Search

Background: Cardiovascular (CV) pathologies remain a leading cause of death worldwide, often associated with common comorbidities such as overweight, obesity, type 2 diabetes or hypertension. An innovative mouse model of metabolic syndrome induced by postnatal overfeeding (PNOF) through litter size reduction after birth was developed experimentally. This study aimed to evaluate the impact of PNOF on cardiac remodelling and the development of heart failure following myocardial infarction., Methods: C57BL/6 male mice were raised in litter adjusted to 9 or 3 pups for normally-fed (NF) control and PNOF group respectively. After weaning, all mice had free access to standard diet and water. At 4 months, mice were subjected to myocardial infarction (MI). Echocardiographic follows-up were performed up to 6-months post-surgery and biomolecular analyses were carried-out after heart collection., Findings: At 4 months, PNOF mice exhibited a significant increase in body weight, along with a basal reduction in left ventricular ejection fraction (LVEF) and an increase in left ventricular end-systolic area (LVESA), compared to NF mice. Following MI, PNOF mice demonstrated a significant decrease in stroke volume and an increased heart rate compared to their respective initial values, as well as a notable reduction in cardiac output 4-months after MI. After 6-months, left ventricle and lung masses, fibrosis staining, and mRNA expression were all similar in the NF-MI and PNOF-MI groups., Interpretation: After MI, PNOF mice display signs of cardiac function worsening as evidenced by a decrease in cardiac output, which could indicate an early sign of heart failure decompensation., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The importance of parental diet in relation to eventual offspring health is increasing in prominence due to the increased frequency of parents of reproductive age consuming poor diets. Whilst maternal health and offspring outcome have been studied in some detail, the paternal impacts are not as well understood. A father's poor nutritional status has been shown to have negative consequences on foetal growth and development and ultimately impact the long-term adult health of the offspring. In this study, we examined sperm- and seminal vesicle fluid-mediated mechanisms of preimplantation embryo development alterations in response to sub-optimal paternal diets., Results: Male mice were fed a diet to model either under (low-protein diet (LPD)) or over (high-fat/sugar 'Western' diet (WD)) nutrition, LPD or WD supplemented with methyl donors or a control diet (CD) before mating with age-matched females. Male metabolic health was influenced by WD and MD-WD, with significant changes in multiple serum lipid classes and hepatic 1-carbon metabolites. Sperm RNA sequencing revealed significant changes to mRNA profiles in all groups when compared to CD (LPD: 32, MD-LPD: 17, WD: 53, MD-WD: 35 transcripts). Separate analysis of the seminal vesicle fluid proteome revealed a significant number of differentially expressed proteins in all groups (LPD: 13, MD-LPD: 27, WD: 24, MD-WD: 19) when compared to control. Following mating, in vitro time-lapse imaging of preimplantation embryos revealed a significant increase in the timing of development in all experimental groups when compared to CD embryos. Finally, qPCR analysis of uterine tissue at the time of implantation identified perturbed expression of Cd14 and Ptgs1 following mating with WD-fed males., Conclusions: Our current study shows that paternal nutritional status has the potential to influence male metabolic and reproductive health, impacting on embryonic development and the maternal reproductive tract. This study highlights potential direct (sperm-mediated) and indirect (seminal vesicle fluid-mediated) pathways in which a father's poor diet could shape the long-term health of his offspring., (© 2024. The Author(s).)

Scope: Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice., Methods and Results: Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status., Conclusion: Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

