Carmen Cabanelas Pazos-Moura

The Autocrine/Paracrine Regulation of Thyrotropin Secretion

Peptides originally described in other tissues have been located in the anterior pituitary gland. Detection of their encoding mRNAs and specific receptors, together with demonstration of peptide local action led to the postulation of the existence of a paracrine/autocrine regulation of pituitary function. Direct evidence for the role of endogenous peptides has come from studies aiming to block their action through immunoneutralization or pharmacologic blockade. Here we review evidence of pituitary produced peptides as potential candidates as local regulators of thyrotropin secretion. Few studies have approached the subject and most data are not conclusive. Until now, the most consistent data relate to neuromedin B, a bombesin-like peptide. The combined observation of high peptide concentration in rat thyrotrophs, the ability of the exogenous peptide to inhibit thyrotropin (TSH) release in physiologic doses plus the effect of the specific neuromedin B antiserum to increase basal TSH release from isolated pituitaries suggest that neuromedin B acts as a constitutive autocrine TSH-release inhibitor. Neuromedin B is upregulated by thyroid hormones and downregulated by thyrotropin-releasing hormone (TRH) that is consistent with proposed role of local factors, namely to partially mediate or modulate the effects of hormones on pituitary function. However, future studies will certainly confirm other candidates as local regulators of TSH secretion, as well as their relevance at physiologic and pathologic conditions.

Cardiac Dysfunction Caused by Myocardium-Specific Expression of a Mutant Thyroid Hormone Receptor

Thyroid hormone deficiency has profound effects on the cardiovascular system, resulting in decreased cardiac contractility, adrenergic responsiveness, and vascular volume and increased peripheral vascular resistance. To determine the importance of direct cardiac effects in the genesis of hypothyroid cardiac dysfunction, the cardiac myocyte was specifically targeted with a mutant thyroid hormone receptor (TR)-beta (Delta337T-TR-beta(1)) driven by the alpha-myosin heavy chain (alpha-MHC) gene promoter. As a control in these experiments, a wild-type (Wt) TR-beta(1) was also targeted to the heart by using the same promoter. Transgenic mice expressing the mutant TR displayed an mRNA expression pattern consistent with cardiac hypothyroidism, even though their peripheral thyroid hormone levels were normal. When these animals were rendered hypothyroid or thyrotoxic, mRNA expression of MHC isoforms remained unchanged in the hearts of the Delta337T transgenic animals, in contrast to Wt controls or transgenic animals expressing Wt TR-beta(1), which exhibited the expected changes in steady-state MHC mRNA levels. Studies in Langendorff heart preparations from mutant TR-beta(1) transgenic animals revealed evidence of heart failure with a significant reduction in +dP/dT, -dP/dT, and force-frequency responses compared with values in Wt controls and transgenic mice overexpressing the Wt TR-beta(1). In contrast, in vivo measures of cardiac performance were similar between Wt and mutant animals, indicating that the diminished performance of the mutant transgenic heart in vitro was compensated for by other mechanisms in vivo. This is the first demonstration indicating that isolated cardiac hypothyroidism causes cardiac dysfunction in the absence of changes in the adrenergic or peripheral vascular system.

Non-classic thyroid hormone signalling involved in hepatic lipid metabolism

Thyroid hormones are important modulators of lipid metabolism because the liver is a primary hormonal target. The hypolipidaemic effects of thyroid hormones result from the balance between direct and indirect actions resulting in stimulation of lipid synthesis and lipid oxidation, which favours degradation pathways. Originally, it was believed that thyroid hormone activity was only transduced by alteration of gene transcription mediated by the nuclear receptor thyroid hormone receptors, comprising the classic action of thyroid hormone. However, the discovery of other effects independent of this classic mechanism characterised a new model of thyroid hormone action, the non-classic mechanism that involves other signalling pathways. To date, this mechanism and its relevance have been intensively described. Considering the increasing evidence for non-classic signalling of thyroid hormones and the major influence of these hormones in the regulation of lipid metabolism, we reviewed the role of thyroid hormone in cytosolic signalling cascades, focusing on the regulation of second messengers, and the activity of effector proteins and the implication of these mechanisms on the control of hepatic lipid metabolism.

