Search

Maternal high-fat-diet (HFD) consumption during pregnancy decreased fetal body weight and impacted development of hypothalamic melanocortin neural circuitry in nonhuman primate offspring. We investigated whether these impairments during gestation persisted in juvenile offspring and examined the interaction between maternal and early postnatal HFD consumption. Adult dams consumed either a control diet (CTR; 15% calories from fat) or a high-saturated-fat diet (HFD; 37% calories from fat) during pregnancy. Offspring were weaned onto a CTR or HFD at ~8 mo of age. Offspring from HFD-fed dams displayed early catch-up growth and elevated body weight at 6 and 13 mo of age. Maternal and postnatal HFD exposure reduced the amount of agouti-related peptide fibers in the paraventricular nucleus of the hypothalamus. Postnatal HFD consumption also decreased the amount of agouti-related peptide fibers in the arcuate nucleus of the hypothalamus. Postnatal HFD was associated with decreased food intake and increased activity. These results support and extend our previous findings of maternal diet effects on fetal development and reveal, for the first time in a nonhuman primate model, that maternal HFD-induced disturbances in offspring body weight regulation extended past gestation into the juvenile period. Maternal HFD consumption increases the risk for offspring developing obesity, with the developmental timing of HFD exposure differentially impacting the melanocortin system and energy balance regulation. The present findings provide translational insight into human clinical populations, suggesting that profound health consequences may await individuals later in life following intrauterine and postnatal HFD exposure.

Early life inadequate nutrition triggers developmental adaptations and adult chronic disease. Maternal high-fat (HF) diet promotes visceral obesity and hypothalamic leptin resistance in male rat offspring at weaning and adulthood. Obesity is related to over active endocannabinoid system (ECS). The ECS consists mainly of endogenous ligands, cannabinoid receptors (CB1 and CB2), and the enzymes fatty acid anandamide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). We hypothesized that perinatal maternal HF diet would regulate offspring ECS in hypothalamus and brown adipose tissue (BAT) at birth, prior to visceral obesity development, and program food preference and energy expenditure of adult offspring. Female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, and throughout gestation and lactation. We evaluated C and HF offspring at birth and adulthood. At birth, maternal HF diet decreased leptinemia and increased hypothalamic CB1, orexin-A, and proopiomelanocortin while it decreased thyrotropin-releasing hormone (Trh) in male pups. Differentially, maternal HF diet increased hypothalamic CB2 in female pups. In BAT, maternal HF diet decreased CB1 and increased CB2 in male and female pups, respectively. Besides presenting different molecular ECS profile at birth, HF adult offspring developed overweight, higher adiposity and high-fat diet preference, independently of the sex, but only males presented hyperleptinemia and higher energy expenditure. In conclusion, maternal HF diet alters ECS components and energy metabolism targets in hypothalamus and BAT of offspring at birth, in a sex-specific manner, which may contribute for hyperphagia, food preference and higher adiposity later in life.

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

The increased prevalence and high comorbidity of metabolic syndrome and mental health disorders have prompted investigation into the potential contributing mechanisms. There is a bidirectional association between metabolic syndrome and mental health disorders including schizophrenia, bipolar disorder, depression, anxiety, attention deficit/hyperactivity disorder, and autism spectrum disorders. Medication side effects and social repercussions are contributing environmental factors, but there are a number of shared underlying neurological and physiological mechanisms that explain the high comorbidity between these two disorders. Inflammation is a state shared by both disorders, and it contributes to disruptions of neuroregulatory systems, including the serotonergic, dopaminergic, and neuropeptide Y systems, as well as dysregulation of the hypothalamic-pituitary-adrenal axis. Metabolic syndrome in pregnant women also exposes the developing fetal brain to inflammatory factors that predispose the offspring to metabolic syndrome and mental health disorders. Due to the shared nature of these conditions, treatment should address aspects of both mental health and metabolic disorders. Additionally, interventions need to be developed that can interrupt the transfer of increased risk of the disorders to the next generation.

