Maternal high-fat diet (HF) programs obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), hypertriglyceridemia, and hyperglycemia associated with increased endocannabinoid system (ECS) in the liver of adult male rat offspring. We hypothesized that maternal HF would induce sex specific ECS changes in the liver of newborn rats, prior to obesity onset, and maternal fish oil (FO) supplementation would reprogram the ECS and lipid metabolism markers preventing liver triglycerides (TG) accumulation. Female rats received a control (CT) (10.9

Maternal obesity during perinatal period increases the risk of metabolic and behavioral deleterious outcomes in the offspring, since it is critical for brain development, maturation, and reorganization. These processes are highly modulated by the endocannabinoid system (ECS), which comprises the main lipid ligands anandamide and 2-arachidonoylglycerol, cannabinoid receptors 1 and 2 (CB1R and CB2R), and several metabolizing enzymes. The ECS is overactivated in obesity and it contributes to the physiological activity of the hypothalamus-pituitary-adrenal (HPA) axis, promoting stress relief. We have previously demonstrated that maternal high-fat diet during gestation and lactation programmed the food preference for fat in adolescent male offspring and adult male and female offspring. In the present study, we hypothesized that maternal diet-induced obesity would induce sex-specific changes of the ECS in the hypothalamus and dorsal hippocampus of rat offspring associated with dysregulation of the HPA axis and stress-related behavior in adolescence. Rat dams were fed a control (C) or an obesogenic high-fat high-sugar diet (OD) for nine weeks prior to mating and throughout gestation and lactation. Maternal obesity differentially altered the CB1R in the hypothalamus of neonate offspring, with significant increase in male but not in female pups, associated with decreased CB2R prior to obesity development. In adolescence, maternal obesity induced anxiety-like behavior only in adolescent females which was associated with increased content of CB1R in the dorsal hippocampus. Our findings suggest that the early origins of anxiety disorders induced by maternal exposome is associated with dysregulation of the brain ECS, with females being more susceptible.

Perinatal maternal high-fat (HF) diet induces metabolic disorders in offspring associated with mitochondrial damage in their skeletal muscle. We hypothesized that gestational supplementation with fish oil (FO), rich in n-3 polyunsaturated fatty acids, may attenuate mitochondrial injury in the soleus muscle of male and female weanling HF offspring. Female rats received control or HF diet from 8 weeks premating throughout lactation. During gestation, part of HF dams received HF diet containing 3 % FO. Gestational FO mitigated HF-induced soleus sarcomere misalignment and mitochondrial ultrastructural injury in weanling offspring. FO increased mitochondrial complex proteins I and III in males and uncoupling protein-3 and PGC1 alpha (biogenesis marker) in both sexes. FO enhanced fusion proteins mitofusin-2 (males) and OPA-1 (females) and mitochondrial size, suggesting increased mitochondrial fusion. Thus, gestational FO supplementation to maternal HF diet enhances biogenesis and mitochondrial fusion markers, improving mitochondria quality and potentially function in soleus muscle of weanling HF offspring.

The small intestine, including the endocannabinoid system (ECS), regulates the energy homeostasis. If maternal obesity modifies the intestinal ECS of the offspring favoring metabolic disorders throughout life is unexplored. Regardless maternal insults, overaction of the ECS has been related to obesity, mainly via type 1 cannabinoid receptor (CB1) signaling, while type 2 cannabinoid receptor (CB2) signaling and the endocannabinoid-like compounds, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), have been associated with anti-inflammatory effects. We hypothesized that maternal obesity changes the ECS in the small intestine of weanling rat offspring in a sex-specific manner associated with altered fecal metabolites. Female rats received a control diet (C; 9% fat) or an obesogenic diet (OD; 37.2% fat, 11.8% sucrose) 9 weeks before mating, gestation and lactation. Offspring were euthanized at weaning. Maternal obesity increased CB2 protein content and mRNA levels of monocyte chemoattractant protein-1 in the small intestine in male offspring, while decreased fecal content of PEA and OEA in both sexes. Maternal obesity decreased gut permeability, but impaired glycemic homeostasis. Concerning fecal levels of γ-aminobutyric acid, amino acids and hypoxanthine, maternal obesity induced a fecal signature related to inflammatory and glycemic homeostasis impairment and dysbiosis. Maternal obesity induced intestinal inflammation and the signaling of CB2, PEA, and OEA might be part of a counter-regulatory response, contributing to reduced gut permeability, but not enough to avoid overweight and glycemic impairment in the offspring at weaning. Our findings provide molecular insights into the intestinal and fecal biomarkers for metabolic disorders.