Calcium supplementation reverts central adiposity, leptin, and insulin resistance in adult offspring programed by neonatal nicotine exposure

Obesity is a worldwide epidemic. Calcium influences energy metabolism regulation, causing body weight loss. Because maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance (IR), and hypothyroidism, we decided to evaluate the possible effect of dietary calcium supplementation on these endocrine dysfunctions in this experimental model. Osmotic minipumps containing nicotine solution (N: 6 mg/kg per day for 14 days) or saline (C) were s.c. implanted in lactating rats 2 days after giving birth (P2). At P120, N and C offspring were subdivided into four groups: 1) C - standard diet; 2) C with calcium supplementation (CCa, 10 g calcium carbonate/kg rat chow); 3) N - standard diet; and 4) N with calcium supplementation (NCa). Rats were killed at P180. As expected, N offspring showed higher visceral and total body fat, hyperleptinemia, lower hypothalamus leptin receptor (OB-R) content, hyperinsulinemia, and higher IR index. Also, higher tyrosine hydroxylase (TH) expression (+51%), catecholamine content (+37%), and serum 25-hydroxyvitamin D(3) (+76%) were observed in N offspring. Dietary calcium supplementation reversed adiposity, hyperleptinemia, OB-R underexpression, IR, TH overexpression, and vitamin D. However, this supplementation did not reverse hypothyroidism. In NCa offspring, Sirt1 mRNA was lower in visceral fat (-37%) and higher in liver (+42%). In conclusion, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in adult offspring programed by maternal nicotine exposure during lactation. It is conceivable that the reduction in fat mass per se, induced by calcium therapy, is the main mechanism that leads to the increment of insulin action.

Thyroid hormone contributes to the hypolipidemic effect of polyunsaturated fatty acids from fish oil: in vivo evidence for cross talking mechanisms

n-3 polyunsaturated fatty acids (n-3 PUFA) from fish oil (FO) exert important lipid-lowering effects, an effect also ascribed to thyroid hormones (TH) and TH receptor β1 (TRβ1)-specific agonists. n-3 PUFA effects are mediated by nuclear receptors, such as peroxisome proliferator-activated receptors (PPAR) and others. In this study, we investigated a role for TH signaling in n-3 PUFA effects. Euthyroid and hypothyroid adult rats (methimazole-treated for 5 weeks) received FO or soybean oil (control) by oral administration for 3 weeks. In euthyroid rats, FO treatment reduced serum triglycerides and cholesterol, diminished body fat, and increased protein content of the animals. In addition, FO-treated rats exhibited higher liver expression of TRβ1 and mitochondrial α-glycerophosphate dehydrogenase (mGPD), at protein and mRNA levels, but no alteration of glutathione S-transferase or type 1 deiodinase. In hypothyroid condition, FO induced reduction in serum cholesterol and increase in body protein content, but lost the ability to reduce triglycerides and body fat, and to induce TRβ1 and mGDP expression. FO did not change PPARα liver abundance regardless of thyroid state; however, hypothyroidism led to a marked increase in PPARα liver content but did not alter TRβ1 or TRα expression. The data suggest that part of the effect of n-3 PUFA from FO on lipid metabolism is dependent on TH signaling in specific steps and together with the marked upregulation of PPARα in liver of hypothyroid rats suggest important in vivo consequences of the cross-talking between those fatty acids and TH pathways in liver metabolism.

Resveratrol reduces lipid peroxidation and increases sirtuin 1 expression in adult animals programed by neonatal protein restriction