Postnatal early overfeeding (EO) is related to later development of overweight and other metabolic disorders. As oxidative stress is implicated in most human diseases, as obesity and diabetes, we decided to study some parameters related to oxidative stress and insulin signaling in liver from EO animals in adult life. To induce EO, litter size was reduced to three pups per litter (SL: small litter) and groups with normal litter size (NL:10 pups per litter) were used as control. After weaning, rats had free access to standard diet and water. Body weight and food intake were monitored daily and offspring were killed at 180 days-old. Significant differences had P.05 or less. As expected, SL rats had hyperphagia, higher body weight and higher visceral fat mass at weaning and adulthood. In liver, postnatal EO programmed for lower catalase (-42%), superoxide dismutase (-45%) and glutathione peroxidase (-65%) activities. The evaluation of liver injury in adult SL group showed lower nitrite content (-10%), higher liver and plasma malondialdehyde content (+25% and 1.1-fold increase, respectively). No changes of total protein bound carbonyl or Cu/Zn superoxide dismutase protein expression in liver were detected between the groups. Regarding insulin signaling pathway in liver, SL offspring showed lower IRβ (-66%), IRS1 (-50%), phospho-IRS1 (-73%), PI3-K (-30%) and Akt1 (-58%). Indeed, morphological analysis showed that SL rats presented focal areas of inflammatory cell infiltrate and lipid drops in their cytoplasm characterizing a microsteatosis. Thus, we evidenced that postnatal EO can program the oxidative stress in liver, maybe contributing for impairment of the insulin signaling.

Maternal nutritional status affects the future development of offspring. Both undernutrition and overnutrition in critical periods of life (gestation or lactation) may cause several hormonal changes in the pups and programme obesity in the adult offspring. We have shown that hyperleptinaemia during lactation results in central leptin resistance, higher adrenal catecholamine secretion, hyperthyroidism, and higher blood pressure and heart rate in the adult rats. Here, we evaluated the effect of a maternal isocaloric high-fat diet on breast milk composition and its impact on leptinaemia, energy metabolism, and adrenal and thyroid function of the offspring at weaning. We hypothesised that the altered source of fat in the maternal diet even under normal calorie intake would disturb the metabolism of the offspring. Female Wistar rats were fed a normal (9% fat; C group) or high-fat diet (29% fat as lard; HF group) for 8 weeks before mating and during pregnancy and lactation. HF mothers presented increased total body fat content after 8 weeks (+27%, P < 0.05) and a similar fat content at the end of lactation. In consequence, the breast milk from the HF group had higher concentration of protein (+18%, P < 0.05), cholesterol (+52%, P < 0.05) and triglycerides (+86%, P < 0.05). At weaning, HF offspring had increased body weight (+53%, P < 0.05) and adiposity (2 fold, P < 0.05), which was associated with lower β3-adrenoreceptor content in adipose tissue (-40%, P < 0.05). The offspring also presented hyperglycaemia (+30%, P < 0.05) and hyperleptinaemia (+62%, P < 0.05). In the leptin signalling pathway in the hypothalamus, we found lower p-STAT3/STAT3 (-40%, P < 0.05) and SOCS3 (-55%, P < 0.05) content in the arcuate nucleus, suggesting leptin resistance. HF offspring also had higher adrenal catecholamine content (+17%, P < 0.05), liver glycogen content (+50%, P < 0.05) and hyperactivity of the thyroid axis at weaning. Our results suggest that a high fat diet increases maternal body fat and this additional energy is transferred to the offspring during lactation, since at weaning the dams had normal fat and the pups were obese. The higher fat and protein concentrations in the breast milk seemed to induce early overnutrition in the HF offspring. In addition to storing energy as fat, the HF offspring had a larger reserve of glycogen and hyperglycaemia that may have resulted from increased gluconeogenesis. Hyperleptinaemia may stimulate both adrenal medullary and thyroid function, which may contribute to the development of cardiovascular diseases. These early changes induced by the maternal high-fat diet may contribute to development of metabolic syndrome.

Early weaning is associated with changes in the developmental plasticity. Here, we studied the adipocytes morphology, adipokines expression or content in adipose tissue as well as adrenal and thyroid function of neonate and adult offspring primed by early weaning. After birth, lactating rats were divided into 2 groups: EW (early weaning) – dams were wrapped with a bandage to block access to milk during the last 3 days of lactation, and Control – dams whose pups had free access to milk throughout lactation (21 days). At postnatal day (PN) 21, EW pups had lower visceral and subcutaneous adipocyte area ( − 67.7% and − 62%, respectively), body fat mass ( − 26%), and leptin expression in visceral adipocyte ( − 64%) but higher leptin expression in subcutaneous adipocyte (2.9-fold increase). Adrenal evaluations were normal, but neonate EW pups presented lower serum T3 ( − 55%) and TSH ( − 44%). At PN 180, EW offspring showed higher food intake, higher body fat mass (+21.6%), visceral and subcutaneous adipocyte area (both 3-fold increase), higher leptin (+95%) and ADRβ3 (2-fold increase) content in visceral adipose tissue, and higher adiponectin expression in subcutaneous adipose tissue (+47%) but lower in visceral adipose tissue ( − 40%). Adult EW offspring presented higher adrenal catecholamine content (+31%), but no changes in serum corticosterone or thyroid status. Thus, early weaning primed for hypothyroidism at weaning, which can be associated with the adipocyte hypertrophy at adulthood. The marked changes in catecholamine adrenal content and visceral adipocyte ADRB3 are generally found in obesity, contributing to the development of other cardiovascular and metabolic disturbances.