It is well known that overnutrition, overweight, and obesity in children can modulate brain mechanisms of plasticity, monoaminergic systems, and mitochondrial function. The immediate effect of overnutrition during the developmental period has not been thoroughly examined in rats until the present. This study sought to evaluate the impact on adult rats of early life overfeeding and fluoxetine treatment from post-natal day 1 (PND1) to post-natal day 21 (PND21) relative to mitochondrial function, oxidative balance, and expression of specific monoaminergic genes in the hippocampus. The following were evaluated: mitochondrial function markers, oxidative stress biomarkers, dopamine-and serotonin-related genes, and BDNF mRNA levels. Overfeeding during the lactation period deregulates cellular metabolism and the monoaminergic systems in the hippocampus. Strikingly, serotonin modulation by fluoxetine treatment protected against some of the effects of early overnutrition. We conclude that overfeeding during brain development induce detrimental effects in mitochondria and in the genes that regulate homeostatic status that can be the molecular mechanisms related to neurological diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The neuroendocrine system coordinates metabolic and behavioral adaptations to fasting, including reducing energy expenditure, promoting counterregulation, and suppressing satiation and anxiety to engage refeeding. Here, we show that steroid receptor coactivator-2 (SRC-2) in pro-opiomelanocortin (POMC) neurons is a key regulator of all these responses to fasting. POMC-specific deletion of SRC-2 enhances the basal excitability of POMC neurons; mutant mice fail to efficiently suppress energy expenditure during food deprivation. SRC-2 deficiency blunts electric responses of POMC neurons to glucose fluctuations, causing impaired counterregulation. When food becomes available, these mutant mice show insufficient refeeding associated with enhanced satiation and discoordination of anxiety and food-seeking behavior. SRC-2 coactivates Forkhead box protein O1 (FoxO1) to suppress POMC gene expression. POMC-specific deletion of SRC-2 protects mice from weight gain induced by an obesogenic diet feeding and/or FoxO1 overexpression. Collectively, we identify SRC-2 as a key molecule that coordinates multifaceted adaptive responses to food shortage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ability to generate new hippocampal neurons throughout adulthood and successfully integrate them into existing neural networks is critical to cognitive function, while disordered regulation of this process results in neurodegenerative or psychiatric disease. Consequently, identifying the molecular mechanisms promoting homeostatic hippocampal neurogenesis in adults is essential to understanding the etiologies of these disorders and developing therapeutic interventions. For example, recent evidence identifies a strong association between metabolic function and adult hippocampal neurogenesis. Hippocampal neural stem cell (NSC) fate dynamically fluctuates with changes in substrate availability and energy status (AMP/ATP and NAD + /NADH ratios). Furthermore, many metabolic hormones, such as insulin, insulin-like growth factors, and leptin exhibit dual functions also modulating hippocampal neurogenesis and neuron survivability. These diverse metabolic inputs to NSC's from various tissues seemingly suggest the existence of a system in which energy status can finely modulate hippocampal neurogenesis. Supporting this hypothesis, interventions promoting energy balance, such as caloric restriction, intermittent fasting, and exercise, have shown encouraging potential enhancing hippocampal neurogenesis and cognitive function. Overall, there is a clear relationship between whole body energy status, adult hippocampal neurogenesis, and neuron survival; however, the molecular mechanisms underlying this phenomenon are multifaceted. Thus, the aim of this review is to analyze the literature investigating energy status-mediated regulation of adult neurogenesis in the hippocampus, highlight the neurocircuitry and intracellular signaling involved, and propose impactful future directions in the field., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: We sought to evaluate the effects of overfeeding during lactation on the feeding behavior and expression of specific regulatory genes in brain areas associated with food intake in 22- and 60-day old male rats., Methods: We evaluated body weight, food intake of standard and palatable diet, and mRNA expression of dopamine receptor D1 (DDR1), dopamine receptor (DDR2), melanocortin 4 receptor (MC4R), the μ-opioid receptor (MOR), neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), cocaine-and amphetamine-regulated transcript (CART), serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT), 5-hydroxytryptamine receptor 1B (5-HT1B), 5-hydroxytryptamine receptor 2C receptor (5-HT2C), Clock (CLOK), cryptochrome protein 1 (Cry1) and period circadian protein homolog 2 (Per2) in the striatum, hypothalamus and brainstem of male rats at post-natal days (PND) 22 and 60., Key Findings: Overfeeding resulted in significantly increased body weight through PND60, and a 2-fold increase in palatable food intake at PND22, but not at PND60. We observed significant increases in DDR1, DDR2, and MC4R gene expression in the striatum and brainstem and POMC/CART in the hypothalamus of the OF group at PND22 that were reversed by PND60. Hypothalamic levels of 5-HT1B, 5-HT2C and NPY/AGRP on the other hand were decreased at PND22 and increased at PND60 in OF animals. Clock genes were unaffected by OF at PND22, but were significantly elevated at PND60., Significance: Overfeeding during early development of the rat brain results in obesity and altered feeding behavior in early adulthood. The altered behavior might be the consequence of the changes in food intake and reward gene expression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children., Methods: We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m 2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up., Results: >All participants were normal weight at baseline (BMIZ -0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm 2 ), VAT (2.0 [95% CI 0.1, 3.8] mm 2 ), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD)., Conclusions/interpretation: Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The recent identification of brown adipose tissue in adult humans offers a new strategy to increase energy expenditure to treat obesity and associated metabolic disease. While white adipose tissue (WAT) is primarily for energy storage, brown adipose tissue (BAT) is a thermogenic organ that increases energy expenditure to generate heat. BAT is activated upon cold exposure and improves insulin sensitivity and lipid clearance, highlighting its beneficial role in metabolic health in humans. This review provides an overview of BAT physiology in conditions of overnutrition (obesity and associated metabolic disease), undernutrition and in conditions of altered fat distribution such as lipodystrophy. We review the impact of exercise, dietary macronutrients and bioactive compounds on BAT activity. Finally, we discuss the therapeutic potential of dietary manipulations or supplementation to increase energy expenditure and BAT thermogenesis. We conclude that chronic nutritional interventions may represent a useful nonpharmacological means to enhance BAT mass and activity to aid weight loss and/or improve metabolic health.

