Leptin negatively regulates thyroid function of Wistar rats

Abstract

Leptin plays a major role in the regulation of energy intake and energy expenditure, triggering effects on several tissues, such as the hypothalamic-pituitary-thyroid axis. The reported effects of leptin on the thyroid are controversial, being mainly explored during energy imbalance. Therefore, the aim of this study was to evaluate the effects of leptin on thyroid function of rats fed ad libitum distinguishing direct leptin responses from those mediated by leptin-dependent suppression of food intake by comparing leptin-treated (L) with pair-fed (PF) animals. Leptin administration resulted in a decrease of 10% in food intake. Reduced mass gain was observed on both L and PF groups. Leptin administration decreased serum corticosterone, which did not occur in the PF group. TSH levels were reduced in PF group, but not in the L group. Both L and PF animals presented reduced iodide uptake and type 1 deiodinase (D1) activity in the thyroid gland. A decrease of D1 activity was also found in the PCCl3 rat thyroid cell lineage treated with leptin. Taken together the data suggest that leptin exerts paradoxical effects: a stimulatory effect on the hypothalamic-pituitary-thyroid axis by increasing TSH levels while directly inhibiting thyrocyte function in a TSH-independent fashion.

Key words
deiodinase; hypothalamus-pituitary-thyroid axis; iodide uptake; leptin; thyroid

INTRODUCTION

The homeostatic mechanisms that regulate body mass and food intake are fairly complex and may involve numerous hormones, neurotransmitters and peptides that modulate responses in both the central nervous system and in peripheral tissues. Leptin, a 16 kDa peptide hormone secreted mainly by adipocytes, plays a major role in this issue, regulating both energy intake and energy expenditure (Ahima et al. 1996, Frederich et al. 1995, Pelleymounter et al. 1995, Zhang et al. 1994). This hormone acts predominantly on hypothalamic nuclei and, also, in neuronal circuits of the brainstem that regulate feeding behavior and energy balance (Campfield et al. 1995, Elmquist et al. 1999). When serum leptin levels are high, such as after a meal or when the adipose tissue mass accumulates, excitatory signals to hypothalamic neurons that express α-MSH/CART predominate, as well as inhibitory signals and connections to neurons that express NPY/AgRP. As a result, there is a reduction of orexin and melanin-concentrating hormone (MCH) expression in the lateral nucleus of the hypothalamus, which altogether lead to diminished food intake (Horvath et al. 1999, Schwartz et al. 1996, 2000). It is well established that, in rodents and humans, mutations in the leptin or leptin receptor genes cause hyperphagia, morbid obesity, metabolic and neuroendocrine abnormalities, including hyperinsulinemia, hypercortisolism and hypothalamic hypogonadism (Coleman 1978, Halaas et al. 1995).

Central regulation by leptin triggers complex processes that lead to indirect effects on peripheral tissues. Such leptin effects include the activation of the hypothalamic-pituitary-thyroid axis. Nillni et al. (2000) demonstrated that leptin exerts important central regulation, such as the increase in proTRH gene expression and TRH release in the paraventricular nucleus of the hypothalamus (Nillni et al. 2000). Moreover, proTRH expression can be indirectly stimulated by leptin, since α-MSH (positively modulated by leptin) stimulates the secretion of TRH, whereas AgRP (negatively modulated by leptin) inhibits it (Fekete et al. 2000, 2002, Ghamari-Langroudi et al. 2010, Kim et al. 2000). Besides this action on the hypophysiotropic TRH neurons, the presence of the leptin receptor in pituitary and in thyroid gland suggests that leptin may also exert direct actions on the secretion of TSH and thyroid function (Jin et al. 2000, Nowak et al. 2002). In humans, a strong positive correlation between the circadian cycles of leptin and TSH has been demonstrated, and the circadian cycle of TSH is drastically altered in individuals with leptin production deficiency (Mantzoros et al. 2001).In rodents fed ad libitum, an acute treatment with leptin was able to positively modulate TSH secretion in vivo and, paradoxically, to regulate it negatively in vitro (Ortiga-Carvalho et al. 2002).

