Differential effects of leptin and refeeding on the fasting-induced decrease of pituitary type 2 deiodinase and thyroid hormone receptor β2 mRNA expression in mice

Boelen, Anita; Kwakkel, Joan; Vos, Xander G; Wiersinga, Wilmar M.; Fliers, Eric

doi:10.1677/joe.1.06872

Cited by 36 publications

(23 citation statements)

References 40 publications

(39 reference statements)

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“…Chronic leptin treatment could also prevent the fall in T 4 determined by 70 h of fasting (3). On the other hand, other studies (11) have shown that leptin (20 g/0.5 ml twice a day) did not restore the decreased serum T 3 and T 4 in 24-h-fasted mice, despite serum leptin normalization. Lujan et al (31), using rhesus monkeys submitted to a prolonged dietary regimen, also observed that leptin infusion for 16 wk did not restore serum T 3 .…”

Section: Discussionmentioning

confidence: 82%

“…Therefore, further studies are needed in order to understand the influence of leptin on the thyroid axis during fasting and food restriction, which correspond to quite different physiological conditions. Boelen et al (11) showed that refeeding after 24 h of fasting in mice resulted in marked increase in serum leptin levels, which were not different compared with control mice; however, it did not result in a complete recovery of serum T 4 and T 3 levels. These results indicate that normalization of leptin levels does not always parallel restoration of serum thyroid hormone levels, suggesting that other peripheral signals may play a role in the regulation of thyroid gland economy during caloric deprivation.…”

Section: Discussionmentioning

confidence: 98%

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Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

Araújo

Andrade²,

Silva³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Araujo RL, Andrade BM, da Silva ML, Ferreira AC, Carvalho DP. Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats. Am J Physiol Endocrinol Metab 296: E1157-E1163, 2009. First published February 10, 2009 doi:10.1152/ajpendo.90869.2008The relationship between thyroid function and leptin has been extensively studied; however, the mechanisms underlying the changes in thyroid hormone economy that occur during caloric deprivation remain elusive. Our goal was to evaluate the thyroid function of rats submitted to 40% food restriction after chronic leptin replacement. Caloric restriction for 25 days led to significantly reduced serum leptin, thyroid-stimulating hormone (TSH), thyroxine (T 4), and triiodothyronine (T3) and increased serum corticosterone, while liver, kidney, and thyroid type I deiodinase (D1) and brown adipose tissue (BAT) type II deiodinase (D2) activities were decreased and hypothalamic D2 was significantly increased. Interestingly, thyroid iodide uptake was unchanged by caloric restriction, but thyroperoxidase (TPO) activity was significantly reduced. Leptin replacement for the last 10 days of caloric restriction normalized serum leptin and TSH levels, but serum T 4 and T3 levels and thyroid D1 and TPO activities were not reestablished. Also, a negative effect of leptin administration on Na ϩ -I Ϫ symporter function was detected. Liver and kidney D1 and hypothalamic and BAT D2 were normalized by leptin, while pituitary D2 was significantly decreased. In conclusion, a tissue-specific modulation of deiodinases might be implicated in the normalization of thyroid function during leptin replacement in food-restricted rats. Although leptin restores the hypothalamus-pituitary axis during food restriction, it exerts a direct negative effect on the thyroid gland; thus normalization of serum thyroid hormones might depend on changes in deiodinase activities and the long-term thyroid stimulation by TSH to counterbalance the direct negative effects of leptin on the thyroid gland.hypothalamus; pituitary; thyroid; caloric deprivation; thyrotropin MODERATE REDUCTION in caloric intake promotes well-known systemic effects such as body and fat mass reduction; however, homeostatic mechanisms impair further weight loss after longer periods of food restriction (40, 41). Studies in rodents suggest that the reduction in serum leptin levels that occurs during weight loss signals to the central nervous system, leading to decreased energy expenditure (1,2,3,5). This rapid fall in serum leptin in response to starvation also suppresses immunity, reproductive, and thyroid functions through central mechanisms (1,16,21,23,46).It is well documented that food restriction exerts profound effects on the hypothalamic-pituitary-thyroid axis, resulting in low plasma thyroxine (T 4 ) and triiodothyronine (T 3 ) levels that seem to be secondary to decreased thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) secretion (4,29,38). The relationship between thyroid hormon...