It is known that Ca therapy may have anti-obesity effects. Since early weaning leads to obesity, hyperleptinaemia and insulin resistance, we studied the effect of dietary Ca supplementation in a rat model. Lactating rats were separated into two groups: early weaning (EW) – dams were wrapped with a bandage to interrupt lactation in the last 3 d of lactation and control (C) – dams whose pups had free access to milk during the entire lactation period (21 d). At 120 d, EW and C offspring were subdivided into four groups: (1) C, received standard diet; (2) CCa, received Ca supplementation (10 g of calcium carbonate/kg of rat chow); (3) EW, received standard diet; (4) EWCa, received Ca supplementation similar to CCa. The rats were killed at 180 d. The significance level was atP 3(fourfold increase), but lower adiponectinaemia:adipose tissue ratio (44 %). In addition, they showed Janus tyrosine kinase 2 and phosphorylated signal transducer and activator of transcription 3 underexpression in hypothalamus (36 and 34 %, respectively), suggesting leptin resistance. Supplementation of Ca for 2 months normalised these disorders. The EW group had no change in serum insulin, thyroxine or triiodothyronine, and Ca treatment did not alter these hormones. In conclusion, we reinforced that early weaning leads to late development of some components of the metabolic syndrome and leptin resistance. Dietary Ca supplementation seems to protect against the development of endocrine and metabolic disorders in EW offspring, maybe through vitamin D inhibition.

Litter size reduction during lactation is a good model for childhood obesity since it induces overnutrition and programming for obesity at adulthood. Adult offspring develop higher fat mass content, hyperinsulinemia and insulin resistance, hypertension, lower HDL cholesterol, hyperphagia, and leptin resistance. Leptin resistance is often associated with hyperleptinemia. Although we observed higher SOCS3 and lower STAT3 in the hypothalamus of rats raised in small litters featuring a central leptin resistance, they showed unexpected normoleptinemia at 180 days old. Then, to clarify why early overfed rats did not develop hyperleptinemia when adult, we studied the leptin production by the visceral and subcutaneous adipose tissue and skeletal muscle as well as the morphology in the 2 different fat depots. To induce EO, litter size was reduced to 3 pups/litter (SL group) on the 3 (rd) day of life. In controls (NL group), litter size was adjusted to 10 pups/litter. Rats were killed at 180 days old. The programming of adipose tissue morphology by early overnutrition is specific between the different fat depots with hypertrophy only in the visceral compartment. In addition, the visceral adipocyte showed lower leptin content that may indicate a reduced leptin synthesis. These data suggest that adipocytes from SL rats are dysfunctional, since a higher leptin production in larger adipose cells is expected. In conclusion, postnatal nutrition is determinant for future leptin production by different fat depots as well as adipocyte morphology. These changes seem to be related to the severity of obesity and its metabolic consequences.

Hyperleptinemia during lactation programs for higher serum leptin in 30-day-old and adult rats, associated with metabolic changes. Here we evaluated the inhibition of serum leptin at 29 and 30 days on the metabolic phenotype of rats programmed with leptin during lactation. Pups from Wistar rats were saline-injected or leptin-injected from postnatal day 1 to day 10. At 29 and 30 days old, animals were injected with anti-leptin antibody (LA and CA) or saline (LS and CS). In adult animals, higher visceral (+53%) and total fat mass (+33%), hyperleptinemia (+67%), hypertriglyceridemia (+47%), and hypoadiponectinemia (-44%) observed in LS group compared to CS were prevented by immunoneutralization of leptin, since LA group had those parameters values similar to CS group. However, immunoblockade of leptin in normal animals led to the same metabolic changes seen in leptin-treated animals, in addition to lower serum adiponectin (-77% vs. CS) and higher insulin resistance index (+37%). Liver sirtuin1 (SIRT1) was higher (+41%) only in LA group, suggesting a role for SIRT1 in the prevention of leptin programming. Hypothalamic OBR was lower and SOCS3 higher in LS group and these changes were normalized in LA group. In conclusion, blocking leptin action one week after weaning seems to revert most of the alterations observed in rats programmed by neonatal hyperleptinemia. Higher liver SIRT1 expression may be one of the mechanisms involved, leading to a better glucose and lipid metabolism. Our data suggest that the lack or the excess of leptin programs an adverse metabolic phenotype in adulthood.