Resveratrol (Res) has been associated with protective effects against oxidative stress. This study evaluated the effect of Res over lipid peroxidation, antioxidant defense, hepatic sirtuin 1 (SIRT1), which up-regulates antioxidant enzymes, and copper/zinc superoxide dismutase (Cu/Zn SOD) in adult offspring whose mothers were protein restricted during lactation. Lactating Wistar rats were divided into control (C) group, which were fed a normal diet (23% protein), and low-protein and high-carbohydrate (LPHC) group, which were fed a diet containing 8% protein. After weaning (21 days), C and LPHC offspring were fed a normal diet until they were 180 days old. At the 160th day, animals were separated into four groups as follows: control, control+Res, LPHC, and LPHC+Res. Resveratrol was given for 20 days (30u200a mg/kg per day by gavage). LPHC animals showed a higher total antioxidant capacity (TAC) without change in lipid peroxidation and SIRT1 expression. The treatment with Res increased TAC only in the control group without effect on lipid peroxidation and SIRT1. LPHC animals treated with Res had lower lipid peroxidation and higher protein and mRNA expression of SIRT1 without any further increase in TAC. No significant difference in liver Cu/Zn SOD expression was observed among the groups. In conclusion, maternal protein restriction during lactation programs the offspring for a higher antioxidant capacity, and these animals seem to respond to Res treatment with a lower lipid peroxidation and higher hepatic SIRT1 expression that we did not observe in the Res-treated controls. It is probable that the protective effect can be attributed to Res activating SIRT1, only in the LPHC-programmed group.

The Somatostatin Analogue Octreotide Modulates Iodothyronine Deiodinase Activity and Pituitary Neuromedin B

Somatostatin inhibits growth hormone and thyrotropin (TSH) secretion. It also enhances the inhibitory effect of thyroid hormone (TH) on TSH by poorly understood mechanisms. We investigated the acute effect of the long-acting somatostatin analogue, octreotide (OCT), on anterior pituitary type 1 (D1) and 2 (D2) deiodinase activity, on liver D1, and on pituitary content of neuromedin B (NB), an autocrine inhibitor of TSH secretion, which is positively regulated by thyroid hormones. Euthyroid or hypothyroid rats were sacrificed at different times after a single subcutaneous injection of OCT (1 microg/kg body weight [BW]). D1 and D2 activities were measured by the release of 125I from 125I reverse triiodothyronine (rT3) under different assay conditions. NB, TSH, T3, and thyroxine (T4) were quantitated by radioimmunoassay (RIA). In euthyroid rats, liver and pituitary D1 activities were decreased (50%) 6 hours after OCT injection; pituitary D2 and NB remained unchanged. In hypothyroid rats, OCT increased near to the level of normal rats both pituitary D1 activity (but not liver) and NB content, at 24 hours and at 6 and 24 hours, respectively (p < 0.05). Pituitary D2, greatly increased by hypothyroidism, showed a small (25%) but significant reduction at 3 hours, persisting at 24 hours (p < 0.01), although it remained higher than that of euthyroid control. Serum thyroid hormones were not affected by OCT injection. The results show that octreotide acutely regulates pituitary deiodinases and NB content, both representing mechanisms that potentially can contribute to somatostatin and octreotide actions on pituitary growth hormone (GH) and TSH secretion and to modulate these cells sensitivity to thyroid hormone action.

Acute effects of endocannabinoid anandamide and CB1 receptor antagonist, AM251 in the regulation of thyrotropin secretion

We examined the acute effects of endocannabinoid, anandamide, and of synthetic cannabinoid receptor antagonist, AM251[N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], on TSH, thyroxine (T(4)), and triiodothyronine (T(3)) secretions. Euthyroid male rats showed a 42% decrease in serum TSH, 2 h after a single i.p. injection of 0.02, but not 0.2 mg/kg body weight (BW), anandamide, accompanied by a 39% reduction in serum T(4), without alteration in serum T(3). At 0.5 and 1 h, these serum hormones showed no significant change. Hypothyroid rats showed a 35% reduction in serum TSH (P<0.01), 2 h after anandamide injection, which had no effect on hyperthyroid rats. In both thyroid states, no modification of serum thyroid hormones was observed. Intraperitoneal injection of 0.17 or 1.7 mg/kg BW AM251 in euthyroid rats caused, 1.5 h later, 1.7-fold or 4.3-fold increase in serum TSH respectively, without changing thyroid hormones. Stimulatory effect of 0.17 mg/kg BW AM251 and inhibitory effect of anandamide was abolished in the group injected with AM251 followed by an anandamide injection, 30 min later. Intracerebroventricular injection of 20 ng (but not 200 ng) anandamide induced a decrease in serum TSH at 60 min after injection, which tended to disappear at 120 min. Anterior pituitary explants presented significant reduction in TSH release in the presence of 10(-7) M anandamide in incubation medium, which was blocked by 10(-7) M AM251. In conclusion, anandamide has the ability to acutely inhibit TSH release in eu- and hypothyroid rats, acting at the hypothalamus-pituitary axis. Since, in addition, the cannabinoid receptor antagonist AM251 increased TSH release, we suggest that endocannabinoid system has a role as negative regulator of TSH secretion.