Aims: Investigate the impact of hypothyroidism on mitochondrial dynamics and mitophagy in the heart under fed and fasting conditions. Methods: Hypothyroidism was induced in male Wistar rats with methimazole (0.03 %) for 21 days. Half of the euthyroid and hypothyroid groups underwent a 48-h fasting. Mitochondrial number and ultrastructure were evaluated by transmission electron microscopy. Fusion, fission, mitophagy, oxidative stress, and mitochondrial oxidative phosphorylation system (OXPHOS) components were analyzed by Western Blot and qPCR. Results: Hypothyroidism increased DRP1 activation and the p-DRP1/OPA1 ratio, indicating a shift toward mitochondrial fission over fusion. Under fasting, hypothyroidism prevented the increases in mitochondrial size, elongation, OPA1, and OXPHOS seen in euthyroid fasted rats. Hypothyroidism also raised 4-HNE content, an oxidative stress product, increased mitochondrial injury, and exacerbated fasting-related mitochondrial damage. This was accompanied by elevated Parkin levels in both fed and fasted hypothyroid groups, but without changes in PINK1 levels or Parkin activation. While fasting upregulated Bnip3l and Map1lc3b expression in euthyroid rats, hypothyroidism suppressed this response, though it did not prevent fasting-induced Bnip3 increases. Conclusions: Hypothyroidism increases the activation of mitochondrial fission machinery and oxidative stress, and induces mitochondrial damage without activation of mitophagy proteins, suggesting disrupted mitophagy signaling. It also interferes with fasting-induced mitochondrial dynamics adaptations, highlighting the essential role of thyroid hormones in metabolic adaptation to fasting.

SCOPE:Perinatal maternal moderately high-fat diet (mHFD) is associated with obesity and fatty liver disease in offspring, and maternal fish oil (FO: n-3 PUFA source) supplementation may attenuate these disorders. This study evaluates the effects of FO given to pregnant rats fed a mHFD on the offspring's liver at weaning.METHODS AND RESULTS:Female Wistar rats receive an isoenergetic, control (CT: 10.9% from fat) or high-fat (HF: 28.7% from fat) diet before mating, and throughout pregnancy and lactation. FO supplementation (HFFO: 2.9% of FO in the HF diet) is given to one subgroup of HF dams during pregnancy. At weaning, male and female mHFD offspring display higher body mass, adiposity, and hepatic cellular damage, steatosis, and inflammation, accompanied by increased damaged mitochondria. FO does not protect pups from systemic metabolic alterations and partially mitigates hepatic histological damage induced by mHFD only in females. However, FO reduces mRNA expression of lipogenic genes, and mitochondrial damage, and modified mitochondrial morphology suggestive of early adaptations via mitochondrial dynamics.CONCLUSIONS:Gestational FO supplementation has limited beneficial effects on the damage caused by perinatal mHFD consumption in offspring's liver at weaning. However, FO imprinting effect on lipid metabolism and mitochondria may have beneficial long-term outcomes.

Introduction Maternal high-fat (HF) diet during gestation and lactation programs obesity in rat offspring associated with sex-dependent and tissue-specific changes of the endocannabinoid system (ECS). The ECS activation induces food intake and preference for fat as well as lipogenesis. We hypothesized that maternal HF diet would increase the lipid endocannabinoid levels in breast milk programming cannabinoid and dopamine signaling and food preference in rat offspring. Methods Female Wistar rats were assigned into two experimental groups: control group (C), which received a standard diet (10% fat), or HF group, which received a high-fat diet (29% fat) for 8 weeks before mating and during gestation and lactation. Milk samples were collected to measure endocannabinoids and fatty acids by mass spectrometry. Cannabinoid and dopamine signaling were evaluated in the nucleus accumbens (NAc) of male and female weanling offspring. C and HF offspring received C diet after weaning and food preference was assessed in adolescence. Results Maternal HF diet reduced the milk content of anandamide (AEA) (p<0.05) and 2-arachidonoylglycerol (2-AG) (p<0.05). In parallel, maternal HF diet increased adiposity in male (p<0.05) and female offspring (p<0.05) at weaning. Maternal HF diet increased cannabinoid and dopamine signaling in the NAc only in male offspring (p<0.05), which was associated with higher preference for fat in adolescence (p<0.05). Conclusion Contrary to our hypothesis, maternal HF diet reduced AEA and 2-AG in breast milk. We speculate that decreased endocannabinoid exposure during lactation may induce sex-dependent adaptive changes of the cannabinoid-dopamine crosstalk signaling in the developing NAc, contributing to alterations in neurodevelopment and programming of preference for fat in adolescent male offspring.

