Early life nicotine exposure alters mRNA and microRNA expressions related to thyroid function and lipid metabolism in liver and BAT of adult wistar rats.

In rats, maternal nicotine exposure during lactation induces obesity, thyroid dysfunction, brown adipose tissue (BAT) hypofunction and liver alterations in adult offspring. Both thyroid function and lipid metabolism are influenced by gene silencing mediated by microRNAs (miRNAs). Here we investigated long-term effects of early nicotine exposure on molecular and epigenetic mechanisms closely related to thyroid and lipid metabolism, through the expression of mRNAs and miRNAs in BAT and liver of adult male and female offspring. At postnatal day 2 (PND2), lactating control (CON) or nicotine (NIC) dams were subcutaneously implanted with osmotic minipumps containing, respectively, saline or 6 mg/kg nicotine. Litters were adjusted to 3 males and 3 females. Offspring's euthanasia occurred at PND180. In the BAT, NIC females showed higher Dio2 mRNA expression, while miR-382* expression was not altered in both sexes. In the liver, NIC offspring of both sexes showed lower Dio1 mRNA expression and higher miR-224 expression, while only NIC females had higher miR-383 and miR-21 expressions. NIC offspring of both sexes showed higher mRNA expression of SCD1 in the liver; NIC males had decreased CPT1 expression, whereas NIC females had increased FASN, miR-370 and miR-122 expressions. Regardless of sex, alterations in liver Dio1, miR-224 and SCD1 expressions are involved in the disturbances caused by maternal nicotine exposure during breastfeeding. Interestingly, females had more altered miRs in the liver. Early nicotine exposure induces a sex dimorphism, particularly regarding hepatic lipid metabolism, through miRs expression.

Protein restriction during pregnancy impairs intra-islet GLP-1 and the expansion of ß-cell mass.

We evaluated whether protein restriction during pregnancy alters the morphometry of pancreatic islets, the intra-islet glucagon-like peptide-1 (GLP-1) production, and the anti-apoptotic signalling pathway modulated by GLP-1. Control non-pregnant (CNP) and control pregnant (CP) rats were fed a 17% protein diet, and low-protein non-pregnant (LPNP) and low-protein pregnant (LPP) groups were fed a 6% protein diet. The masses of islets and ß-cells were similar in the LPNP group and the CNP group but were higher in the CP group than in the CNP group and were equal in the LPP group and the LPNP group. Both variables were lower in the LPP group than in the CP group. Prohormone convertase 2 and GLP-1 fluorescence in α-cells was lower in the low-protein groups than in the control groups. The least PC2/glucagon colocalization was observed in the LPP group, and the most was observed in the CP group. There was less prohormone convertase 1/3/glucagon colocalization in the LPP group than in the CP group. GLP-1/glucagon colocalization was similar in the LPP, CP and CNP groups, which showed less GLP-1/glucagon colocalization than the LPNP group. The mRNA Pka, Creb and Pdx-1 contents were higher in islets from pregnant rats than in islets from non-pregnant rats. Protein restriction during pregnancy impaired the mass of ß-cells and the intra-islet GLP-1 production but did not interfere with the transcription of genes of the anti-apoptotic signalling pathway modulated by GLP-1.

Tobacco smoking during breastfeeding increases the risk of developing metabolic syndrome in adulthood: Lessons from experimental models.

Metabolic syndrome (MetS) is characterized by increased abdominal fat, dyslipidemia, diabetes mellitus and hypertension. A high MetS prevalence is strongly associated with obesity. Obesity is a public health problem in which several complex factors have been implicated, including environmental pollutants. For instance, maternal smoking seems to play a role in obesogenesis in childhood. Given the association between endocrine disruptors, obesity and metabolic programming, over the past 10 years, our research group has contributed to studies based on the hypothesis that early exposure to nicotine/tobacco causes offspring to become MetS-prone. The mechanism by which tobacco smoking during breastfeeding induces metabolic dysfunctions is not completely understood; however, increased metabolic programming has been shown in studies that focus on this topic. Here, we reviewed the literature mainly based in light of our latest data from experimental models. Nicotine or tobacco exposure during breastfeeding induces several endocrine dysfunctions in a sex- and tissue-specific manner. This review provides an updated summary regarding the hypothesis that early exposure to nicotine/tobacco causes offspring to become MetS-prone. An understanding of this issue can provide support to prevent long-term disorders, mainly related to the risk of obesity and its comorbidities, in future generations.

Maternal soy protein isolate diet during lactation programmes to higher metabolic risk in adult male offspring.

