Changes in gut-brain axis parameters in adult rats of both sexes with different feeding pattern that were early nicotine-exposed.

Nicotine is an endocrine disruptor and imprinting factor during breastfeeding that can cause food intake imbalance in the adulthood. As nicotine affects the intestinal microbiota, altering the composition of the bacterial communities and short-chain fatty acids (SCFAs) synthesis in a sex-dependent manner, we hypothesized that nicotine could program the gut-brain axis, consequently modifying the eating pattern of adult male and female rats in a model of maternal nicotine exposure (MNE) during breastfeeding. Lactating Wistar rat dams received minipumps that release 6 mg/kg/day of nicotine (MNE group) or saline for 14 days. The progeny received standard diet from weaning until euthanasia (26 weeks of age). We measured: in vivo electrical activity of the vagus nerve; c-Fos expression in the nucleus tractus solitarius, gastrointestinal peptides receptors, intestinal brain-derived neurotrophic factor (BDNF), SCFAs and microbiota. MNE females showed hyperphagia despite normal adiposity, while MNE males had unchanged food intake, despite obesity. Adult MNE offspring showed decreased Bacteroidetes and increased Firmicutes, Actinobacteria and Proteobacteria. MNE females had lower fecal acetate while MNE males showed higher vagus nerve activity. In summary nicotine exposure through the milk induces long-term intestinal dysbiosis, which may affect eating patterns of adult offspring in a sex-dependent manner.

Nicotine exposure during lactation causes disruption of hedonic eating behavior and alters dopaminergic system in adult female rats.

Tobacco smoke during gestation is associated with increased consumption of palatable foods by the offspring in humans and rats. Postpartum relapse is observed in lactating women who quit smoking during pregnancy, putting their children at risk of adverse health outcomes caused by secondhand smoke. Nicotine is transferred through milk and alters the dopaminergic reward system of adult male rats, reducing dopamine action in the nucleus accumbens (NAc) and hypothalamic arcuate nucleus. Here, we evaluated the long-term effects of nicotine-only exposure during lactation on eating behavior, anxiety, locomotion, dopaminergic system, hypothalamic leptin signaling and nicotinic receptor in the adult female rat progeny. Two days after birth (PN2), Wistar rat dams were separated into control and nicotine (Nic) groups for implantation of osmotic minipumps that released respectively saline or 6 mg/kg nicotine. Lactating dams were kept with 6 pups. After weaning (PN21; nicotine withdrawal), only the female offspring were studied. Euthanasia occurred at PN180. Nic females showed hyperphagia, preference for a high-sucrose diet, increased anxiety-like behavior, lower tyrosine hydroxylase (TH), lower dopamine transporter and higher dopamine receptor (Drd2) in NAc; lower Drd1 in prefrontal cortex and lower TH in dorsal striatum (DS). These animals showed changes that can explain their hyperphagia, such as: lower leptin signaling pathway (Leprb, pJAK2, pSTAT3) and Chrna7 expression in hypothalamus. Neonatal nicotine exposure affects the brain reward system of the female progeny differently from males, mainly decreasing dopamine production in NAc and DS. Therefore, Nic females are more susceptible to develop food addiction and obesity.

Nicotine exposure during breastfeeding reduces sympathetic activity in brown adipose tissue and increases in white adipose tissue in adult rats: Sex-related differences.

Nicotine transfer via breast milk induces obesity in the adult offspring. We hypothesize that sympathetic nervous system (SNS) activity, brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) lipogenesis/adipogenesis are altered in adult rats that were exposed to nicotine exclusively during the breastfeeding period. Lactating Wistar rats were separated into two groups: nicotine (NIC), dams implanted with osmotic minipumps containing 6 mg/kg of nicotine at postnatal day (PN) 2; control, dams were implanted with saline-containing minipumps. Euthanasia occurred at PN120 or PN180. NIC offspring had lower BAT SNS activity and higher BAT lipid content. NIC males showed lower UCP1, ß3-AR and CPT1a, while NIC females showed lower UCP1, TRα1, CPT1a, suggesting lower thermogenesis. NIC males showed higher WAT SNS activity, WAT ß3-AR, adrenal catecholamine, FAS, PPARγ and adipocytes area, while NIC females showed higher ACC, FAS, CEBPß and PPARγ. These findings indicate increased lipogenesis/adipogenesis in both sexes, with a possible compensatory sympathetic activated-lipolysis in males. NIC males had higher hypothalamic pAMPK/AMPK, explaining the lower BAT sympathetic activity. Neonatal nicotine exposure reduces BAT SNS activity and thermogenesis, and, only in males, increases WAT adipogenesis/lipogenesis, despite higher WAT SNS activity. These alterations can be associated with obesogenesis in this programming model.

