiponectin and body fat mass estimated by BMI, and between adiponectin and HOMA-IR, an index of insulin resistance, is maintained in hypothyroid patients (64). The positive association between adiponectin and high density lipoprotein (HDL)-cholesterol also persisted in hypothyroid patients (61,64).
ADIPONECTIN AND HYPERTHYROIDISM
Thyroid hormone excess is associated with weight loss, reduction in fat mass, depletion in lipid storage and reduction of some serum lipids (4,67). Glucose intolerance and insulin resistance are also frequent findings in patients with thyrotoxicosis (68).
Data from animal investigation showed that serum adiponectin levels in levothyroxine-treated rats were 3.2-fold higher than that of euthyroid ones (58). In rats, adiponectin concentrations correlated positively with serum T4 and T3 and negatively with TSH. Furthermore, there was a negative correlation between serum adiponectin levels and visceral white adipose mass, which was reduced in hyperthyroid animals. A positive association between serum adiponectin levels and brown adipose tissue mass was also found. (58). The elevation of serum adiponectin levels in rats with experimental hyperthyroidism was not accompanied by changes in baseline serum insulin, blood glucose concentrations or glucose tolerance, as compared with euthyroid rats.
The elevation of serum adiponectin in experimental hyperthyroidism raises the question of the putative contributing effect of this adipokine to the effects of thyroid hormone excess. On the other hand, the hyperadiponectinemia present in thyroxine-treated rats might represent a compensatory mechanism that counteracts the effects of excess thyroid hormone concentrations. Human studies evaluating to circulating adiponectin in thyroid hyperfunction have shown variable results (Table 2). High adiponectin levels have been reported accompanying the elevation of thyroid hormone concentrations in hyperthyroid patients by some investigators (63,66,69,70), whereas other authors have found no significant differences in serum adiponectin between euthyroid subjects and hyperthyroid patients (44,59,60,64,65).
Treatment of thyrotoxicosis with appropriate therapy was followed by a significant decrease of serum adiponectin levels in some studies (69,71), but this decrement was not found in our study or in those of other authors (44,59,65).
The negative correlation between adiponectin and body mass index (64,65,71) and between adiponectin and insulin resistance (64) was maintained in hyperthyroid patients in some studies, but was lost in others (69). A positive correlation between adiponectin and HDL-cholesterol has also been reported in patients with hyperthyroidism (64).
A positive correlation between adiponectin and free T4 in patients with hyperthyroidism before (44,66,69-71) and after (71) treatment has also been reported. In patients with Graves’ disease treated with thionamide drugs, a weak correlation has been found between changes in adiponectin and changes in free T4 levels (71).
Discrepancies among the above mentioned studies in humans may be accounted for, at leas in part, by the different etiology of the thyroid hyperfunction in the analyzed populations. Most of the studies that have found elevation of circulating adiponectin in hyperthyroid patients evaluated subjects with Graves’ disease, whereas studies showing no significant changes included patients with hyperthyroidism of autoimmune and non-autoimmune etiology. It is possible that, although thyroid hormones might influence serum levels of adiponectin, some of the changes observed in patients with hyperthyroidism were also influenced by the adaptation to the changes in energy expenditure and intermediate metabolism in response to changes in thyroid hormone levels. This compensatory mechanism may be variable according to the duration of the thyroid dysfunction and may contribute to explain the discrepancies found in studies in patients with thyroid hyperfunction (62).
It has also been suggested that elevated levels of adiponectin in hyperthyroid patients might be the result of stimulating action of thyroid hormones on transcriptional induction of adiponectin through PPARγ pathway. Thyroid hormone receptor and PPAR are members of the nuclear receptors superfamily and they both have the capacity to form heterodimers with retinoid X receptor, and it could be a crosstalk between PPAR and thyroid hormone signalling pathways (69,70).