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

Araújo

Andrade²,

Silva³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

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“…In mice, fasting decreased the expression of D2 in the pituitary (41). It had been shown in rats that D2 activity and mRNA expression in BAT are up-regulated by insulin (19 -21), and more so in insulindeficient rats than in normal rats (21).…”

Section: Discussionmentioning

confidence: 97%

Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting

Heemstra

Soeters

Fliers

et al. 2009

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context:The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T 3 production.Objective: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia.Design: This was a prospective study. Setting:The study was conducted at a university hospital. Patients:We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T 4 replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting.Mean Outcome Measures: D2 activity and D2 mRNA levels were measured in skeletal muscle samples.Results: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T 4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. Conclusion:Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle. (J Clin Endocrinol Metab 94: 2144 -2150, 2009) P eripheral thyroid hormone metabolism is mainly regulated by the iodothyronine deiodinases D1, D2, and D3 (1, 2). D1 is expressed in liver, kidney, thyroid, and at a lower level in the pituitary. This enzyme converts the prohormone T 4 to active T 3 and is very active in the breakdown of rT 3 (1, 3). Although D1 contributes significantly to peripheral T 4 to T 3 conversion, it is probably not the major source of extrathyroidal T 3 production in humans (1, 2, 4, 5). D2 also catalyzes the production of T 3

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“…Some studies have reported that icv leptin administered after a 48-hour fast restores the fasting-induced decrease of serum TSH in rats (46), suggesting a major role for downregulation of TRH expression in the PVN. However, there are probably additional factors independent from hypothalamic TRH, since leptin administration during or following fasting does not prevent the decrease in TSHb mRNA expression despite restored hypothalamic proTRH mRNA expression (47). In addition, a relatively short period of refeeding does not result in restored pituitary TSHb mRNA expression (47), while it is sufficient to restore hypothalamic NPY and POMC expression (48).…”

Section: Pituitarymentioning

confidence: 99%

Fasting-Induced Changes in the Hypothalamus–Pituitary–Thyroid Axis

Boelen

Wiersinga

Fliers

2008

Thyroid

167

115

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Fasting induces profound changes in the hypothalamus-pituitary-thyroid (HPT) axis. The alterations observed in humans and rodents are similar in many ways, although they may be more pronounced and more acute in rodents. The molecular mechanisms underlying the resetting of HPT axis regulation in the framework of caloric deprivation are still incompletely understood. Fascinating studies in rats and mice have shown a dramatic downregulation of thyrotropin-releasing hormone (TRH) gene expression in hypophysiotropic paraventricular nucleus (PVN) neurons during fasting. Direct and indirect effects of decreased serum leptin, as well as effects of increased local triiodothyronine (T3) concentrations, in the hypothalamus during food deprivation contribute to the decreased activity of TRH neurons in the PVN. However, the relative contributions of these complex determinants remain to be defined in more detail. Pituitary thyroid-stimulating hormone (TSH) beta mRNA expression decreases during fasting, and this may be relatively independent of leptin and/or TRH, since leptin administration in this setting does not fully restore pituitary TSH expression, while it does restore TRH expression in the PVN. There may be a role for pituitary peptides, such as neuromedin B, in altered TSH gene expression during fasting. The observed decrease in serum thyroid hormone concentrations results to some extent from diminished thyroidal secretion of thyroid hormones, especially in rodents. Decreased thyroxine (T4) and T3 contribute to the downregulation of T3-responsive genes such as liver D1. The overall result of these complex HPT axis changes in various tissues during fasting is downregulation of the HPT axis, which is assumed to represent an energy-saving mechanism, instrumental in times of food shortage.

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Differential effects of leptin and refeeding on the fasting-induced decrease of pituitary type 2 deiodinase and thyroid hormone receptor β2 mRNA expression in mice

Cited by 36 publications

References 40 publications

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats

Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting

Fasting-Induced Changes in the Hypothalamus–Pituitary–Thyroid Axis

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