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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, 1 mg 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.

Early weaning is associated with changes in the developmental plasticity. Here, we studied the adipocytes morphology, adipokines expression or content in adipose tissue as well as adrenal and thyroid function of neonate and adult offspring primed by early weaning. After birth, lactating rats were divided into 2 groups: EW (early weaning) – dams were wrapped with a bandage to block access to milk during the last 3 days of lactation, and Control – dams whose pups had free access to milk throughout lactation (21 days). At postnatal day (PN) 21, EW pups had lower visceral and subcutaneous adipocyte area ( − 67.7% and − 62%, respectively), body fat mass ( − 26%), and leptin expression in visceral adipocyte ( − 64%) but higher leptin expression in subcutaneous adipocyte (2.9-fold increase). Adrenal evaluations were normal, but neonate EW pups presented lower serum T3 ( − 55%) and TSH ( − 44%). At PN 180, EW offspring showed higher food intake, higher body fat mass (+21.6%), visceral and subcutaneous adipocyte area (both 3-fold increase), higher leptin (+95%) and ADRβ3 (2-fold increase) content in visceral adipose tissue, and higher adiponectin expression in subcutaneous adipose tissue (+47%) but lower in visceral adipose tissue ( − 40%). Adult EW offspring presented higher adrenal catecholamine content (+31%), but no changes in serum corticosterone or thyroid status. Thus, early weaning primed for hypothyroidism at weaning, which can be associated with the adipocyte hypertrophy at adulthood. The marked changes in catecholamine adrenal content and visceral adipocyte ADRB3 are generally found in obesity, contributing to the development of other cardiovascular and metabolic disturbances.

Hyperleptinemia during lactation programs for higher serum leptin in 30-day-old and adult rats, associated with metabolic changes. Here we evaluated the inhibition of serum leptin at 29 and 30 days on the metabolic phenotype of rats programmed with leptin during lactation. Pups from Wistar rats were saline-injected or leptin-injected from postnatal day 1 to day 10. At 29 and 30 days old, animals were injected with anti-leptin antibody (LA and CA) or saline (LS and CS). In adult animals, higher visceral (+53%) and total fat mass (+33%), hyperleptinemia (+67%), hypertriglyceridemia (+47%), and hypoadiponectinemia (-44%) observed in LS group compared to CS were prevented by immunoneutralization of leptin, since LA group had those parameters values similar to CS group. However, immunoblockade of leptin in normal animals led to the same metabolic changes seen in leptin-treated animals, in addition to lower serum adiponectin (-77% vs. CS) and higher insulin resistance index (+37%). Liver sirtuin1 (SIRT1) was higher (+41%) only in LA group, suggesting a role for SIRT1 in the prevention of leptin programming. Hypothalamic OBR was lower and SOCS3 higher in LS group and these changes were normalized in LA group. In conclusion, blocking leptin action one week after weaning seems to revert most of the alterations observed in rats programmed by neonatal hyperleptinemia. Higher liver SIRT1 expression may be one of the mechanisms involved, leading to a better glucose and lipid metabolism. Our data suggest that the lack or the excess of leptin programs an adverse metabolic phenotype in adulthood.

Previous studies have shown that alterations in thyroid status may lead to changes in serum leptin and adiponectin, both in humans and rodents. The mechanisms, especially for adiponectin, are unclear. In the present study, we investigated the effect of triiodothyronine (T3) on the expression of adiponectin mRNA and the release of leptin and adiponectin by white adipose tissue (WAT) explants obtained from epididymal (visceral) or inguinal (subcutaneous) depots from normal rats. We also analyzed the effects of other known regulators of adiponectin and leptin release, such as rosiglitazone and dexamethasone. T3 acted directly at rat WAT explants in a depot-specific manner and in a unique fashion to each hormone. T3 was able to inhibit leptin release only by epididymal explants, and to reduce adiponectin mRNA expression only in inguinal explants. However, T3 was incapable of modifying adiponectin release by both explants. Additionally, rosiglitazone exhibited an inhibitory effect on adiponectin release by both WAT explants, even though adiponectin mRNA was importantly upregulated only in inguinal explants. Rosiglitazone acted as an inhibitor of leptin release by both studied fat depots, while only epididymal explants responded to the stimulatory effect of dexamethasone on leptin release. Therefore, the present model of isolated rat white adipose tissue explants highlights the fact that the regulation of hormonal production by white adipose tissue depends on the type of depot and its anatomical location. In this context, our results show for the first time a potential inhibitory effect of T3 on adiponectin mRNA expression specifically on WAT from a subcutaneous depot.