Similarly, reports of leptin actions on the thyroid gland are controversial. Iodide is essential for thyroid hormones biosynthesis and the sodium-iodide symporter (NIS) ensures the active transport of iodide into the thyrocytes. It has already been shown that leptin administration had inhibitory effects over thyroid iodide uptake in FRTL5 cells and in thyroid explants (Isozaki et al. 2004, de Oliveira et al. 2007). However, in vivo, treatment of rats with leptin for 6 days stimulated iodide uptake by the thyroid, whereas the acute treatment (1 day) did not cause modifications in this parameter (de Oliveira et al. 2007). It has also been demonstrated that leptin has a stimulatory effect on the thyroid type I deiodinase (D1) (Lisboa et al. 2003). These data suggest that leptin should be a modulator of thyroid function, independently of its central regulation mediated by TRH and TSH.

In addition to its role as an anorexigenic hormone, leptin mediates the adaptation to fasting. This response is mediated by a reduction in insulin and a rise in counterregulatory hormones, i.e., glucagon, epinephrine, and glucocorticoids (Schwartz et al. 1997). Previous studies suggest that negative energy balance leads to suppression of the hypothalamus-pituitary-thyroid axis, while positive energy balance stimulates it (Araujo et al. 2009, 2010, Connors et al. 1985, Rondeel et al. 1992). In situations of energy deprivation, when serum levels of leptin are low, there is inhibition of TRH release, a fact attributed to suppression of the proTRH gene and its processing into mature TRH (Légrádi et al. 1997, Nillni et al. 2000, Sanchez et al. 2004). TRH inhibition decreases TSH secretion, which leads to a reduction in thyroid function (Blake et al. 1991, Rondeel et al. 1992) In such a negative energy status, leptin administration was able to stimulate proTRH expression and to reestablish serum levels of thyroid hormones (Sanchez et al. 2004).

It is well known that TSH is the most important stimulator of thyroid hormone biosynthesis and, thus, stimulates iodide uptake and thyroid type 1 deiodinase expression. Replacement of leptin in rats that are food restricted, and therefore have low serum leptin, restored serum TSH levels but inhibited iodide uptake, this reinforces the idea of a direct negative effect of leptin on NIS regulation (Araujo et al. 2009).

The investigation concerning the action of this hormone under different physiological conditions remain poorly understood. It is important to note that the vast majority of studies previously published in the field have used models of energy imbalance (fasting, food restriction or obesity), while the effect of leptin on the hypothalamic-pituitary-thyroid axis under dynamic equilibrium conditions is not well known. Therefore, the main objective of this study was to investigate the direct influence of leptin on thyroid function in vitro and in vivo in rats fed ad libitum, differentiating direct leptin-responses from those secondary to suppression of food intake that might be secondary to energy imbalance rather than to leptin actions.

MATERIALS AND METHODS

Animals

Adult male Wistar rats weighing around 250 g were housed at controlled temperature (24 ± 2°C) with daily exposure to a 12 h light:12 h darkness cycle (lights on at 07:00 pm), and free access to tap water and standard rat chow. Animal care and procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No.85-23, revised 1996) and the study was approved by the Institutional Animal Welfare Committee (CEUA - IBCCF 077). All the animals were individually housed for a 2-week acclimation period and baseline control food intake was assessed.

Leptin treatment

Rats were randomly assigned to three groups: Control (C), Leptin (L) and Pair-Fed (PF). The treatment protocol entailed 10 consecutive days with twice daily (08:00 am and 05:00 pm) subcutaneous injections of 10 µg/100 g of body weight of recombinant rat leptin (National Institute of Diabetes & Digestive & Kidney Diseases - NIDDK) reconstituted in PBS buffer (pH 7.4) for L group. The leptin dose of each injection was daily adjusted for body weight. Control and Pair-Fed groups received PBS buffer (pH 7.4) injections at the same hours.