Soy consumption and its components, including its protein, are related to the beneficial effects of the lipid profile, decreased insulin resistance and glycaemia. However, the safety of the consumption of products containing phytoestrogens in critical stages of development has been questioned, since they may be associated with endocrine-metabolic dysfunctions in adult life. The purpose is to evaluate the effects of maternal dietary soy protein isolate (SPI) during lactation on the breast milk composition, body composition, lipid and glycaemic profiles, and thyroid hormones of dams and offspring at weaning (21 days) and in adulthood (150 days). Lactating rats were divided into casein control (C) and SPI diet groups. At 150 days, the SPI offspring presented lower body protein mass and total mineral content, higher serum FT4, insulin, TC and TG. Maternal consumption of SPI during lactation programmes the progeny to higher metabolic risk profile.

Programming of hepatic lipid metabolism in a rat model of postnatal nicotine exposure - Sex-related differences.

Maternal nicotine exposure during lactation induces liver damage in adult male rats. However, the mechanism in males is unknown and females have not been tested. Here, we determined the liver lipid composition and lipogenic enzymes in male and female offspring at two ages in a model of postnatal nicotine exposure. Osmotic minipumps were implanted in lactating Wistar rat dams at postnatal day (PND) 2 to release 6 mg/kg/day of nicotine (NIC group) or saline (CON group) for 14 days. Offspring received a standard diet from weaning until euthanasia at PND120 (1 pup/litter/sex) or PND180 (2 pups/litter/sex). At PND120, NIC males showed lower plasma triglycerides (TG), steatosis degree 1, higher hepatic cholesterol (CHOL) ester, free fatty acids, monoacylglycerol content as well as acetyl-coa carboxylase-1 (ACC-1) and fatty acid synthase (FAS) protein expression in the liver compared to CON males. At this age, NIC females had preserved hepatocytes architecture, higher plasma CHOL, higher CHOL ester and lower total CHOL content in the liver compared to CON females. At PND180, NIC males showed steatosis degrees 1 and 2, higher TG, lower free fatty acids and total CHOL content in the liver and an increase in ACC-1 hepatic protein expression. NIC females had higher plasma TG and CHOL levels, no change in hepatic morphology, lower CHOL ester and free fatty acids in the liver, which also showed higher total ACC-1 and FAS protein expression. Maternal nicotine exposure induces long-term liver dysfunction, with an alteration in hepatic cytoarchitecture that was aggravated with age in males. Concerning females, despite unchanged hepatic cytoarchitecture, lipid metabolism was compromised, which deserves further attention.

Cigarette Smoke During Breastfeeding in Rats Changes Glucocorticoid and Vitamin D Status in Obese Adult Offspring.

Maternal smoking increases obesogenesis in the progeny. Obesity is associated with several hormonal dysfunctions. In a rat model of postnatal tobacco smoke exposure, we previously reported increased central fat depot and disruption of some hormonal systems in the adult offspring. As both glucocorticoids and vitamin D alter lipogenesis and adipogenesis, here we evaluated the metabolism of these two hormones in visceral adipose tissue (VAT) and liver by Western blotting, and possible associations with lipogenesis biomarkers in adult rats that were exposed to tobacco smoke during their suckling period. At postnatal day (PN) 3, dams and offspring of both sexes were exposed (S group) or not (C group) to tobacco smoke, 4 × 1 h/day. At PN180, corticosteronemia was lower in S male and higher in S female offspring, without alterations in peripheral glucocorticoid metabolism and receptor. Adrenal ACTH receptor (MC2R) was higher in both sexes of S group. Despite unchanged serum vitamin D, liver 25-hydroxylase was higher in both sexes of S group. Male S offspring had higher 1α-hydroxylase, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) in VAT. Both sexes showed increased ACC protein content and reduced sirtuin mRNA in liver. Male S offspring had lower liver peroxisome proliferator-activated receptor-α. Tobacco exposure during lactation induced abdominal obesity in both sexes via distinct mechanisms. Males and females seem to develop HPA-axis dysfunction instead of changes in glucocorticoid metabolism and action. Lipogenesis in VAT and liver, as well as vitamin D status, are more influenced by postnatal smoke exposure in male than in female adult rat offspring.

Short term low-calorie diet improves insulin sensitivity and metabolic parameters in obese women.