PURPOSE:Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats.METHODS:Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated.RESULTS:Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRβ, phosphorylated IRβ, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups.CONCLUSION:In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.

The increasing incidence of metabolic diseases is in part due to the high fructose consumption, a carbohydrate vastly used in industry, with a potent lipogenic capacity. Thyroid hormones (TH) are essential for metabolism regulation and are associated with changes in body weight, energy expenditure, insulin sensitivity, and dyslipidemia. This study aimed to investigate the influence of fructose intake on thyroid function and thyroid-related genes. Male Wistar rats were divided into Control (CT, n=8) and Fructose (FT - 10% in drinking water, n=8) groups for three weeks. The FT group showed higher glycemia and serum triacylglycerol, indicating metabolic disturbances, and increased thyroid mass, accompanied by higher expression of Srebf1c and Lpl, suggesting increased lipid synthesis. The FT group also presented higher expression of Tpo and Dio1 in the thyroid, suggesting activation of the thyroid gland, but with no alterations in serum TH concentrations. Brown adipose tissue (BAT) of the FT group exhibited higher expression of Dio2, Thra, and Thrb, indicating increased T3 intra-tissue bioavailability and signaling. These responses were accompanied by increased BAT mass and higher expression of Adrb3, Pparg, Srebf1c, Fasn, Ppara, and Ucp1, suggesting increased BAT adrenergic sensitivity, lipid synthesis, oxidation, and thermogenesis. Therefore, short-term fructose consumption induced thyroid molecular alterations and increased BAT expression of thyroid hormone-related signaling genes that potentially contributed to higher BAT activity.

SCOPE:Perinatal maternal obesity and excessive fructose consumption have been associated with liver metabolic diseases. The study investigates whether moderate maternal high-fat diet affects the liver mitochondria responses to fructose intake in adult offspring.METHODS AND RESULTS:Wistar female rats have received a standard diet (mSTD) or high-fat diet (mHFD) (9% and 28.6% fat, respectively), before mating until the end of lactation. Male offspring were fed standard diet from weaning to adulthood and received water or fructose-drinking water (15%) from 120 to 150 days old. Fructose induces liver mitochondrial ultrastructural alterations with higher intensity in mHFD offspring, accompanied by reduced autophagy markers. Isolated mitochondria respirometry shows unaltered ATP-coupled oxygen consumption with increased Atp5f1b mRNA only in mHFD offspring. Fructose increases basal respiration and encoding complex I-III mRNA, only in mSTD offspring. Uncoupled respiration is lower in mHFD mitochondria that are unable to exhibit fructose-induced increase Ucp2 mRNA. Fructose decreases antioxidative defense markers, increases unfolded protein response and insulin resistance only in mHFD offspring without fructose-induced hepatic lipid accumulation.CONCLUSION:Mitochondrial dysfunction and homeostatic disturbances in response to fructose are early events evidencing the higher risk of fructose damage in the liver of adult offspring from dams fed an isocaloric moderate high-fat diet.

The dramatic increase in both the number of novel infectious agents and resistance to antimicrobial drugs has incited the need for adjunct therapies in the war against infectious diseases. Exciting recent studies have demonstrated the use of antibodies in the form of intravenous immunoglobulin (IVIg) against infections. By virtue of the diverse repertoire of immunoglobulins that possess a wide spectrum of antibacterial and antiviral specificities, IVIg provides antimicrobial efficacy independently of pathogen resistance and represents a promising alternative strategy for the treatment of diseases for which a specific therapy is not yet available.

