[Show abstract][Hide abstract] ABSTRACT: Postnatal nicotine exposure leads to obesity and hypothyroidism at adulthood. Then, we studied the effects of maternal nicotine exposure during lactation on thyroid hormone metabolism and function in adult offspring. Lactating rats were implanted with osmotic minipumps releasing nicotine (NIC, 6 mg/kg/day s.c.) or saline (control) from postnatal day 2 to 16. Offspring were killed at 180 days-old. We measured type 1 and 2 deiodinase activity and mRNA, mitochondrial α-glycerol-3-phosphate dehydrogenase (mGPD) activity, thyroid hormone receptor (TR) and uncoupling protein 1 (UCP1), hypothalamic TRH and pituitary TSH, and "in vitro" TRH-stimulated TSH secretion. Expression of deiodinase mRNAs followed the same profile of the enzymatic activity. NIC exposure caused lower 5'-D1 and mGPD activities, and TRβ1 content in liver as well as lower 5'-D1 activity in muscle, higher 5'-D2 activity in brown adipose tissue (BAT), heart and testis, which are in accordance with hypothyroidism. Although deiodinase activities were not changed in hypothalamus, pituitary and thyroid of NIC offspring, UCP1 was lower in BAT. Both TRH and TSH were lower in NIC offspring, which presented higher basal "in vitro" TSH secretion, which was not increased after TRH. Thus, the hypothyroidism in NIC offspring at adulthood was caused, in part, by TRH-TSH "in vivo" suppression and lower sensitivity to TRH. Despite the hypothyroid status of peripheral tissues, these animals seem to develop an adaptive mechanism to preserve T4 to T3 conversion at central level.
Journal of Endocrinology 02/2015; 224(3). DOI:10.1530/JOE-14-0473 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early nicotine exposure causes future obesity and insulin resistance. We evaluated the long-term effect of the maternal nicotine exposure during lactation in liver oxidative status, insulin sensitivity and morphology in adult offspring. Two days after birth, osmotic minipumps were implanted in the dams: nicotine (N), 6 mg/kg/day for 14 days or saline (C). Offspring were killed at 180 days. Protein content of superoxide dismutase, glutathione peroxidase, catalase, nitrotyrosine, 4HNE, IRS1, Akt1 and PPARs were measured. MDA, bound protein carbonyl content, SOD, GPx and catalase activities were determined in liver and plasma. Hepatic morphology and triglycerides content were evaluated. Albumin and bilirubin were determined. In plasma, N offspring had higher catalase activity, and SOD/GPx ratio, albumin and bilirubin levels but lower MDA content. In liver, they presented higher MDA and 4HNE levels, bound protein carbonyl content, SOD activity but lower GPx activity. N offspring presented an increase of lipid droplet, higher triglyceride content and a trend to lower PPARα in liver despite unchanged insulin signaling pathway. Early nicotine exposure causes oxidative stress in liver at adulthood, while protect against it at plasma level. In addition, N offspring develop liver microsteatosis, which is related to oxidative stress but not to insulin resistance.
Food and Chemical Toxicology 02/2015; 78. DOI:10.1016/j.fct.2015.01.025 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signalling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2(nd) postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6mg/Kg/day) or saline for 14 days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had P<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fibre density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 04/2013; 58. DOI:10.1016/j.fct.2013.04.036 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Children from pregnant smokers show more susceptibility to develop obesity in adult life. Previously, we failed to demonstrate in rats offspring a programming for obesity when only the mothers were tobacco smoke-exposed during lactation. Here, we studied the short- and long-term effects of smoke exposure to both dams and their pups during lactation upon endocrine and metabolic parameters. For this, we designed an experimental model where nursing rats and their pups were divided into: SE group, smoke-exposed in a cigarette smoking machine (4 times/day, from the 3rd to the 21th day of lactation) and C group, exposed to filtered air. Pups were killed at 21 and 180 days old. At weaning, SE pups showed lower body weight (7%), length (5%), retroperitoneal fat mass (59%), visceral adipocyte area (60%) and higher subcutaneous adipocyte area (95%) with hypoinsulinemia (-29%), hyperthyroxinemia (59%), hypercorticosteronemia (60%) and higher adrenal catecholamine content (+58%). In adulthood, SE offspring showed higher food intake (+10%), body total fat mass (+50%), visceral fat mass (retroperitoneal: 55%; mesenteric: 67%; epididymal: 55%), and lower subcutaneous adipocyte area (24%) with higher serum glucose (11%), leptin (85%), adiponectin (1.4 fold-increase), TT3 (71%), FT4 (57%), TSH (36%), triglycerides (65%), VLDL-c (+66%), HDL-c (91%) levels, lower corticosteronemia (41%) and adrenal cathecolamine content (57%). Our present findings suggest that tobacco smoke exposure to both dams and their pups during lactation causes a malnutrition in early life that programs for obesity and hormonal and metabolic disturbances in adulthood, only if the pups are submitted to the same smoke environment than the mother.