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. 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). 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. Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity.

We have previously shown that early weaning in rats increases the risk of obesity and insulin resistance at adulthood, and leptin resistance can be a prime factor leading to these changes. Resveratrol is reported to decrease oxidative stress, insulin resistance, and cardiovascular risk. However, there is no report about its effect on leptin resistance. Thus, in this study we have evaluated resveratrol-preventing effect on the development of visceral obesity, insulin, and leptin resistance in rats programmed by early weaning. To induce early weaning, lactating dams were separated into 2 groups: early weaning (EW) – dams were wrapped with a bandage to interrupt lactation in the last 3 days of lactation and control (C) – dams whose pups had free access to milk during throughout lactation period (21 days). At 150 days-old, EW offspring were subdivided into 2 groups: EW+res – treated with resveratrol solution (30 mg/kg BW/day) or EW – receiving equal volume of vehicle solution, both given by gavage during 30 days. Control group received vehicle solution. Resveratrol prevented the higher body weight, hyperphagia, visceral obesity, hyperleptinemia, hyperglycemia, insulin resistance, and hypoadiponectinemia at adulthood in animals that were early weaned. Leptin resistance, associated with lower JAK2 and pSTAT3 and higher NPY in hypothalamus of EW rats were also normalized by resveratrol. The present results suggest that resveratrol is useful as therapeutic tool in treating obesity, mainly because it prevents the development of central leptin resistance.

We showed that early weaned rats developed obesity, hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content. To induce early weaning, lactating rats’ teats were blocked with a bandage to interrupt lactation during the last 3 days (EW group), while control offspring had free access to milk throughout lactation (C group). In postnatal day (PN) 150, EW offspring were subdivided into: EW and EW+ mate groups treated, respectively, with water or yerba mate aqueous solution (1 g/kg BW/day, gavage) during 30 days. C offspring received water for gavage. In PN180, offspring were killed. EW+ mate group presented lower body weight (−10 %), adipose mass (retroperitoneal:−40 % and epididymal:−44 %), total body fat (−43 %), subcutaneous fat (−46 %), visceral adipocyte area (−21 %), triglyceridemia (−31 %) and hypothalamic NPY content (−37 %) compared to EW group. However, hyperglycemia and lower HDL-c levels observed in EW group were not reverted with mate treatment. Although the hyperleptinemia, lower hypothalamic JAK2 and pSTAT3 content of EW group were not corrected by mate treatment, the hyperphagia and higher hypothalamic SOCS-3 content were normalized in EW+ mate group, indicating that the central leptin resistance could be restored. Thus, the therapy with yerba mate solution was capable to reverse abdominal obesity, leptin resistance and hypertriglyceridemia, suggesting an important role of this bioactive component in the management of obesity in this programming model.

Intense physical activity is associated with biological adaptations involving hormones and trace elements. Zinc supplementation may affect plasma copper concentration, thyroid-stimulating hormone (TSH), thyroid hormones, insulin, and glucose homeostasis, but data in athletes are scarce. The aim of this study was to evaluate in competitive athletes (cyclists, n = 7, 32 ± 8 years) the effect of zinc supplementation (22 mg/day as zinc gluconate) during 30 days, and discontinuation using placebo (maltodextrin) during the following 30 days, on plasma zinc and copper concentrations, serum thyroid hormones, insulin and glucose levels, and HOMA2-IR. Compared to baseline, plasma zinc and Zn:Cu plasma ratio increased, but plasma copper decreased after zinc supplementation (day 30) and discontinuation (day 60) (p < 0.05). Zn supplementation and discontinuation had no effect on TSH, T3, and T4. Fasting serum insulin and HOMA2-IR increased (27% and 47%, respectively) on day 60 compared to baseline (p = 0.03), suggesting a delayed effect of zinc supplementation. Moreover, plasma zinc was positively associated with serum insulin (r = 0.87, p = 0.009) and HOMA2-IR (r = 0.81, p = 0.03) after zinc supplementation (day 30), indicating that supplemental zinc may impair glucose utilization in cyclists.