Pair-feeding

Because leptin administration results in reduced food intake (Mistry et al. 1997), a Pair-Fed (PF) group was created to rule out the effects of food restriction per se on the thyroid function, since we are specifically interested in the possible direct effects of leptin on thyroid. The PF group was fed with the average food intake of the leptin-treated group corrected for body mass. Example: If L group’s average food intake on day 2 were 9.0 g/100 g of body weight, a pair-fed animal weighing 300 g would receive 27.0 g of chow on day 3. The values of food intake related to animal weight were corrected daily.

Blood and thyroid gland collection

After the experimental period (10 days), all animals were euthanized by decapitation and blood was collected from the trunk. The animals were euthanized 3 h after the last leptin or vehicle administration. Serum was obtained after centrifugation of blood at 1,500 × g for 20 minutes at room temperature and stored at -20°C until specific radioimmunoassay (TSH, T3, T4, corticosterone and leptin) was performed. The thyroid gland was used for in vivo iodide uptake measurement (as described below) or stored at -70°C until processing for type 1 deiodinase enzyme (D1) activity analysis.

Cell culture

The PCCl3 rat thyroid cell line (Fusco et al. 1987) was maintained in Coon’s modified Ham’s F-12 medium supplemented with 5% fetal bovine serum, and a six-hormone mixture containing 5 µg/mL transferrin, 10 nM hydrocortisone, 10 ng/mL somatostatin, and 10 ng/mL glycyl-L-histidyl-L-lysine acetate, 1 mU/mL TSH, 10 µg/ml insulin (Souza et al. 2010). The effect of 100 ng/mL of recombinant leptin on type 1 deiodinase activity was studied using near-confluent cells in the absence of TSH and insulin, in the presence of 0.2% fetal bovine serum (starving medium) for 24 hours. TSH, insulin, transferrin, hydrocortisone, somatostatin, glycyl-L-histidyl-L-lysine acetate and dithiothreitol were purchased from Sigma-Aldrich Corporation (St. Louis, MO, USA). F-12 medium was obtained from HiMedia® (Mumbai, India) and Fetal Bovine Serum (FBS) from ThermoFischer (Waltham, MA, USA).

Serum TSH, leptin, corticosterone and total T3 and T4

Serum TSH levels were evaluated by a specific RIA obtained from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK, Bethesda, MD, USA). Serum total T3 and T4 concentrations were measured using commercial RIA kits (T3: DSL - 3100 Active; T4: DSL - 3200 Active; DSL, TX, USA), based on the presence of specific antibodies adhered to the internal surface of propylene tubes. Rat hormone-stripped serum was used for standard curves of TSH. Serum leptin concentrations were measured using a specific RIA for rat leptin obtained from the Linco Research Company (St. Charles, MO, USA). Serum corticosterone concentrations were measured using a specific RIA (ImmuChemTM ¹²⁵I) obtained from MP Biomedicals, LCC (Orangeburg, NY, USA). All the procedures were carried out following the manufacturer recommendations.

In vivo rat thyroid iodide uptake

In vivo iodide uptake by the thyroid gland was performed as previously described (Ferreira et al. 2005). The animals received [¹²⁵I] NaI (3,700 Bq/300,000 CPM i.p., Amersham) 15 min prior to decapitation. Thyroids were removed and weighed, and their radioactivity was measured using a gamma counter. The iodide uptake by the thyroid gland was expressed as percentage of total ¹²⁵I injected per mg of thyroid tissue.

