[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 · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The suppression of prolactin production with bromocriptine (BRO) in the last 3 d of lactation reduces milk yield (early weaning) and increases the transfer of leptin through the milk, causing hyperleptinaemia in pups. In adulthood, several changes occur in the offspring as a result of metabolic programming, including overweight, higher visceral fat mass, hypothyroidism, hyperglycaemia, insulin resistance, hyperleptinaemia and central leptin resistance. In the present study, we investigated whether overweight rats programmed by early weaning with maternal BRO treatment have hypothalamic alterations in adulthood. We analysed the expression of neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC) and α-melanocyte-stimulating hormone (α-MSH) by immunohistochemistry in the following hypothalamic nuclei: medial and lateral arcuate nucleus (ARC); paraventricular nucleus (PVN); lateral hypothalamus (LH). Additionally, we sought to determine whether these programmed rats exhibited hypothalamic inflammation as indicated by astrogliosis. NPY immunostaining showed a denser NPY-positive fibre network in the ARC and PVN (+82 % in both nuclei) of BRO offspring. Regarding the anorexigenic neuropeptides, no difference was found for CART, POMC and α-MSH. The number of astrocytes was higher in all the nuclei of BRO rats. The fibre density of glial fibrillary acidic protein was also increased in both medial and lateral ARC (6·06-fold increase and 9·13-fold increase, respectively), PVN (5·75-fold increase) and LH (2·68-fold increase) of BRO rats. We suggest that early weaning has a long-term effect on the expression of NPY as a consequence of developmental plasticity, and the presence of astrogliosis indicates hypothalamic inflammation that is closely related to overweight and hyperleptinaemia observed in our model.
British Journal Of Nutrition 01/2015; 113(03):1-10. DOI:10.1017/S0007114514003882 · 3.34 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 · 2.61 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. METHODS: 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. RESULTS: 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. β(3)-adrenergic receptor content in visceral adipose tissue was unchanged in SL rats, but the β(2)-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. CONCLUSIONS: Neonatal overfeeding led to higher adrenomedullary function, but the liver β(2)-adrenergic receptor content was reduced. These results may contribute to the hepatic dysfunction characteristic of liver obesity complications.
European Journal of Nutrition 09/2012; DOI:10.1007/s00394-012-0448-8 · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interruption of lactation for a short period, without the use of pharmacological substances or maternal separation, causes offspring malnutrition and hypoleptinaemia and programmes for metabolic disorders such as higher body weight and adiposity, hyperphagia, hyperleptinaemia and central leptin resistance in adulthood. Here, in order to clarify the mechanisms underlying the phenotype observed in adult early-weaned (EW) rats, we studied the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in different hypothalamic nuclei by immunohistochemistry and Western blot. In the EW group, the teats of lactating rats were blocked with a bandage to interrupt lactation during the last 3 d, while control pups had free access to milk throughout the entire lactation period. At age 180 d, EW offspring showed higher NPY staining in the paraventricular nucleus (PVN), as well as NPY protein content (+68 %) in total hypothalamus than control ones. AgRP showed no changes in staining or Western blot. POMC content was not affected; however, its distribution pattern was altered. CART-positive cells of EW offspring had lower immunoreactivity associated with reduced cell number in the PVN and lower protein content ( - 38 %) in total hypothalamus. The present data indicate that precocious weaning can imprint the neuronal circuitry, especially in the PVN, and cause a long-term effect on the expression of specific orexigenic and anorexigenic neuropeptides, such as NPY and CART, that can be caused by leptin resistance and are coherent with the hyperphagia observed in these animals.
The British journal of nutrition 07/2012; 108(12):1-10. DOI:10.1017/S0007114512000487 · 3.34 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 · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is important for both long-term survival and timing of the progression of oligodendrocyte differentiation. Oligodendroglial cells treated with MEK inhibitor were distinguished by using stage specific markers: NG2 proteoglycan, A2B5, 2'3'nucleotide-cyclic 3'phosphodiesterase (CNPase) and myelin basic protein (MBP), and classified according to their morphology into different developmental stages. Treatment significantly increased the number of cells with more immature morphologies and decreased the number of mature cells. Furthermore, it increased the number of rounded cells that could not be classified into any of the oligodendroglial developmental stages. The strongest effects were usually observed shortly after treatment. Rounded cells were CNPase/MBP positive and they were not stained by anti-NG2 or A2B5, indicating that they were mature cells unable either to extend and/or to maintain their processes. These data showed an effect of the MAPK/ERK pathway on oligodendroglial branching, with possible consequences for the formation of the myelin sheath.
International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 09/2009; 27(8):757-68. DOI:10.1016/j.ijdevneu.2009.08.014 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myelination depends on the proper differentiation of oligodendrocytes and several factors may influence this event. For instance, thyroid hormone (T3) affects the timing of differentiation and regulates the expression of several enzymes involved in the synthesis of complex lipids and in the expression of some myelin structural proteins. We investigated the effect of T3 deficiency on oligodendroglial differentiation and in the distribution of oligodendrocyte/myelin proteins 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and myelin basic protein (MBP). Oligodendroglial-enriched cultures were obtained from cerebra of neonate rats grown in a modified medium. The T3-deficient status was induced by using medium devoid of T3. We observed a delay, in T3-deficient cultures, in oligodendroglial maturation characterized by less extensive processes and membrane vellum than in controls. In control cultures, CNPase immunoreactivity was punctated, showing cell bodies and processes at earlier stages and redistribution to cytoskeleton vein-like structures in later stages. In T3-deficient cultures, CNPase remained in a punctated pattern and only at 10 days in vitro we observed CNPase redistribution to the presumptive cytoskeleton vein-like structures. MBP in control cultures was distributed through the whole cell body and processes whereas in T3-deficient cultures, MBP immunoreactivity was concentrated in the perinuclear region. These results reinforce the hypothesis that T3 is an important factor in oligodendrocyte differentiation, particularly regarding the distribution of myelin proteins.
International Journal of Developmental Neuroscience 12/2006; 24(7):445-53. DOI:10.1016/j.ijdevneu.2006.08.004 · 2.92 Impact Factor