Journal of Endocrinology 04/2013; 218(1). DOI:10.1530/JOE-13-0003 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Rats that are overfed during lactation exhibit neonatal hyperleptinemia and higher visceral adiposity, hypertension, higher liver oxidative stress and insulin resistance in the liver as adults. Previously, we demonstrated that neonatal hyperleptinemia is associated with adrenal medullary hyperfunction, hypertension and liver steatosis in adulthood. Therefore, we hypothesised that adrenal and liver functions are altered in adult obese rats that were overfed during lactation, which would underlie their hypertension and liver alterations.
The litter size was reduced from ten to three male pups on the third day of lactation until weaning (SL) to induce early overfeeding in Wistar rats. The control group had ten rats per litter (NL). Rats had free access to standard diet, and water after weaning until the rats were 180 days old.
The SL group exhibited higher adrenal catecholamine content (absolute: +35% and relative: +40%), tyrosine hydroxylase (+31%) and DOPA decarboxylase (+90%) protein contents and basal catecholamine secretion in vitro (+57%). However, the hormones of the hypothalamic-pituitary-adrenal cortex axis were unchanged. β₃-adrenergic receptor content in visceral adipose tissue was unchanged in SL rats, but the β₂-adrenergic receptor content in the liver was lower in this group (-45%). The SL group exhibited higher glycogen and triglycerides contents in the liver (+79 and +49%, respectively), which suggested microesteatosis.
Neonatal overfeeding led to higher adrenomedullary function, but the liver β₂-adrenergic receptor content was reduced. These results may contribute to the hepatic dysfunction characteristic of liver obesity complications.
European Journal of Nutrition 09/2012; 52(4). DOI:10.1007/s00394-012-0448-8 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Hormone and Metabolic Research 09/2012; 45(1). DOI:10.1055/s-0032-1323703 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previously, we have shown that maternal smoke exposure during lactation, even when pups are not exposed, affects biochemical profiles in the offspring at weaning, eliciting lower body adiposity, hyperinsulinemia, hypocorticosteronemia and lower adrenal catecholamine content. However, the future impact of tobacco exposure is still unknown. As postnatal nicotine exposure causes short- and long-term effects on pups' biochemistry and endocrine profiles, we have now evaluated some endocrine and metabolic parameters of the adult offspring whose mothers were tobacco exposed during lactation. For this, from day 3 to 21 of lactation, rat dams were divided in: 1) SE group, cigarette smoke-exposed (1.7 mg nicotine/cigarettes for 1 h, 4 times/day, daily), without their pups, and 2) C group, exposed to air, in the same conditions. Offspring were killed at 180-days-old. Body weight and food intake were evaluated. Blood, white adipose tissue, adrenal, and liver were collected. All significant data were p<0.05. The adult SE offspring showed no change in body weight, cumulative food intake, serum hormone profile, serum lipid profile, or triglycerides content in liver. However, in adrenal gland, adult SE offspring showed lower catecholamine content ( - 50%) and lower tyrosine hydroxylase protein expression ( - 56%). Despite the hormonal alterations during lactation, tobacco smoke exposure through breast milk only programmed the adrenal medullary function at adulthood and this dysfunction can have consequence on stress response. Thus, an environment free of smoke during lactation period is essential to improve health outcomes in adult offspring.
Hormone and Metabolic Research 05/2012; 44(7):550-4. DOI:10.1055/s-0032-1312597 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neonate male rats whose mothers were nicotine-treated during lactation have higher adiposity, hyperleptinemia, and adrenal dysfunction. At adulthood, they still present higher adiposity and hyperleptinemia, but there was no report about their adrenal function. Also, there was no report of this developmental plasticity on females. Here, we evaluated the adrenal function and leptin content in adipocytes and muscle of male and female adult offspring whose mothers were nicotine-treated during lactation. On the 2nd postnatal day (PN2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6 mg/kg/day) or saline for 14 days (12 litters/group and 2 rats/litter). Male and female offspring were killed on PN180. Significant data were p<0.05. Male NIC offspring presented higher adrenal catecholamine content (+ 89%) and TH expression (+ 38%), lower "in vitro" catecholamine release (- 19%), and higher adrenergic β3 receptor (ADRB3, + 59%) content in visceral adipose tissue (VAT). Serum corticosterone was higher (+ 77%) in male NIC group, coherent with the increase of both CRH and ACTH immunostaining in hypothalamus and pituitary, respectively. Leptin content was higher in VAT (+ 23%), which may justify the observed hyperleptinemia. Female NIC offspring presented lower ADRB3 content in VAT (- 39%) and lower leptin content in subcutaneous adipose tissue (SAT) (- 46%), but higher leptin content in soleus muscle (+ 22%), although leptinemia was normal. We evidenced a sex dimorphism in the model of maternal nicotine exposure during lactation. The adrenal function in adult offspring was primed only in male offspring while the female offspring displayed relevant alterations in leptin content on muscle and adipocytes.