Rat thyroid type 1 deiodinase assay

Type 1 iodothyronine deiodinase activity was evaluated by measuring the release of ¹²⁵I- from [¹²⁵I]-rT3 as previously described by our group (Araujo et al. 2008) and based on Berry et al. (1991). Fifteen milligrams of thyroid tissue were homogenized in 1 mL of 0.1 M sodium phosphate buffer containing 1 mM EDTA, 0.25 M sucrose, and 10 mM dithiothreitol (pH 6.9). Protein concentration was measured by the Bradford method (Bradford 1976). Thyroid homogenates containing 15 µg of protein were incubated for 1 hour at 37°C with 1 µM rT3 (Sigma, St. Louis, MO, USA), containing [¹²⁵I]-rT3 (Perkin-Elmer Life Sciences, Boston, MA, USA; previously purified using sephadex LH-2), in a final volume of 300 µL of homogenization buffer. Negative control incubations were performed in the absence of sample. The reaction was stopped at 4°C by the addition of 200 µL fetal bovine serum (Cultilab, Campinas, Brazil) and 100 µL trichloroacetic acid (50%, v/v). The samples were centrifuged at 8,000 × g for 3 min, and 360 µL of the supernatant was collected for measurement of ¹²⁵I released from deiodination reaction using an automated gamma counter. The specific enzyme activity was expressed as picomoles of product per minute per milligram of protein (pmoles min^-1 mg^-1).

Statistical analysis

Results are expressed as mean ± S.E.M., and were analyzed by one-way ANOVA, followed by Bonferroni’s multiple comparison tests. In vitro results were analyzed by two-tailed t-test. Serum TSH concentration was analyzed by Kruskal-Wallis followed by the Dunn’s multiple comparison tests. Results were analyzed with GraphPad Prism (version 8, GraphPad Software, Inc., San Diego, CA, USA). Differences were considered significant when P < 0.05.

RESULTS

Leptin effects on body mass, food intake and fat pads mass

The administration of 10 µg/100 g b.w. of leptin twice a day for 10 days promoted a statistically significant reduction in body mass gain in relation to the control animals. Remarkably, the vehicle-treated pair-fed animals had an even stronger reduction in mass gain (Figure 1c). Leptin administration diminished food intake by 10% (Figure 1a-b) and this reduction was used to calculate the mass of food offered for the pair-fed animals. Although body mass gain was altered in both L and PF animals, the absolute and relative masses of epididymal and retroperitoneal fat deposits were not affected (Figure 1d-e).

Figure 1
Leptin effects on body mass, food intake, and fat deposits mass. a. Absolute food consumption of control and leptin groups. The pair-fed group was fed with the exact amount of chow consumed by the leptin group in the earlier day. b. Area under the curve of food consumption. c. Mean body mass gain of control, leptin, and pair-fed animals relative to the first day of treatment of each group. d-e. Absolute and relative values of epididymal (d) and retroperitoneal (d) fat deposits. N = 15-20 animals per group. *P<0.05, ****P<0.0001.

Serum hormone concentrations are influenced by leptin treatment

After the 10-day experiment, serum was collected for hormonal analysis. Hyperleptinemia was confirmed by radioimmunoassay (Figure 2a). Corticosterone was suppressed in the leptin-treated group but not in the pair-fed group (Figure 2b). Indeed, a statistically significative negative correlation was observed between serum leptin and corticosterone (Figure 2c). The serum concentrations of total T3 and T4 were not altered by the treatments (Figure 2d-e), even though serum TSH was diminished in the pair-fed group (Figure 2f).

Figure 2
Serum hormone concentrations are influenced by leptin treatment. a-f. Serum hormone concentrations of leptin, corticosterone, total T3, total T4, and TSH were measured by radioimmunoassay after 10 days of leptin treatment or pair-feeding. c. Pearson’s correlation between serum leptin and serum corticosterone of animals from the three groups. N = 8-10 animals per group. *P<0.05, ****P<0.0001, ns: non-significant.