Early weaning alters the thermogenic capacity of brown adipose tissue in adult male and female rats.

PURPOSE: Early weaning (EW) is a risk factor for obesity development. Brown adipose tissue (BAT) hypofunction is related to obesity onset. Here, we evaluated whether sympathetic nervous system (SNS) activity in BAT and the thermogenic function of BAT are decreased in adulthood in obese rats from two EW models. METHODS: At the time of birth, lactating Wistar rats and their pups (three males and three females) were separated into three groups: the control group, in which pups consumed milk throughout lactation; the non-pharmacological EW (NPEW) group, in which suckling was interrupted with a bandage during the last 3 days of lactation; and the pharmacological EW (PEW) group, in which dams were treated with bromocriptine (0.5 mg/twice a day) 3 days before weaning. The offspring were sacrificed on PN180. RESULTS: Adult male rats from both EW models exhibited lower BAT SNS activity. Female rats from the PEW group showed a decrease in BAT SNS activity. The protein levels of UCP1 were lower in the NPEW males, while PGC1α levels were lower in both PEW and NPEW males. Both groups of EW females showed reductions in the levels of ß3-AR, TRß1, and PGC1α. The UCP1 protein level was reduced only in the NPEW females. The EW groups of both sexes had lower AMPK protein levels in BAT. In the hypothalamus, only the PEW females showed an increase in AMPK protein levels. In both groups of EW males, adrenal catecholamine was increased and tyrosine hydroxylase was decreased, while in EW females, adrenal catecholamine was decreased. CONCLUSIONS: Early weaning alters the thermogenic capacity of BAT, which partially contributes to obesity in adulthood, and there are sex-related differences in these alterations.

Hypothalamic Neuropeptides Expression and Hypothalamic Inflammation in Adult Rats that Were Exposed to Tobacco Smoke during Breastfeeding: Sex-Related Differences.

The hypothalamus controls food intake and energy expenditure. In rats, maternal exposure to nicotine during breastfeeding alters the hypothalamic circuitry of the adult offspring, resulting in leptin resistance, neuropeptides changes and gliosis. Tobacco smoke exposure during lactation causes greater adiposity, hyperphagia and hyperleptinemia in the adult progeny. To understand the central mechanisms underlying the obese phenotype of adult rats that were directly and indirectly exposed to cigarette smoke during lactation, we investigated leptin signaling, orexigenic and anorexigenic neuropeptides expression, as well as astrocyte and microglia markers in hypothalamus. From postnatal day (PND) 3 to 21, Wistar lactating rat dams and their pups were divided into two groups: SE, smoke-exposed in a cigarette-smoking machine (four times/day); Crtl, exposed to filtered air. Offspring of both sexes were euthanized at PND180. The leptin pathway was not altered in SE animals from both sexes. SE males showed increased NPY (arcuate nucleus, ARC), CRH (paraventricular nucleus, PVN), as well as higher GFAP fiber density (ARC and PVN) and IL6 protein content. TRH (PVN) immunohistochemistry was reduced. SE females had lower CART-positive cells (ARC) and lower α-MSH immunostaining intensity (PVN and lateral hypothalamus), with no change of GFAP or IL-6. The protein contents of CX3CR1 (marker of activated microglia) and α7nAChR (anti-inflammatory marker) were not altered in both SE males and females. Neonatal cigarette smoke is deleterious to the hypothalamic circuitry, inducing changes in energy homeostasis favoring hyperphagia and decreased energy expenditure at adulthood in both sexes; however sex-dependent mechanisms were observed.

Cigarette smoke during lactation in rat female progeny: Late effects on endocannabinoid and dopaminergic systems.