ADIPONECTIN AND AUTOIMMUNE THYROID DISEASE
In some studies a positive association between adiponectin and TSH receptor antibodies has been found (69,70). In the study by Saito et al. (69), TSH receptor antibodies made the strongest contribution to serum adiponectin concentrations in patients with Graves’ disease. It has been suggested that stimulation of TSH receptor by autoantibodies could be connected with inducing adiponectin production (70). This is in agreement with the fact that adipokines are also secreted by immune cells contained within adipose tissue (48). However, there was no correlation between serum adiponectin and thyroid peroxidase or thyroglobulin autoantibodies (69). A recent study has shown that, in patients with Graves’ hyperthyroidism, there were no differences in serum adiponectin between patients with and without thyroid associated ophthalmopathy (70), thus suggesting that adiponectin do not have a role in the autoimmune processes involved in Graves’ ophthalmopathy.
On the other hand, the stimulation of TSH receptor by autoantibodies in Graves’ disease could be related to the production of adiponectin. PPARγ pathway stimulates the differentiation of preadipocytes into mature adipocytes that express TSH receptor, and also potentiates adiponectin production. High levels of adiponectin contribute to growth and proliferantion of preadipocytes (72). Kumar et al. (73,74) showed that several genes were up-regulated in orbital adipose tissue from patients with Graves’ ophthalmopathy compared with normal orbital adipose tissue. Among these, PPARγ and adiponectin were found to be 44- and 25-fold overexpressed, respectively. Treatment of orbital preadipocytes with recombinant secreted frizzled-related protein-1 (sFRP-1) significantly increased adiponectin and TRH receptor RNA levels (74). Nevertheless, the possible role of this adipokine in the pathogenesis of thyroid associated ophthalmopathy is largely unknown.
Although anti-inflammatory properties of adiponectin are well known, under certain circumstances this adipokine has been involved in the regulation of the immune processes in response to T cell activation (75) and may exhibit pro-inflammarory actions (76). High levels of adiponectin have been reported in inflammatory conditions, such as rheumatoid arthritis (77), inflammatory bowel disease (78), and systemic lupus erythematosus (79). So far, now the involvement of adiponectin in the autoimmune processes in Graves’ disease and other autoimmune diseases is merely speculative. As mentioned above, it is possible that elevated serum adiponectin found in patients with autoimmune conditions is a compensatory response of the adipose tissue against these pro-inflammatory states.
CONCLUSION
In summary, adiponectin, a unique adipokine with insulin sensitizing, anti-inflammatory and antiatherogenic properties, is a collagen-like protein expressed in adipose tissue that circulates in human plasma at high concentrations and in several molecular isoforms. Adiponectin and thyroid hormone share some physiological actions as reduction of body fat by increasing thermogenesis and lipid oxidation. Hence, it has been speculated that this adipokine might participate in the regulation of thyroid hormone production, through the interaction with the gC1q receptor found in the mitochondria of the thyroid cells, although a clear demonstration of the role of adiponectin in thyroid hormone biosynthesis is lacking. On the other hand, the pituitary-thyroid axis may act through several mechanisms to regulate adiponectin production. TSH receptors have been found in rat adipose tissue, and some investigators, although not all, have found that thyroid hormone are able to stimulate adiponectin expression and secretion in brown adipose tissue. The PPARγ or SREBP pathways might also be involved in the transcriptional induction of adiponectin by thyroid hormone.
A number of clinical studies suggested that deficiency of thyroid hormone, as seen in human hypothyroidism, does not seem to be associated with significant changes in adiponectin neither before nor after control of thyroid function. However, hyperthyroidism is sometimes accompanied by an elevation in circulating levels, especially when Graves’ disease is the etiology of thyroid hyperfunction. A positive association between adiponectin and TSH receptor antibodies has been found, suggesting the participation of this adipokine in autoimmune thyroid disease, although an association between adiponectin and thyroid perixodase and thyroglobulin autoantibodies has not been found, and there is no proof for the involvement of adiponectin in Graves’ ophthalmopathy. Altogether, these results suggest that changes in serum adiponectin play a modest role in thyroid dysfunction in humans. Furthermore, with present data the involvement of adiponectin in autoimmune thyroid disease is merely speculative.
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Title: Hot Thyroidology; Abbreviated key title: Hot Thyroidol.; Online ISSN: 2075-2202
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