Leptin negatively impacts thyroid function

In order to investigate thyroid function, the activity of two key steps in the thyroid hormone secretion that are stimulated by TSH, the iodide uptake by the sodium-iodide symporter (NIS) and type 1 deiodinase (D1) activity, were evaluated (Carvalho & Dupuy 2017). In rats, thyroid D1 activity was suppressed by both leptin treatment and pair-feeding (Figure 3a). Leptin also inhibited D1 activity in PCCl3 cells, an immortalized rat thyroid cell lineage (Figure 3b). The iodide uptake by the thyroid gland was also impaired in both Leptin and Pair-fed (Figure 4).

Figure 3
Ex vivo and in vitro thyroid type 1 deiodinase activities are suppressed by leptin. a. Ex vivo D1 activity in the thyroid gland of male Wistar rats. N = 9-12 animals per group. b. In vitro D1 activity in PCCl3 cell line. N = 3 independent experiments. *P<0.05, **P<0.01, ns: non-significant.

Figure 4
Leptin and pair-feeding impair in-vivo iodide uptake by the thyroid gland. Radioactivity was measured in the thyroid of Wistar rats 15 min after [¹²⁵I] NaI (3,700 Bq/300,000 CPM) i.p. injection. N = 6-9 animals per group. *P<0.05, **P<0.01, ns: non-significant.

DISCUSSION

The direct effects of leptin on the thyroid gland remain controversial, probably as a result of the different methodologies used for each study, such as different leptin doses (Cabanelas et al. 2007), routes of administration (Deem et al. 2018), treatment duration (Lisboa et al. 2003, de Oliveira et al. 2007), and mainly, the energy status of the subjects (fed, fasted, food restricted or obese) (Araujo et al. 2009, 2010, Lisboa et al. 2015, Perello et al. 2010). Indeed, most of our current understanding about the role of leptin on the thyroid gland comes from animal models with energy imbalance (Ahima et al. 1996, Araujo et al. 2009, Blake et al. 1991, Légrádi et al. 1997, Rondeel et al. 1992) with very little information about its role in animals fed ad libitum. Thus, we designed a 10-days protocol in which male adult rats with free access to standard chow were injected twice a day, and constantly monitored for body mass gain and food intake. All experiments were conducted with a pair-fed group, allowing us to distinguish the direct effects of leptin from those secondary to the suppression of food intake.

Our first observation was a very robust impact of leptin on body mass gain (Figure 1c). It is well established that leptin, besides its central effects on appetite, activates major metabolic pathways related to energy expenditure and may, hence, affect body mass (Döring et al. 1998, Hwa et al. 1997, Scarpace et al. 1997, Yadav et al. 2009). We also observed in the pair-fed group, composed of animals that ate as much as the leptin-treated animals - but received no leptin - an even stronger impact on body mass loss. A major difference between these two groups is the fact that even though both are energy deprived, the leptin group is satiated, while the pair-fed group may be under mild starvation stress. Consistent with data from the literature (Araujo et al. 2009), the daily administration of 0.2 µg/g b.w. was able to suppress food intake by 10% (Figure 1a-b). Other studies that evaluated the effect of leptin administration on food intake of animals fed ad libitum with doses ranging from 0.5 to 10 µg/ g b.w. per day detected an inhibition ranging from 33 to 50%, disclosing a dose-dependent inhibitory effect of leptin on food intake (Barzilai et al. 1997, Cettour-Rose et al. 2002, Steinberg et al. 2002). Although we did observe a modulation of both body mass and food intake, fat deposits were not significantly altered by the 10 days treatment in either the leptin or the pair-fed group (Figure 1d-e).