AIMS: Maternal smoking is considered a risk factor for childhood obesity. In a rat model of tobacco exposure during breastfeeding, we previously reported hyperphagia, overweight, increased visceral fat and hyperleptinemia in adult female offspring. Obesity and eating disorders are associated with impairment in the endocannabinoid (EC) and dopaminergic (DA) systems. Considering that women are prone to eating disorders, we hypothesize that adult female Wistar rats that were exposed to cigarette smoke (CS) during the suckling period would develop EC and DA systems deregulation, possibly explaining the eating disorder in this model. MATERIAL AND METHODS: To mimic maternal smoking, from postnatal day 3 to 21, dams and offspring were exposed to a smoking machine, 4×/day/1 h (CS group). Control animals were exposed to ambient air. Offspring were evaluated at 26 weeks of age. KEY FINDINGS: Concerning the EC system, the CS group had increased expression of diacylglycerol lipase (DAGL) in the lateral hypothalamus (LH) and decreased in the liver. In the visceral adipose tissue, the EC receptor (CB1r) was decreased. Regarding the DA system, the CS group showed higher dopamine transporter (DAT) protein expression in the prefrontal cortex (PFC) and lower DA receptor (D2r) in the arcuate nucleus (ARC). We also assessed the hypothalamic leptin signaling, which was shown to be unchanged. CS offspring showed decreased plasma 17ß-estradiol. SIGNIFICANCE: Neonatal CS exposure induces changes in some biomarkers of the EC and DA systems, which can partially explain the hyperphagia observed in female rats.

Effects of maternal bisphenol A on behavior, sex steroid and thyroid hormones levels in the adult rat offspring.

AIMS: Bisphenol A (BPA), an endocrine disruptor used in industrial applications, has been detected in both placenta and milk. We studied the effects of BPA exposure during pregnancy and lactation on body composition, palatable food intake, biochemical, hormonal and behavioral profiles of young and adult Wistar rat offspring. MAIN METHODS: Female rats were divided into: control, BPA10 (10 µg/kg/day) and BPA50 (50 µg/kg/day). BPA was administered by gavage to dams from gestation until the end of lactation. Euthanasia occurred at weaning [postnatal day (PN) 21] or adulthood (PN180). KEY FINDINGS: At weaning, BPA10 female pups had higher plasma cholesterol and triacylglycerol. BPA10 male pups showed lower plasma T3. BPA10 pups of both sexes had higher plasma progesterone, testosterone and estradiol. At adulthood, females of both BPA groups had lower food intake and higher insulinemia, whereas males had lower visceral fat, lower progesterone and testosterone concentrations. BPA10 females and males had lower T4 levels, while only males showed lower estradiol. BPA50 females showed lower fat mass, higher lean mass and lower corticosteronemia, while males had lower food intake. In the feeding study, BPA10 males ate more fat at 30 min, while BPA10 females and males ingested less fat after 12 h. BPA10 females showed hyperactivity while both groups showed less exploration. SIGNIFICANCE: Maternal exposure to BPA during gestation and lactation, even at low doses, induces life-long changes in the regulation of metabolic homeostasis of the progeny, affects sex steroids and thyroid hormones levels, compromises behavior, but does not lead to obesity or dyslipidemia.

Treatment with Ilex paraguariensis (yerba mate) aqueous solution prevents hepatic redox imbalance, elevated triglycerides, and microsteatosis in overweight adult rats that were precociously weaned.

Early weaning (EW) leads to overweight, visceral obesity, hyperleptinemia, and insulin resistance in adulthood. Treatment with Ilex paraguariensis (yerba mate) improves obesity and insulin resistance in these animals. Here, we evaluated the effects of chronic treatment with yerba mate on the redox balance and liver morphology of overweight early-weaned rats. To induce EW, we wrapped the dams with bandages to interrupt milk access during the last 3 days of lactation. Control pups (C) had free access to maternal milk for the full 21 days of lactation. On postnatal day (PN) 150, EW offspring were subdivided into the EW+YM group, which received the aqueous extract of yerba mate (1 g/kg bw by gavage once a day for 30 days) and the EW group, which received water by gavage for the same period. All rats were euthanized on PN180. The EW group showed higher bound carbonyl (a marker of total protein oxidation), higher TBARS levels (a marker of lipid peroxidation), and lower superoxide dismutase (SOD) activity in liver tissue than the C group, as well as higher triglyceride content and microsteatosis. In plasma, the EW offspring showed higher TBARS levels. One month of yerba mate treatment normalized these parameters. Thus, we have shown evidence that yerba mate improved antioxidant defenses and mitigated liver dysfunction in overweight adult rats that were weaned prematurely.