Leptin has been shown to modulate deiodinase type 1 (D1) and type 2 (D2) enzymes responsible for thyroxine (T4) to triiodothyronine (T3) conversion. Previously, it was demonstrated that a single injection of leptin in euthyroid fed rats rapidly increased liver, pituitary, and thyroid D1 activity, and simultaneously decreased brown adipose tissue (BAT) and hypothalamic D2 activity. We have now examined D1 and D2 activities, two hours after a single subcutaneous injection of leptin (8 microg/100 g BW) into hypo- and hyperthyroid rats. In hypothyroid rats, leptin did not modify pituitary, liver and thyroid D1, and thyroid D2 activity, while pituitary D2 was decreased by 41% (p

We investigated the influence of hypo- and hyperthyroidism on the ability of leptin to modulate TSH secretion. Two hours after receiving leptin (8 μg leptin/100 g BW; s.c.), hyperthyroid rats (10 μg thyroxine (T4)/100 g body weight (BW) for 5 days) showed a 1.7-fold increase in serum TSH (P−9 and 10−7M leptin showed reductions in TSH release of 40 and 50% respectively (PPPin vivo and in vitro responsiveness of TSH to leptin is abolished in hypothyroidism and is preserved in short-term hyperthyroidism, in comparison to previous reports in euthyroidism. In addition, the inhibitory action of pituitary leptin is enhanced in hyperthyroid glands, which may suggest a role for locally produced leptin in the suppression of TSH release associated with hyperthyroidism.

We have shown that protein restriction during lactation is associated with higher levels of serum and milk tri-iodothyronine (T(3)) with lower serum thyroxine (T(4)), suggesting an increased T(4) to T(3) conversion. To investigate this hypothesis, the activity of type 1 (D1) and/or type 2 (D2) iodothyronine deiodinases was evaluated on days 4, 12 and 21 of lactation in several tIssues of dams fed an 8% protein-restricted (PR) diet and controls fed a 23% protein diet. Serum TSH, T(3) and T(4) were measured by radioimmunoassay. Deiodinase activity was determined by the release of (125)I from (125)I-reverse T(3), under specific conditions for D1 or D2. PR dams had a transitory reduction in liver D1 activity (P

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.

The effect of substance P (SP) on thyrotropin (TSH) secretion is controversial. In this study we evaluated the effect of SP on TSH secretion by hemipituitaries of 3-month-old Wistar rats in vitro and its interaction with gastrin-releasing peptide (GRP) at equimolar concentrations (1 microM and 10 microM). TSH release was measured under basal conditions and 30 min after incubation in the absence or presence of SP, GRP or both peptides. Pituitary TSH content was also measured in the pituitary homogenate after incubation. SP at both concentrations caused a significant (P

Maternal nutritional status affects the future development of offspring. Both undernutrition and overnutrition in critical periods of life (gestation or lactation) may cause several hormonal changes in the pups and programme obesity in the adult offspring. We have shown that hyperleptinaemia during lactation results in central leptin resistance, higher adrenal catecholamine secretion, hyperthyroidism, and higher blood pressure and heart rate in the adult rats. Here, we evaluated the effect of a maternal isocaloric high-fat diet on breast milk composition and its impact on leptinaemia, energy metabolism, and adrenal and thyroid function of the offspring at weaning. We hypothesised that the altered source of fat in the maternal diet even under normal calorie intake would disturb the metabolism of the offspring. Female Wistar rats were fed a normal (9% fat; C group) or high-fat diet (29% fat as lard; HF group) for 8 weeks before mating and during pregnancy and lactation. HF mothers presented increased total body fat content after 8 weeks (+27%, P0.05) and a similar fat content at the end of lactation. In consequence, the breast milk from the HF group had higher concentration of protein (+18%, P0.05), cholesterol (+52%, P0.05) and triglycerides (+86%, P0.05). At weaning, HF offspring had increased body weight (+53%, P0.05) and adiposity (2 fold, P0.05), which was associated with lower β3-adrenoreceptor content in adipose tissue (-40%, P0.05). The offspring also presented hyperglycaemia (+30%, P0.05) and hyperleptinaemia (+62%, P0.05). In the leptin signalling pathway in the hypothalamus, we found lower p-STAT3/STAT3 (-40%, P0.05) and SOCS3 (-55%, P0.05) content in the arcuate nucleus, suggesting leptin resistance. HF offspring also had higher adrenal catecholamine content (+17%, P0.05), liver glycogen content (+50%, P0.05) and hyperactivity of the thyroid axis at weaning. Our results suggest that a high fat diet increases maternal body fat and this additional energy is transferred to the offspring during lactation, since at weaning the dams had normal fat and the pups were obese. The higher fat and protein concentrations in the breast milk seemed to induce early overnutrition in the HF offspring. In addition to storing energy as fat, the HF offspring had a larger reserve of glycogen and hyperglycaemia that may have resulted from increased gluconeogenesis. Hyperleptinaemia may stimulate both adrenal medullary and thyroid function, which may contribute to the development of cardiovascular diseases. These early changes induced by the maternal high-fat diet may contribute to development of metabolic syndrome.