Aims: Perinatal maternal hypercaloric diets increase the susceptibility to metabolic disorders in the offspring. We hypothesized that maternal intake of an isocaloric moderate-fat diet (mMFD) would disturb the glucose ho-meostasis and favor the 8-cell failure in response to fructose overload in adult male offspring. Methods: Female Wistar rats received an isocaloric diet (3.9 kcal/g) containing 29 % (mMFD) or 9 % as fat (mSTD) prior mating and throughout gestation and lactation. After weaning, male offspring received standard chow and fructose-drinking water (15 %) between 120 and 150 days old.Key findings: mMFD offspring had higher body weight, visceral adiposity and, fasting glycemia, with normal insulinemia. Fructose increased glycemia at 15 min from oral glucose administration, but only mMFD had returned to basal glucose levels at 120 min. Fructose increased HOMA-IR index regardless diet, but only mMFD exhibited hyperinsulinemia and a higher HOMA-8 index. mMFD pancreatic islets showed increased area and insulin immunostaining density, suggesting 8-cell hypertrophy. Fructose induced the expected compensatory hypertrophy in mSTD islets, while the opposite occurred in mMFD islets, associated with reduced insulin im-munostaining, suggesting lower insulin storage. Pancreatic islets isolated from mMFD offspring exhibited higher glucose-stimulated insulin release at physiological concentrations. However, at higher glucose concentrations, the islets from fructose-treated mMFD reduced dramatically their insulin release, suggesting exhaustion. Significance: Isocaloric mMFD induced adaptive mechanism in the offspring allowing insulin hypersecretion, but under metabolic challenge with fructose, 8-cell compensation shifts to exhaustion, favoring dysfunction. Therefore, a maternal MFD may contribute to developing diabetes under fructose overload in the adult offspring.

Maternal high-fat diet (HFD) is associated with metabolic disturbances in the offspring. Fructose is a highly consumed lipogenic sugar; however, it is unknown whether skeletal muscle of maternal HFD offspring respond differentially to a fructose overload. Female Wistar rats received standard diet (STD: 9% fat) or isocaloric high-fat diet (HFD: 29% fat) during 8 weeks before mating until weaning. After weaning, male offspring received STD and, from 120 to 150 days-old, they drank water or 15% fructose in water (STD-F and HFD-F). At 150th day, we collected the oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles. Fructose-treated groups exhibited hypertriglyceridemia, regardless of maternal diet. Soleus of maternal HFD offspring showed increased triglycerides and monounsaturated fatty acid content, independent of fructose, with increased fatty acid transporters and lipogenesis markers. The EDL exhibited unaltered triglycerides content, with an apparent equilibrium between lipogenesis and lipid oxidation markers in HFD, and higher lipid uptake (fatty acid-binding protein 4) accompanied by enhanced monounsaturated fatty acid in fructose-treated groups. Mitochondrial complexes proteins and Tfam mRNA were increased in the soleus of HFD, while uncoupling protein 3 was decreased markedly in HFD-F. In EDL, maternal HFD increased ATP synthase, while fructose decreased Tfam predominantly in STD offspring. Maternal HFD and fructose induced mitochondria ultrastructural damage, intensified in HFD-F in both muscles. Thus, alterations in molecular markers of lipid metabolism and mitochondrial function in response to fructose are modified by an isocaloric and moderate maternal HFD and are fiber-type specific, representing adaptation/maladaptation mechanisms associated with higher skeletal muscle fructose-induced mitochondria injury in adult offspring.

Neuromedin B (NB), a bombesin-like peptide, exerts its specific actions by binding to the neuromedin B receptor (NBR), a G protein-coupled receptor. Female NBR-knockout (NBR-KO) mice exhibit resistance to diet-induced obesity, without hyperphagia, suggesting possible increase in energy expenditure. Skeletal muscle (SM) is crucial for whole body energy homeostasis, however, the presence of NB-NBR signaling and its effects in SM are unknown. Here, we show that male and female wild type express Nmbr and Nmb mRNA in SM, with higher levels in females. Female NBR-KO gastrocnemius showed increased Myh7 mRNA level, which characterizes type I fibers (oxidative profile). Their permeabilized gastrocnemius fibers, studied by high-resolution respirometry, exhibited higher consumption of O2 coupled to ATP synthesis and unaltered uncoupled respiration. NBR-KO gastrocnemius had higher protein levels of ATP-synthase and Nduf9 mRNA, corresponding to mitochondrial complex I subunit. NBR-KO gastrocnemius exhibited slight increase in mitochondria number, increased thickness of Z line at electron microscopy, and unaltered mitochondrial dynamics markers. Therefore, in the females' gastrocnemius, a predominantly glycolytic SM, the NBR absence promotes changes that favor mitochondrial oxidative phosphorylation capacity. In addition, in L6 myocytes, NB treatment (5 μg/mL/16 h) promoted lower O2 consumption coupled to ATP synthesis, suggesting direct action at SM cells. Altogether, the study reinforces the hypothesis that inhibition of NB-NBR signaling enhances the capacity for oxidative phosphorylation of white SM, encouraging future studies to elucidate their contribution on other types of SM and whole body energy expenditure, which may lead to a new target to drug development for obesity treatment.NEW & NOTEWORTHY This study describes neuromedin B (NB) and NB receptor as new regulators of skeletal muscle mitochondrial function. The white skeletal muscle mitochondrial oxidative phosphorylation capacity was increased by NB receptor genetic disruption in female mice. These findings may contribute to the resistance to diet-induced obesity, previously found in these mice, which requires future studies. Thus, investigations are necessary to clarify if blockade of NB receptor may be an approach to develop drugs to combat obesity.