Hyperleptinemia was confirmed in the leptin group and was not observed in the pair-fed group (Figure 2a). The levels of corticosterone were diminished in the leptin group but not in the pair-fed, suggesting a direct role of leptin on the adrenal and/or hypothalamus-pituitary-adrenal axis, and not an effect secondary to food restriction (Figure 2b). An inverse relationship between leptin and corticosterone was first observed by Ahima (1996) more than 20 years ago, in a seminal paper, which suggested that leptin could regulate the pattern of diurnal corticosterone secretion in mice. It has been shown that leptin administration could prevent the fast-induced rise in corticosterone in rats (Ahima et al. 1996) and even suppress corticosterone levels in both fed and 48h-fasted rats (Coppola et al. 2005). Moreover, we detected a statistically significant negative correlation between serum leptin and corticosterone levels (Figure 2c). Of note, the leptin-induced suppression of corticosterone, an orexigenic hormone, might be a synergistic mechanism of leptin’s central effects on the arcuate nucleus in promoting anorexia.

Serum T3 and T4 levels are typically decreased in response to long-term energy deprivation, as an homeostatic mechanism to save energy by preventing catabolic pathways and thermogenesis (Iwen et al. 2018). This decrease is secondary to a suppression of the hypothalamus-pituitary-thyroid (HPT) axis that is triggered by multiple circulating factors, including low levels of leptin. A study from our group revealed that animals submitted to 25 days of a 40% food restriction presents decreased levels of leptin, T3, T4, and TSH. However, when leptin was administered during the last 10 days of the 25-day restriction protocol, all suppressed hormones were at least partially restored (Araujo et al. 2009). Still, it remained unclear whether the rescue of thyroid hormones levels was secondary to an attenuation in HPT axis suppression or a direct effect of leptin on the thyroid gland. Our results indicate that neither leptin treatment nor the 10% restriction to which pair-fed animals were submitted provoked a decrease in serum thyroid hormones (Figure 2d-e), corroborating previous data that compared various degrees of food restriction and revealed that only restrictions greater than 30% are capable of promoting low serum T3 and T4 (Laws et al. 2007).

Additionally, serum concentrations of thyroid stimulating hormone (TSH) can be ambiguously modulated by leptin. Ortiga-Carvalho (2002) showed that the incubation of pituitary explants with nanomolar concentrations of leptin in vitro inhibited TSH secretion. However, this direct effect observed under non-physiological conditions seems to be surpassed in vivo by the positive effect of leptin on TRH, since the treatment of ad libitum fed rats with leptin leads to an increase in serum TSH (Ortiga-Carvalho et al. 2002). Our results show that food restriction of about 10% (pair-fed group) led to decreased serum TSH levels, while leptin treatment that induces the same level of food restriction, prevented TSH inhibition, suggesting a direct stimulatory effect of leptin on the pituitary (Figure 2f). One possible interpretation of this phenomena is that the mild food restriction to which leptin and pair-fed groups are submitted are inducing a decrease in TSH levels. However, due to the well stablished stimulatory effect of leptin on TRH, and consequently, TSH secretion, the leptin group has its TSH levels restored, while pair-fed animals do not, which corroborates previous data showing that leptin can restore TSH levels in rats and humans under negative energy balance (Araujo et al. 2009, Chan et al. 2003, Sanchez et al. 2004). Glucocorticoids are well-known regulators of HPT axis, reducing hypophyseal TSH secretion in both humans and rodent models (Annunziato et al. 1977, Pamenter & Hedge 1980, Samuels 1994, 2000, Wilber & Utiger 1969). It is important to note that the leptin-induced decrease of corticosterone serum levels found in our model, might be an additional mechanism involved in the TSH restoration in the leptin treated group (Figure 2b).