Leptin modulates the hypothalamus-pituitary-thyroid axis and peripheral metabolism of thyroid hormones (THs). We have studied the effect of acute and chronic leptin treatment upon liver mitochondrial glycerol phosphate dehydrogenase activity (mGPD), whose expression and activity are TH dependent. We performed 2 experiments: 1) acute leptin treatment - LepA: adult rats received a single leptin injection (8 microg/100 g BW); 2) chronic leptin treatment - LepC: adult rats received leptin (8 microg/100 g BW) daily, for 6 days. In both experiments, control groups were saline-treated. All rats were sacrificed 2 hours after the last dose. Liver mGPD activity was determined by colorimetric method. Liver D1 activity was measured by the release of (125)I from (125)I-rT3. Serum hormones were measured by RIA. LepA rats showed higher serum thyroid stimulating hormone (TSH) (+ 64%, p

Peptide YY (PYY)3-36 is a gut-derived hormone, with a proposed role in central mediation of postprandial satiety signals, as well as in long-term energy balance. In addition, recently, the ability of the hormone to regulate gonadotropin secretion, acting at pituitary and at hypothalamus has been reported. Here, we examined PYY3-36 effects on thyrotropin (TSH) secretion, both in vitro and in vivo. PYY3-36-incubated rat pituitary glands showed a dose-dependent decrease in TSH release, with 44 and 62% reduction at 10−8 and 10−6 M (P < 0.05 and P < 0.001 respectively), and no alteration in TSH response to thyrotropin-releasing hormone. In vivo, PYY3-36 i.p. single injection in the doses of 3 or 30 cg/kg body weight, administered to rats fed ad libitum, was not able to change serum TSH after 15 or 30 min. However, in fasted rats, PYY3-36 at both doses elicited a significant rise (approximately twofold increase, P < 0.05) in serum TSH observed 15 min after the hormone injection. PYY3-36 treatment did not modify significantly serum T4, T3, or leptin. Therefore, in the present paper, we have demonstrated that the gut hormone PYY3-36 acts directly on the pituitary gland to inhibit TSH release, and in the fasting situation, in vivo, when serum PYY3-36 is reduced, the activity of thyroid axis is reduced as well. In such a situation, systemically injected PYY3-36 was able to acutely activate the thyrotrope axis, suggesting a new role for PYY3-36 as a regulator of the hypothalamic–pituitary–thyroid axis.

Lactating rats were fed with free access to an 8% protein-restricted diet (PR); the control group was fed a 23% protein diet (C). An energy-restricted (pair-fed) group was given the same food as the animals in the control group, but the amounts of food consumed by both PF and PR were about the same. The body weight and serum albumin concentration of PR and PF dams were significantly (P0. 05) lower than that of the controls. The PR group had a significant increase in serum-free triiodothyronine (FT3) concentration, 24-hr mammary gland and milk radioiodine (I131) uptake (67%, 278%, and 200%, respectively) as compared with the controls. On the other hand, those animals had a significantly lower serum-free thyroxine (FT4) concentration and 2- and 24-hr thyroid I131 uptake (67%, 64%, and 74%, respectively). Protein malnutrition during lactation did not alter thyroid or liver 5'-deiodinase activity significantly. However, PF dams had a significantly lower (25%) thyroid 5'-deiodinase activity. These data suggest that protein-restricted lactating dams had an adaptive change in the thyroid function, which could be important to increase the transference of iodine or triiodothyronine through the milk to their pups and prevent sequelae of neonatal hypothyroidism.

There is little information on the possible effects of estrogen on the activity of 5'-deiodinase (5'-ID), an enzyme responsible for the generation of T3, the biologically active thyroid hormone. In the present study, anterior pituitary sonicates or hepatic and thyroid microsomes from ovariectomized (OVX) rats treated or not with estradiol benzoate (EB, 0.7 or 14 micrograms/100 g body weight, s.c., for 10 days) were assayed for type I 5'-ID (5'-ID-I) and type II 5'-ID (5'-ID-II, only in pituitary) activities. The 5'-ID activity was evaluated by the release of 125I from deiodinated 125I rT3, using specific assay conditions for type I or type II. Serum TSH and free T3 and free T4 were measured by radioimmunoassay. OVX alone induced a reduction in pituitary 5'-ID-I (control = 723.7 +/- 67.9 vs OVX = 413.9 +/- 26.9; P0.05), while the EB-treated OVX group showed activity similar to that of the normal group. Thyroid 5'-ID-I showed the same pattern of changes, but these changes were not statistically significant. Pituitary and hepatic 5'-ID-II did not show major alterations. The treatment with the higher EB dose (14 micrograms), contrary to the results obtained with the lower dose, had no effect on the reduced pituitary 5'-ID-I of OVX rats. However, it induced an important increment of 5'-ID-I in the thyroid gland (0.8 times higher than that of the normal group: control = 131.9 +/- 23.7 vs OVX + EB 14 micrograms = 248.0 +/- 31.2; P0.05), which is associated with increased serum TSH (0.6-fold vs OVX, P0.05) but normal serum free T3 and free T4. The data suggest that estrogen is a physiological stimulator of anterior pituitary 5'-ID-I and a potent stimulator of the thyroid enzyme when employed at high doses.