Early obesity is a serious health problem and nutritional therapeutic strategies during young age may improve health outcomes throughout life. Cinnamaldehyde, the major component of cinnamon, exhibits several beneficial metabolic effects. Here we tested the impact of cinnamaldehyde treatment during adolescence in a rat model of obesity programmed by early overnutrition, addressing white (WAT) and brown adipose tissue (BAT). After birth, litters were adjusted to 10 pups or 3 pups (small litter) to induce overfeeding and early obesity. On postnatal day 30, half of the small litter pups received cinnamaldehyde (40 mg per kg of body mass per day) for 30 days. The animals were studied at the end of the treatment at 60 days of age and 4 months thereafter (180 days old). The early overfeeding programmed to higher epididymal WAT mass, adipocyte hypertrophy at both ages, and higher BAT mass associated with higher lipid accumulation in the long term. Cinnamaldehyde reduced the adipocyte hypertrophy associated with reduced lipogenesis machinery expression (Srebf1c, Acaca), while it stimulated oxidative ones (Ppargc1a, Fgf21) in WAT, and increased BAT thermogenesis markers (Ppara, Fgf21, Ucp1). In the long term, cinnamaldehyde treatment reprogrammed the metabolism leading to a diminished WAT adipocyte size, accompanied by reduced expression of lipogenesis-related genes (Pparg, Dgat2). In BAT, cinnamaldehyde led to reduced lipogenesis marker expression (Pparg, Lpl) associated with the reduced whitening phenotype, and a robust increase in Fgf21 expression. These results suggest that cinnamaldehyde intake during adolescence has long-lasting benefits in WAT and BAT metabolism, reinforcing its potential as a reprogramming nutraceutical in the treatment of childhood obesity.

Obesity and high-fat (HF) diet are associated with over activation of the endocannabinoid system (ECS). We have demonstrated that maternal HF diet induces early obesity and modulates cannabinoid signaling in visceral (VIS) and subcutaneous (SUB) white adipose tissue (WAT) in weanling rat offspring. We hypothesized that perinatal maternal HF diet would program the expression of ECS in adipose tissue in a long-term way in parallel to alterations in epigenetic markers and sex hormone signaling. Progenitor female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, gestation, and lactation. All pups were weaned to C diet and they were euthanized at 180 days old. Maternal HF diet induced overweight and increased SUB WAT mass of male and female adult offspring. Maternal HF diet induced hypertrophy of VIS and SUB adipocytes only in female offspring associated with increased type 1 cannabinoid receptor protein (CB1) and mRNA (Cnr1) levels. These changes were associated with increased estrogen receptor α binding to Cnr1 promoter in SUB WAT of adult female offspring, which may contribute to higher expression of Cnr1. Increased CB1 signaling in adipose tissue might contribute to higher adiposity programmed by maternal HF diet because endocannabinoids stimulate the accumulation of fat in the adipose tissue. Our findings provide molecular insights into sex-specific targets for anti-obesity therapies based on the endocannabinoid system.

Metabolic syndrome (MetS) and thyroid dysfunction are common in clinical practice. The objectives of this review are to discuss some proposed mechanisms by which thyroid dysfunctions may lead to MetS, to describe the bidirectional relationship between thyroid hormones (THs) and adiposity and finally, to resume a list of recent studies in humans that evaluated possible associations between thyroid hormone status and MetS or its clinical components. Not solely THs, but also its metabolites regulate metabolic rate, influencing adiposity. The mechanisms enrolled are related to its direct effect on adenosine triphosphate (ATP) utilization, uncoupling synthesis of ATP, mitochondrial biogenesis, and its inotropic and chronotropic effects. THs also act controlling core body temperature, appetite, and sympathetic activity. In a bidirectional way, thyroid function is affected by adiposity. Leptin is one of the hallmarks, but the pro-inflammatory cytokines and also insulin resistance impact thyroid function and perhaps its structure. MetS development and weight gain have been positively associated with thyroid-stimulating hormone (TSH) in several studies. Adverse glucose metabolism may be related to hyperthyroidism, but also to reduction of thyroid function or higher serum TSH, as do abnormal serum triglyceride levels. Hypo- and hyperthyroidism have been related to higher blood pressure (BP), that may be consequence of genomic or nongenomic action of THs on the vasculature and in the heart. In summary, the interaction between THs and components of MetS is complex and not fully understood. More longitudinal studies controlling each of all confounding variables that interact with endpoints or exposure factors are still necessary.