Hormone and Metabolic Research 09/2011; 43(10):693-701. DOI:10.1055/s-0031-1285909 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal nicotine exposure leads to neonatal hypothyroidism that can be returned to euthyroidism after nicotine withdrawal. Here, we examined the transfer of iodine through milk, deiodinase activities (D1 and D2), and serum T3, T4 and TSH in rat offspring after maternal exposure to nicotine. One day after birth, a minipump was implanted to dams releasing nicotine (NIC), 6 mg/kg/day for 13 days or vehicle saline. Animals were killed at the day 15 and 21 of lactation. At day 15, NIC-treated dams showed decreased T4 and mammary 2h-radioiodine uptake (RAIU) and increase of TSH, thyroid 2h-RAIU, liver D1 and mammary D2. At the cessation of NIC-exposure, pups displayed decreased T3, T4 and thyroid 2h-RAIU and increased TSH. At weaning (21-postnatal day), NIC-treated dams recovered their T4 and TSH, but increased deiodinase level in the liver and mammary gland. Milk T3 content in NIC-treated dams was higher at both day 15 and 21, and thyroid function was recovered at the day 21. Thus, thyroid function was affected by nicotine in both mothers and pups, suggesting a primary hypothyroidism. After nicotine withdrawal, pups recovered thyroid function probably due to the increased lactational transfer of T3 in relation with increased mammary gland deiodinase activities.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 05/2011; 49(9):2068-73. DOI:10.1016/j.fct.2011.04.040 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4 × 1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (+50%), hypoinsulinemia (-40%), hypoleptinemia (-46%), as well as lower triglycerides (-53%) and very low-density lipoprotein cholesterol (-50%). Milk of S dams had higher lactose (+52%) and triglycerides (+78%). S pups presented higher body protein (+17%), lower total (-24%) and subcutaneous fat contents (-25%), hypoglycemia (-11%), hyperinsulinemia (+28%), hypocorticosteronemia (-40%), lower adrenal catecholamine content (-40%), hypertriglyceridemia (+34%), higher high-density lipoprotein cholesterol (+16%), and lower low-density lipoprotein cholesterol (-45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny.
Journal of Endocrinology 03/2011; 209(1):75-84. DOI:10.1530/JOE-10-0410 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Postnatal nicotine exposure causes precocious primary hypothyroidism and programs for overweight, hyperleptinemia and secondary hypothyroidism in adulthood. As leptin and thyroid hormones share the ability to increase energy expenditure, we studied the effects of maternal nicotine exposure during lactation on the leptin signaling in the hypothalamus-pituitary-thyroid axis of suckling and adult offspring.
Two days after delivery, osmotic minipumps were implanted in lactating rats, and nicotine (NIC, 6 mg/kg/day s.c.) or saline (C) was administered for 14days. Offspring were killed at 15 and 180 days-old. Proteins belonging to leptin signaling were analyzed by Western blot. Significant differences had p<0.05.
In the hypothalamus, NIC offspring showed higher OB-R and pSTAT-3 content (+58%,+1.34x) at 15 days, and lower OB-R, JAK-2 and pSTAT-3 (-61%, -42%, -56%) at 180 days. In the pituitary gland, NIC offspring showed lower JAK-2 content (-52%) at 15 days, but no differences in adulthood. In the thyroid gland, the NIC group presented lower OB-R, JAK-2 and STAT-3 (-44%, -50%, -47%) and higher pSTAT-3 expression (+80%) at 15 days. At 180 days-old, NIC offspring presented higher thyroid OB-R (+1.54x) and lower pSTAT-3 content (-34%).
Neonatal primary hypothyroidism induced by maternal nicotine exposure during lactation may be partially explained by decreased leptin signaling in the thyroid, though the early stimulation of the central leptin pathway did not prevent the thyroid dysfunction. Long-term effects of postnatal nicotine exposure on leptin signaling in the hypothalamus and thyroid appear to involve central and peripheral leptin resistance in adulthood.