Effects of running wheel training on adult obese rats programmed by maternal prolactin inhibition

The inhibition of maternal prolactin production in late lactation leads to metabolic syndrome and hypothyroidism in adult offspring. Physical training is a therapeutic strategy that could prevent or reverse this condition. We evaluated the effects of a short-duration low-intensity running wheel training program on the metabolic and hormonal alterations in rats. Lactating Wistar rats were treated with bromocriptine (Bro, 1u200amg twice a day) or saline on days 19, 20, and 21 of lactation, and the training of offspring began at 35 days of age. Offspring were divided into sedentary and trained controls (C-Sed and C-Ex) and sedentary and trained Bro-treated rats (Bro-Sed and Bro-Ex). Chronic exercise delayed the onset of weight gain in Bro-Ex offspring, and the food intake did not change during the experimental period. At 180 days, visceral fat mass was higher (+46%) in the Bro-Sed offspring than in C-Sed and Bro-Ex rats. As expected, running capacity was higher in trained animals. Most parameters observed in the Bro-Sed offspring were consistent with hypothyroidism and metabolic syndrome and were reversed in the Bro-Ex group. Chronic exercise did not influence the muscle glycogen in the C-Ex group; however, liver glycogen was higher (+30%) in C-Ex group and was unchanged in both Bro offspring groups. Bro-Ex animals had higher plasma lactate dehydrogenase levels, indicating skeletal muscle damage and intolerance of the training program. Low-intensity chronic training is able to normalize many clinical aspects in Bro animals; however, these animals might have had a lower threshold for exercise adaptation than the control rats.

Maternal cinnamon intake during lactation led to visceral obesity and hepatic metabolic dysfunction in the adult male offspring

PurposeStudies with foods, known to promote health benefits in addition to the nutritive value, show that their consumption by pregnant and/or lactating females could induce negative outcomes to the offspring. It is well characterized that cinnamon intake promotes benefits to energy homeostasis. The present study aimed to analyze the effects of the consumption of an aqueous extract of cinnamon by lactating female rats on the endocrine-metabolic outcomes in the adult offspring.MethodsLactating dams (Wistar rats) were supplemented with cinnamon aqueous extract (400u2009mg/kg body weight/day) for the entire lactating period. The male adult offspring were evaluated at 180 days old (CinLac).ResultsThe offspring presented visceral obesity (Pu2009=u20090.001), hyperleptinemia (Pu2009=u20090.002), and hyperinsulinemia (Pu2009=u20090.016). In the liver, CinLac exhibited reduced p-IRβ (Pu2009=u20090.018) suggesting insulin resistance. However, phosphorylation of IRS1 (Pu2009=u20090.041) and AKT (Pu2009=u20090.050) were increased. JAK2 (Pu2009=u20090.030) and p-STAT3 (Pu2009=u20090.015) expressions were higher, suggesting that the activation of IRS1/AKT in the CinLac group could have resulted from the increased activation of leptin signaling. Although we observed no changes in the gluconeogenic pathway, the CinLac group exhibited lower hepatic glycogen content (Pu2009=u20090.005) accompanied by increased p-GSK3β (Pu2009=u20090.011). In addition, the CinLac group showed increased hepatic triacylglycerol content (Pu2009=u20090.049) and a mild steatosis (Pu2009=u20090.001), accompanied by reduced PPARα mRNA expression (Pu2009=u20090.005).ConclusionWe conclude that maternal intake of aqueous extract of cinnamon induces long-term molecular, metabolic, and hormonal changes in the adult progeny, including visceral obesity, higher lipid accumulation, and lower glycogen content in the liver.