Neonatal tobacco smoke reduces thermogenesis capacity in brown adipose tissue in adult rats.

Maternal smoking is a risk factor for progeny obesity. We have previously shown, in a rat model of neonatal tobacco smoke exposure, a mild increase in food intake and a considerable increase in visceral adiposity in the adult offspring. Males also had secondary hyperthyroidism, while females had only higher T4. Since brown adipose tissue (BAT) hypofunction is related to obesity, here we tested the hypothesis that higher levels of thyroid hormones are not functional in BAT, suggesting a lower metabolic rate. We evaluated autonomic nerve activity in BAT and its function in adult rats that were exposed to tobacco smoke during lactation. At birth, litters were adjusted to 3 male and 3 female pups/litter. From postnatal day (PND) 3 to 21, Wistar lactating rats and their pups were divided into SE group, smoke-exposed in a cigarette smoking machine (4 times/day) and C group, exposed to filtered air. Offspring were sacrificed at PND180. Adult SE rats of both genders had lower interscapular BAT autonomic nervous system activity, with higher BAT mass but no change in morphology. BAT UCP1 and CPT1a protein levels were decreased in the SE groups of both genders. Male SE rats had lower ß3-AR, TRα1, and TRß1 expression while females showed lower PGC1α expression. BAT Dio2 mRNA and hypothalamic POMC and MC4R levels were similar between groups. Hypothalamic pAMPK level was higher in SE males and lower in SE females. Thus, neonatal cigarette smoke exposure induces lower BAT thermogenic capacity, which can be obesogenic at adulthood.

Effects of Ilex paraguariensis (yerba mate) on the hypothalamic signalling of insulin and leptin and liver dysfunction in adult rats overfed during lactation.

Ilex paraguariensis (yerba mate) has a beneficial effect in the management of obesity. Here, we studied the effects of yerba mate on hypothalamic changes in leptin and insulin signalling, oxidative stress and liver morphology and metabolism in postnatal early overfeeding (EO) Wistar rats. To induce EO, the litter size was reduced to three pups per dam, and litters with 10 pups per dam were used as a control (10 litters each). On postnatal day (PN) 150, EO offspring were subdivided into EO and EO+mate groups (10 animals each), which were treated with water or mate tea [1 g/kg body weight (BW)/day, by gavage], respectively, for 30 days. The C offspring received water. On PN180, yerba mate treatment prevented BW gain and reduced total body fat, visceral fat and food intake in comparison with the EO group. Leptin and insulin signalling in the hypothalamus measured by Western blotting was reduced only in the EO group. Yerba mate treatment had a greater impact on insulin signalling normalization. In the liver, yerba mate treatment normalized antioxidant enzyme activities and, consequently, decreased lipid peroxidation, determined by malondialdehyde content. In addition, the steatosis level and the liver triglyceride content were also restored. Thus, for the first time, yerba mate was demonstrated to increase antioxidant defences and improve liver metabolism in adult rats that were overfed during lactation, possibly through improvements in the hypothalamic action of insulin. These findings may be important for the treatment of obesity-related disorders.

Calcium reduces vitamin D and glucocorticoid receptors in the visceral fat of obese male rats.

Rats overfed during lactation show higher visceral adipose tissue (VAT) mass and metabolic dysfunctions at adulthood. As both vitamin D and glucocorticoids change adipogenesis, parameters related to metabolism and action of these hormones in the adipocyte can be altered in rats raised in small litters (SL). We also studied the antiobesity effects of high calcium diet since it decreases visceral fat in obesity models. On postnatal day (PN) 3, litter size was adjusted to 3pups/dam (SL) to induce overfeeding. Control litters (NL) remained with 10pups/dam until weaning. From PN120 to PN180, half of the SL rats were fed standard chow (SL) and the other half was fed a calcium-supplemented chow (SL-Ca, 10g CaCO3/kg). Both SL groups were heavier and hyperphagic when compared with the NL group; however, SL-Ca rats ate less than SL. SL-Ca rats had decreased VAT mass and adipocyte size, associated with lower hypothalamic NPY content, VAT fat acid synthase content and leptinemia. At PN120, SL rats had increased plasma 25(OH)D3, Cyp27b1 mRNA and glucocorticoid receptor (GR-α) in the VAT, but lower vitamin D receptor (Vdr) mRNA. At PN180, Cyp27b1 and GR-α remained higher, while Vdr normalized in SL rats. SL-Ca rats had normal VAT Cyp27b1 and GR-α, but lower Vdr Thus, higher body mass and glucocorticoid receptors in the VAT of SL rats are normalized by calcium-enriched diet, and Vdr expression in this tissue is reduced, suggesting a possible role of glucocorticoids and vitamin D in calcium action in the adipocyte.