Obesity and insulin resistance are associated with an increase of cardiovascular risk factors, including adipocytokines. The aim of this study was to investigate the effect of low-calorie diet on serum lipids, adipokines, insulin resistance and body composition in obese women. It was a clinical trial with class I obese women aged 30-45 years submitted to hypocaloric diet for 90 days. Dietary intake, anthropometric parameters, body composition, serum lipids, glucose, insulin, leptin, adiponectin, HOMA-IR and QUICKI indexes were evaluated at the baseline, 30, 60 and 90 days. There was 30% significant decrease in energy intake, and also decrease in body weight, body mass index and waist circumference (p < 0.01) throughout the treatment period. Despite the amount of lean body mass (kg) reduced in average, it was observed that lean body mass (%) had increased (p < 0.01) and that the amount of fat body mass (kg) had decreased significantly in the third month (p < 0.05). Systolic blood pressure reduced up to -5mmHg (p < 0.05) after 90 days. Was observed a decrease (p < 0.05) on serum insulin and HOMA-IR until the 60th day, while the serum adiponectin increased (p < 0.01) during treatment. Corroborating with the reduction of fat body mass and weight, serum leptin also reduced (p < 0.01). These results suggest that the short-term low-calorie diet reduces total body fat, mainly found in the abdominal region, and efficiently improve insulin sensitivity decreasing cardiovascular risk in obese women.

La obesidad y la resistencia a la insulina se asocian con un aumento de los factores de riesgo cardiovascular, incluyendo las adipocitocinas. El propósito de este estudio fue investigar el efecto de una dieta baja en calorías sobre los lípidos séricos, las adipocinas, la resistencia a la insulina y la composición corporal en mujeres obesas. Se trataba de un estudio clínico en mujeres con obesidad de clase I, con edades entre 30-45 años, sometidas a una dieta hipocalórica durante 90 días. Se evaluaron basalmente y a los 30, 60 y 90 días la ingesta dietética, los parámetros antropométricos, la composición corporal, los lípidos séricos, la glucosa, la insulina, la leptina, la adiponectina y los índices HOMA-IR QUICKI. Hubo un descenso significativo del 30 % en el consumo de energía y un descenso del peso corporal, el índice de masa corporal y la circunferencia de la cintura (p < 0,01) durante todo el periodo de tratamiento. A pesar de que se redujo en promedio la masa magra corporal (kg), se observó que la masa magra corporal (%) se incrementó (p < 0,01) y que la cantidad de masa corporal grasa (Kg) disminuyó significativamente al tercer mes (p < 0,05). La presión sanguínea sistólica se redujo en 5 mmHg (p < 0,05) a los 90 días. Observamos un descenso de la insulina sérica y del HOMA-IR en el día 60 (p < 0,05), mientras que la adiponectina sérica aumentó (p < 0,01) durante el tratamiento. Como corroboración de la reducción de la masa corporal grasa y del peso, la leptina sérica también se redujo (p < 0,01). Estos resultados sugieren que la dieta hipocalórica a corto plazo reduce la grasa corporal total, fundamentalmente en la región abdominal y mejora de forma eficiente la sensibilidad a la insulina disminuyendo el riesgo cardiovascular en mujeres obesas.

Nicotine exposure during the third trimester equivalent of human gestation: time course of effects on the central cholinergic system of rats.

Up to 22% of pregnant women smoke, which constitutes a major health concern. Nicotine, a cholinergic agonist, causes deleterious effects on brain development. However, most studies investigate its effects during rodents' gestation, which corresponds, in terms of neural development, to the first two trimesters of human gestation. Here, we focused on effects of nicotine on the brain cholinergic system during the third trimester equivalent of human gestation. From the 2nd to the 19th day of lactation, dams were exposed either to nicotine (6 mg/kg/day) or to saline via sc osmotic minipumps. Offspring were sacrificed during exposure (PN15, PN, postnatal) or at 2 days (PN21), 11 days (PN30), or 10 weeks (PN90) of withdrawal. In the cerebral cortex, midbrain, and hippocampus, we assessed nicotinic acetylcholine receptor (nAChR) binding, [(3)H]hemicholinium-3 (HC-3) binding to the high-affinity choline transporter, choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) activities. Nicotine-exposed offspring presented nAChR upregulation during exposure in all brain regions, reduced HC-3 binding during and 11 days postexposure, and increased HC-3 binding on PN90. Effects on ChAT and AChE were dependent on the brain region and restricted to the withdrawal period: There were increased activities in the midbrain on PN30. In the hippocampus, AChE as reduced on PN30, whereas, for ChAT, the decrease was followed by late-emergent increased activity. These data indicate that maternal nicotine exposure during the third trimester equivalent of human gestation promotes cholinergic system alterations in the offspring's brain. In addition, detrimental effects are observable even long after the exposure has been interrupted.

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.