Ex vivo, in vivo, and in vitro models were used to assess the activity of key enzymes of thyroid physiology. Previous studies have shown that the thyroid D1 activity is diminished during food restriction, and that leptin reposition to food restricted animals does not restore D1 activity, although serum TSH was reestablished (Araujo et al. 2009). Another report revealed that the acute administration of a single dose of leptin to fed rats stimulates thyroid D1 activity (Lisboa et al. 2003), which is coherent with the acute stimulation of TRH and TSH secretions by leptin, since D1 is modulated by TSH (Araujo et al. 2009, Chan et al. 2003, Légrádi et al. 1997, Ortiga-Carvalho et al. 2002). However, the effect of a longer period of leptin treatment to fed animals remained unclear. We show herein that both leptin and pair-fed rats have diminished thyroid D1 activity compared to controls (Figure 3a). Hence, this result indicated the existence of a direct inhibitory effect of leptin on the thyroid D1, apart from the consequence of food restriction alone, because TSH, a thyroid D1 stimulator, was restored by leptin, but remained low in the pair-fed group. Using a cellular model of rat thyroid cells (PCCl3), we found that leptin can in fact directly suppress thyroid D1 activity (Figure 3b). Thus, it is possible to speculate that leptin-treated rats have decreased D1 activity due to a direct inhibition while pair-fed rats have decreased D1 activity due to lower serum TSH levels.

The role of leptin on iodide uptake by the thyroid, a crucial mechanism for thyroid function, is also a complex issue with divergent reports presented in the literature. Isozaki et al. (2004) showed that leptin treatment of FRTL-5 rat thyroid cell lineage downregulates NIS mRNA and iodide uptake (Isozaki et al. 2004). Conversely, another group showed that the treatment of fed rats with leptin for 6 days stimulates iodide uptake in vivo (de Oliveira et al. 2007). However, when the thyroid glands from these animals were excised and incubated with iodide ex vivo, they had a lower capacity to uptake iodide (de Oliveira et al. 2007). Previous studies from our team also revealed that the treatment of food-restricted rats with leptin resulted in iodide uptake inhibition (Araujo et al. 2009). In the present work, both leptin-treated and pair-fed animals had diminished thyroid iodide uptake compared to controls (Figure 4). It thus seems that, similarly to what happens with D1 activity, while leptin-treated animals are likely to have lower iodide uptake due to a direct effect of leptin, the pair-fed group might have lower iodide uptake due to lower serum TSH.

Considering that both leptin and thyroid hormones play a fundamental role in the regulation of energy expenditure and food intake, it is very important to understand how these hormones interact in order to better understand the mechanisms involved in body mass regulation. In the present study, we investigated the effects of leptin on thyroid D1 activity and iodide uptake that can be directly attributed to hyperleptinemia and dissociate it from those resulting from decreased food intake induced by leptin. It was found that leptin treatment causes a decrease in iodine uptake and thyroid D1 activity, demonstrating a direct inhibitory effect of leptin on these thyroid function parameters, since serum TSH is unchanged in these animals. Despite this, serum levels of TH remained unchanged, showing that 10 days of 10% food restriction is unable to significantly change serum thyroid hormone levels. Therefore, this work contributes to a better understanding of the fundamental role that leptin exerts on hypothalamic-pituitary-thyroid axis and, more specifically, on key-mechanisms related to thyroid gland function (model in Figure 5).

Figure 5
Leptin influences on the hypothalamus-pituitary-thyroid (HPT) axis of rats fed ad libitum. Leptin interacts with its receptor in multiple organs, eliciting direct and indirect effects. Leptin is a known positive regulator of TSH secretion, which might be secondary to its stimulatory effect on hypothalamic TRH. However, hyperleptinemia has repressive effects on thyroid function. Leptin diminishes thyroid iodide uptake and thyroid’s deiodinase 1 activity in vivo and in vitro. Thyroid hormones levels do not seem to be modulated in this condition. Hyperleptinemia also exerts important effects on the hypothalamus-pituitary-adrenal gland, as shown by reduced corticosterone levels.

ACKNOWLEDGMENTS

We are deeply grateful for the valuable contributions of Professor Tamar Frankenfeld (in memorian). The authors also thank Advaldo Nunes Bezerra and Wagner Nunes Bezerra for the technical assistance. This work was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Programa de Núcleos de Excelência (PRONEX), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Publication Dates

• Publication in this collection
  20 Aug 2021
• Date of issue
  2021

History

• Received
  5 Oct 2020
• Accepted
  24 Nov 2020