SCOPE:Non-alcoholic fatty liver disease (NAFLD) among adolescents has been related to fructose intake. Additionally, maternal high-fat diet (mHFD) increases the offspring susceptibility to NAFLD at adulthood. Here, it is hypothesized that mHFD may exacerbate the fructose impact in adolescent male rat offspring, by changing the response of contributing mechanisms to liver injury. METHODS AND RESULTS:Female Wistar rats receive standard (mSTD: 9% fat) or high-fat diet (mHFD: 29% fat) prior mating throughout pregnancy and lactation. After weaning, offspring receive standard chow and, from the 25th to 45th day, receive water or fructose-drinking water (15%). At 46 days old, fructose groups show increased adiposity, increased serum and hepatic triglycerides, regardless of maternal diet. Fructose aggravates the hepatic imbalance of redox state already exhibited by mHFD offspring. The hepatic activation of cellular repair pathways by fructose, such as unfolded protein response and macroautophagy, is disrupted only in mHFD offspring. Fructose does not change the liver morphology of mSTD offspring. However, it intensifies the liver injury already present in mHFD offspring. CONCLUSION:Fructose intake during adolescence accelerates the emergence of NAFLD observed previously at the adult life of mHFD offspring, and reveals a differentiated hepatic response to metabolic insult, depending on the maternal diet.

The modern concept of thyroid disruptors includes synthetic chemicals and bioactive compounds from food that interfere with any aspect of the hypot halamus-pituitarythyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local actions of thyroid hormones. This review highlights relevant disruptors that affect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we r eview effects from the gestational period to adulthood, including evidence from in vitro studies, rodent models, human trials and epidemiological studies.

Maternal nutritional imbalances trigger developmental adaptations involving early epigenetic mechanisms associated with adult chronic disease. Maternal high-fat (HF) diet promotes obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood. Leptin resistance is associated with over activation of the endocannabinoid system (ECS). The ECS mainly consists of endocannabinoids derived from n-6 fatty acids and cannabinoid receptors (CB1 coded by Cnr1 and CB2 coded by Cnr2). The CB1 activation in hypothalamus stimulates feeding and appetite for fat while CB2 activation seems to play an immunomodulatory role. We demonstrated that maternal HF diet increases hypothalamic CB1 in male offspring while increases CB2 in female offspring at birth, prior to obesity development. However, the molecular mechanisms behind these changes remain unexplored. We hypothesized that maternal HF diet would down-regulate leptin signaling and up-regulate Cnr1 mRNA levels in the hypothalamus of the offspring at birth, associated with sex-specific changes in epigenetic markers and sex steroid signaling. To test our hypothesis, we used progenitor female rats that received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) from 8 weeks before mating until delivery. Blood, hypothalamus and carcass from C and HF male and female offspring were collected for biochemical and molecular analyses at birth. Maternal HF diet down-regulated the transcriptional factor STAT3 in the hypothalamus of male and female offspring, but induced hypoleptinemia only in males and decreased phosphorylated STAT3 only in female offspring. Because leptin acts through STAT3 pathway to inhibit central ECS, our results suggest that leptin pathway impairment might contribute to increased levels of Crn1 mRNA in hypothalamus of both sex offspring. Besides, maternal HF diet increased the histone acetylation percentage of Cnr1 promoter in male offspring and increased the androgen receptor binding to the Cnr1 promoter, which can contribute to higher expression of Cnr1 in newborn HF offspring. Maternal HF diet increased plasma n6 to n3 fatty acid ratio in male offspring, which is an important risk factor to metabolic diseases and might indicate an over activation of endocannabinoid signaling. Thus, although maternal HF diet programs a similar phenotype in adult offspring of both sexes (obesity, hyperphagia and higher preference for fat), here we showed that molecular mechanisms involving leptin signaling, ECS, epigenetic markers and sex hormone signaling were modified prior to obesity development and can differ between newborn male and female offspring. These observations may provide molecular insights into sex-specific targets for anti-obesity therapies.