High calcium diet improves the liver oxidative stress and microsteatosis in adult obese rats that were overfed during lactation.

Obesity is related to diabetes, higher oxidative stress and nonalcoholic fatty liver disease, and dietetic therapies, for instance calcium-rich diet, can improve these dysfunctions. Rats raised in small litters (SL) had increased fat depots and insulin resistance at adulthood associated with higher liver oxidative stress and microsteatosis. Thus, we evaluated if dietary calcium can improve these changes. In PN3, litter size was adjusted to 3 pups (SL group) to induce overfeeding, while controls had 10 pups until weaning. At PN120, SL group was randomly divided into: rats fed with standard chow or fed with calcium supplementation (SL-Ca group, 10 g/kg chow) for 60 days. At PN180, dietary calcium normalized food consumption, visceral fat, plasma aspartate aminotransferase (AST) and glycaemia. Concerning oxidative balance, calcium restored both higher hepatic lipid peroxidation and protein carbonylation as well as higher plasma lipid peroxidation. Higher fatty acid synthase (FAS) content, steatosis and lower protein kinase B (Akt) in SL group were normalized by dietary calcium and SL-Ca rats had lower hepatic cholesterol. Thus, calcium supplementation improved the insulin sensitivity, redox balance and steatosis in the liver. Therefore, dietary calcium can be a promising therapy for liver disease in the metabolic syndrome.

Effect of Early Overfeeding on Palatable Food Preference and Brain Dopaminergic Reward System at Adulthood: Role of Calcium Supplementation.

Rats raised in small litters (SL) are obese and hyperphagic. In the present study, we evaluated whether obesity is associated with changes in the mesocorticolimbic dopaminergic reward system in these animals at adulthood. We also assessed the anti-obesity effects of dietary calcium supplementation. To induce early overfeeding, litters were adjusted to three pups on postnatal day (PN)3 (SL group). Control litters were kept with 10 pups each until weaning (NL group). On PN120, SL animals were subdivided into two groups: SL (standard diet) and SL-Ca [SL with calcium supplementation (10 g calcium carbonate/kg rat chow) for 60 days]. On PN175, animals were subjected to a food challenge: animals could choose between a high-fat (HFD) or a high-sugar diet (HSD). Food intake was recorded after 30 min and 12 h. Euthanasia occurred on PN180. SL rats had higher food intake, body mass and central adiposity. Sixty days of dietary calcium supplementation (SL-Ca) prevented these changes. Only SL animals preferred the HFD at 12 h. Both SL groups had lower tyrosine hydroxylase content in the ventral tegmental area, lower dopaminergic transporter content in the nucleus accumbens, and higher type 2 dopamine receptor (D2R) content in the hypothalamic arcuate nucleus (ARC). They also had higher neuropeptide Y (NPY) and lower pro-opiomelanocortin contents in the ARC. Calcium treatment normalised only D2R and NPY contents. Precocious obesity induces long-term effects in the brain dopaminergic system, which can be associated with an increased preference for fat at adulthood. Calcium treatment prevents this last alteration, partially through its actions on ARC D2R and NPY proteins.

Resveratrol treatment rescues hyperleptinemia and improves hypothalamic leptin signaling programmed by maternal high-fat diet in rats.