Life sciences 07/2010; 87(5-6):187-95. DOI:10.1016/j.lfs.2010.06.012 · 2.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal nicotine (NIC) exposure during lactation leads to overweight, hyperleptinemia, and hypothyroidism in adult rat offspring. In this model, we analyzed adipocyte morphology, glucose homeostasis (serum insulin and adiponectin; liver and muscle glycogen), serum lipid, and the leptin signaling pathway. After birth, osmotic minipumps were implanted in lactating rats, which were divided into the groups NIC (6 mg/kg per day s.c. for 14 days) and control (C, saline). NIC and C offspring were killed at the age of 180 days. Adult NIC rats showed higher total body fat (+10%, P<0.05), visceral fat mass (+12%, P<0.05), and cross-sectional area of adipocytes (epididymal: +12% and inguinal: +43%, P<0.05). Serum lipid profile showed no alteration except for apolipoprotein AI, which was lower. We detected a lower adiponectin:fat mass ratio (-24%, P<0.05) and higher insulinemia (+56%, P<0.05), insulin resistance index (+43%, P<0.05), leptinemia (+113%, P<0.05), and leptin:adiponectin ratio (+98%, P<0.05) in the adult NIC group. These rats presented lower hypothalamic contents of the proteins of the leptin signaling pathway (leptin receptor (OB-R): -61%, janus tyrosine kinase 2: -41%, and p-signal transducer and activator of transcription 3: -56%, P<0.05), but higher suppressor of cytokine signaling 3 (+81%, P<0.05). Therefore, NIC exposure only during lactation programs rats for adipocyte hypertrophy in adult life, as well as for leptin and insulin resistance. Through the effects of NIC, perinatal maternal cigarette smoking may be responsible for the future development of some components of the metabolic syndrome in the offspring.
Journal of Endocrinology 07/2010; 206(1):55-63. DOI:10.1677/JOE-10-0104 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leptin serum concentration in early life is an important factor for adequate future development of the offspring. Previously, we demonstrated that hyperleptinemia on lactation programmed for hyperleptinemia, central leptin resistance with lower expression of the long form of leptin receptor at hypothalamus, and higher medullary catecholamine levels with cardiovascular consequences at adulthood. The central objective of this study was to determine the direct effect of leptin on adrenal medullary function of adult rats that were leptin treated during lactation. Adrenal morphology was also accessed. Recombinant murine leptin was injected in the pups during the first 10 days of life (group L, leptin-programmed) or at adulthood during 6 days (group LC). The controls of both experiments received saline (groups C and CC). Both treatments resulted in hyperleptinemia at 150 days old (+78% and 2-fold increase, respectively; P < 0.05). Programmed animals showed hypertrophy of adrenal and higher adrenal catecholamine content at 150 days old (3-fold increase, P < 0.05), and no changes were observed in the LC group. However, LC rats had lower adrenal content of tyrosine hydroxylase (-17%, P < 0.05). Leptin-programmed rats had a lower response to leptin in vitro stimulation (-22%, P < 0.05) and lower expression of key proteins of the leptin signaling pathway, leptin receptor and janus tyrosine kinase 2 in the medullas (-61% and -29%, respectively, P < 0.05). However, they presented higher expression of phosphorylated signal transducer and activator of transcription 3 (+2-fold, P < 0.05). Leptin treatment at adulthood did not affect these parameters. The higher catecholamine synthesis and secretion in the leptin-programmed rats observed in our previous study does not seem to be a consequence of the direct effect of leptin on the medullas. We suggest that the hyperleptinemia of the programmed animals increases adrenal medullary function through sympathetic nervous system activation. In conclusion, high leptin levels on lactation program the activity of the sympathoadrenal system at adulthood that may contribute to the development of adult chronic diseases such as hypertension.
[Show abstract][Hide abstract] ABSTRACT: We have shown that maternal nicotine exposure during lactation has long-lasting effects on body adiposity and hormonal status of rat offspring. Here, we studied the nutritional and hormonal profiles in this experimental model. Two days after birth, osmotic minipumps were implanted in lactating rats divided into two groups: NIC - continuous s.c. infusions of nicotine (6 mg/kg per day) for 14 days and C - saline. Dams and pups were killed at 15 and 21 days of lactation. Body weight and food intake were evaluated. Milk, blood, visceral fat, carcass, and adrenal gland were collected. All the significant data were P<0.05. At the end of nicotine exposure (15 days), dams presented higher milk production, hyperprolactinemia, and higher serum high-density lipoprotein cholesterol (HDL-C). Milk from NIC dams had higher lactose concentration and energy content. After nicotine withdrawal (21 days), dams showed lower food intake and hyperleptinemia. The 15-day-old NIC pups presented higher total body fat, higher HDL-C, serum leptin, serum corticosterone, and adrenal catecholamine content, but lower tyrosine hydroxylase protein levels. The 21-day-old NIC pups had higher body protein content and serum globulin. Thus, maternal nicotine exposure during lactation results in important changes in nutritional, biochemical, and hormonal parameters in dams and offspring. The pattern of these effects is clearly distinct when comparing the nicotine-exposed group to the withdrawal group, which could be important for the programming effects observed previously.
Journal of Endocrinology 02/2010; 205(2):159-70. DOI:10.1677/JOE-09-0430 · 3.72 Impact Factor