PURPOSE: Perinatal high-fat diet is associated with obesity and metabolic diseases in adult offspring. Resveratrol has been shown to exert antioxidant and anti-obesity actions. However, the effects of resveratrol on leptinemia and leptin signaling are still unknown as well as whether resveratrol treatment can improve metabolic outcomes programmed by maternal high-fat diet. We hypothesize that resveratrol treatment in male rats programmed by high-fat diet would decrease body weight and food intake, and leptinemia with changes in central leptin signaling. METHODS: Female Wistar rats were divided into two groups: control group (C), which received a standard diet containing 9 % of the calories as fat, and high-fat group (HF), which received a diet containing 28 % of the calories as fat. Dams were fed in C or HF diet during 8 weeks before mating and throughout gestation and lactation. C and HF male offspring received standard diet throughout life. From 150 until 180 days of age, offspring received resveratrol (30 mg/Kg body weight/day) or vehicle (carboxymethylcellulose). RESULTS: HF offspring had increased body weight, hyperphagia and increased subcutaneous and visceral fat mass compared to controls, and resveratrol treatment decreased adiposity. HF offspring had increased leptinemia as well as increased SOCS3 in the arcuate nucleus of the hypothalamus, which suggest central leptin resistance. Resveratrol treatment rescued leptinemia and increased p-STAT3 content in the hypothalamus with no changes in SOCS3, suggesting improvement in leptin signaling. CONCLUSIONS: Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity.

Neonatal Nicotine Exposure Leads to Hypothalamic Gliosis in Adult Overweight Rats.

Astrocytes and microglia, the immune competent cells of central nercous system, can be activated in response to metabolic signals such as obesity and hyperleptinaemia. In rats, maternal exposure to nicotine during lactation leads to central obesity, hyperleptinaemia, leptin resistance and alterations in hypothalamic neuropeptides in the offspring during adulthood. In the present study, we studied the activation of astrocytes and microglia, as well as the pattern of inflammatory mediators, in adult offspring of this experimental model. On postnatal day 2 (P2), osmotic minipumps releasing nicotine (NIC) (-6 mg/kg/day) or saline for 14 days were s.c. implanted in dams. Male offspring were killed on P180 and hypothalamic immunohistochemistry, retroperitoneal white adipose tissue (WAT) polymerase chain reaction analysis and multiplex analysis for plasma inflammatory mediators were carried out. At P180, NIC astrocyte cell number was higher in the arcuate nucleus (ARC) (medial: +82%; lateral: +110%), in the paraventricular nucleus (PVN) (+144%) and in the lateral hypothalamus (+121%). NIC glial fibrillary acidic protein fibre density was higher in the lateral ARC (+178%) and in the PVN (+183%). Interleukin-6 was not affected in the hypothalamus. NIC monocyte chemotactic protein 1 was only higher in the periventricular nucleus (+287%). NIC microglia (iba-1-positive) cell number was higher (+68%) only in the PVN, as was the chemokine (C-X3-C motif) receptor 1 density (+93%). NIC interleukin-10 was lower in the WAT (-58%) and plasma (-50%). Thus, offspring of mothers exposed to nicotine during lactation present hypothalamic astrogliosis at adulthood and microgliosis in the PVN.

Early redox imbalance is associated with liver dysfunction at weaning in overfed rats.

Neonatal overfeeding induced by litter size reduction leads to further obesity and other metabolic disorders, such as liver oxidative stress and microsteatosis at adulthood. We hypothesized that overfeeding causes an early redox imbalance at weaning, which could programme the animals to future liver dysfunction. Thus, we studied lipogenesis, adipogenesis, catecholamine status and oxidative balance in weaned overfed pups. To induce early overfeeding, litters were adjusted to three pups at the 3rd day of lactation (SL group). The control group contained 10 pups per litter until weaning (NL group). Peripheral autonomic nerve function was determined in vivo at 21 days old. Thereafter, pups were killed for further analysis. Differences were considered significant when P < 0.05. The SL pups presented with a higher visceral adipocyte area, higher content of lipogenic enzymes (ACC, FAS) and with a lower content of adipogenic factors (CEBP, PPARγ) in visceral adipose tissue (VAT). Although autonomic nerve activity and adrenal catecholamine production were not significantly altered, catecholamine receptor (ß3ADR) content was lower in VAT. The SL pups also presented with higher triglyceride, PPARγ, PPARα and PGC1α contents in liver. In plasma and liver, the SL pups showed an oxidative imbalance, with higher lipid peroxidation and protein oxidation. The SL group presented with a higher serum alanine aminotransferase (ALT). The early increase in lipogenesis in adipose tissue and liver in weaned overfed rats suggests that the higher oxidative stress and lower catecholamine content in VAT are associated with the early development of liver dysfunction and adipocyte hypertrophy.

Exposure to nicotine increases dopamine receptor content in the mesocorticolimbic pathway of rat dams and offspring during lactation.

Nicotine exposure causes the release of dopamine from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). We have previously shown that maternal exposure to nicotine during lactation causes hyperleptinemia in dams and pups, and leptin is known to decrease dopamine release from the VTA. Here we evaluated whether maternal exposure to nicotine during lactation causes changes in dopamine and leptin signaling pathways at the end of exposure and after 5days of withdrawal in the: VTA, NAc, arcuate nucleus (ARC) and dorsal striatum (DS). On postnatal day (PN) 2, lactating Wistar rats were implanted with minipumps releasing nicotine (NIC; 6mg/kg/day, s.c.) or saline (C) for 14days. Offspring were tested in the elevated plus maze (EPM) and open field on PN14 or PN20, and euthanized on PN15 or PN21. Entries into the open arms and head dips in the EPM were reduced in NIC pups at P20. At weaning (PN21), NIC dams had: lower tyrosine hydroxylase (TH), higher OBRb and SOCS3 contents in VTA; lower TH, higher D1R, D2R and DAT contents in NAc; higher TH content in DS; and higher D2R and SOCS3 contents in ARC. On PN15, NIC offspring had higher D1R, D2R and lower DAT contents in NAc, while on PN21, they had lower DAT in DS, and lower pSTAT3 content in ARC. We evidenced that postnatal nicotine exposure induces relevant changes in the brain reward system of dams and pups, possibly associated with changes in leptinemia and increased offspring anxiety-like behavior.

Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring.

The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive-like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152­153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus.

Concurrent maternal and pup postnatal tobacco smoke exposure in Wistar rats changes food preference and dopaminergic reward system parameters in the adult male offspring.

Children from pregnant smokers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption. Here, we studied the relationship between tobacco smoke exposure during lactation with feeding, behavior and brain dopaminergic reward system parameters at adulthood. Nursing Wistar rats and their pups were divided into two groups: tobacco smoke-exposed (S: 4times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C). On PN175, both offspring groups were subdivided for a food challenge: S and C that received standard chow (SC) or that chose between high-fat (HFD) and high-sucrose diets (HSDs). Food intake was recorded after 30min and 12h. Offspring were tested in the elevated plus maze and open field on PN178-179; they were euthanized for dopaminergic analysis on PN180. SSD (self-selected diet) animals presented a higher food intake compared to SC ones. S-SSD animals ate more than C-SSD ones at 30min and 12h. Both groups preferred the HFD. However, S-SSD animals consumed relatively more HFD than C-SSD at 30min. No behavioral differences were observed between groups. S animals presented lower tyrosine hydroxylase (TH) content in the ventral tegmental area, lower TH, dopaminergic receptor 2, higher dopaminergic receptor 1 contents in the nucleus accumbens and lower OBRb in hypothalamic arcuate nucleus. Tobacco-smoke exposure during lactation increases preference for fat in the adult progeny possibly due to alterations in the dopaminergic system.

Effects of maternal nicotine exposure on thyroid hormone metabolism and function in adult rat progeny.

Postnatal nicotine exposure leads to obesity and hypothyroidism in adulthood. We studied the effects of maternal nicotine exposure during lactation on thyroid hormone (TH) metabolism and function in adult offspring. Lactating rats received implants of osmotic minipumps releasing nicotine (NIC, 6 mg/kg per day s.c.) or saline (control) from postnatal days 2 to 16. Offspring were killed at 180 days. We measured types 1 and 2 deiodinase activity and mRNA, mitochondrial α-glycerol-3-phosphate dehydrogenase (mGPD) activity, TH receptor (TR), uncoupling protein 1 (UCP1), hypothalamic TRH, pituitary TSH, and in vitro TRH-stimulated TSH secretion. Expression of deiodinase mRNAs followed the same profile as that of the enzymatic activity. NIC exposure caused lower 5'-D1 and mGPD activities; lower TRß1 content in liver as well as lower 5'-D1 activity in muscle; and 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 the hypothalamus, pituitary, and thyroid of NIC offspring, UCP1 expression was lower in BAT. Levels of both TRH and TSH were lower in offspring exposed to NIC, which presented higher basal in vitro TSH secretion, which was not increased in response to TRH. Thus, the hypothyroidism in NIC offspring at adulthood was caused, in part, by in vivo TRH-TSH suppression and lower sensitivity to TRH. Despite the hypothyroid status of peripheral tissues, these animals seem to develop an adaptive mechanism to preserve thyroxine to triiodothyronine conversion in central tissues.