Purpose of Review: This manuscript reviews evidence collected during COVID-19 pandemic and provides information on the impact of body composition on severity and outcomes of the disease, analysing methods used for body composition assessment. Malnutrition-screening tools will also be discussed to screen and diagnose the patients at higher risk of COVID-19 severity and related worse outcomes., Recent Findings: COVID-19 can occur in a wide range of presentation, from asymptomatic to severe forms. Among the major risk factors for worse severity, overnutrition, undernutrition and body composition play a role in the ability to respond to SARS-CoV-2 infection. Excess fat accumulation (i.e. obesity) or lean mass loss and functionality (i.e. sarcopenia) or a combination of both (i.e. sarcopenic obesity) can affect whole-body functioning. These body composition alterations in the short-term can influence susceptibility and immunological responses to the virus, inflammatory reaction, metabolic and respiratory distress, while in the long-term can modulate disease outcomes, namely length of stay, time required for recovery, risk of ICU-acquired weakness and long-term disabilities, and potentially increase the risk of death., Summary: Individuals with malnutrition, sarcopenia, obesity, sarcopenic obesity and older adults with abnormal body composition or malnutrition risk may require tailored medical nutrition therapy to improve short and long-term COVID-19 outcomes., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Recent evidence indicates that levels of breast milk (BM) hormones such as leptin can fluctuate with maternal adiposity, suggesting that BM hormones may signal maternal metabolic and nutritional environments to offspring during postnatal development. The hormone apelin is highly abundant in BM but its regulation during lactation is completely unknown. Here, we evaluated whether maternal obesity and overnutrition impacted BM apelin and leptin levels in clinical cohorts and lactating rats., Methods: BM and plasma samples were collected from normal-weight and obese breastfeeding women, and from lactating rats fed a control or a high fat (HF) diet during lactation. Apelin and leptin levels were assayed by ELISA. Mammary gland (MG) apelin expression and its cellular localization in lactating rats was measured by quantitative RT-PCR and immunofluorescence, respectively., Results: BM apelin levels increased with maternal BMI, whereas plasma apelin levels decreased. BM apelin was also positively correlated with maternal insulin and C-peptide levels. In rats, maternal HF feeding exclusively during lactation was sufficient to increase BM apelin levels and decrease its plasma concentration without changing body weight. In contrast, BM leptin levels increased with maternal BMI in humans, but did not change with maternal HF feeding during lactation in rats. Apelin is highly expressed in the rat MG during lactation and was mainly localized to mammary myoepithelial cells. We found that MG apelin gene expression was up-regulated by maternal HF diet and positively correlated with BM apelin content and maternal insulinemia., Conclusions: Our study indicates that BM apelin levels increase with long- and short-term overnutrition, possibly via maternal hyperinsulinemia and transcriptional upregulation of MG apelin expression in myoepithelial cells. Apelin regulates many physiological processes, including energy metabolism, digestive function, and development. Further studies are needed to unravel the consequences of such changes in offspring development.

Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The prevalence of adolescent obesity has increased dramatically, becoming a serious public health concern. While previous evidence suggests that in utero- and early postnatal overnutrition increases adult-onset obesity risk, the neurobiological mechanisms underlying this outcome are not well understood. Non-neuronal cells play an underestimated role in the physiological responses to metabolic/nutrient signals. Hypothalamic glial-mediated inflammation is now considered a contributing factor in the development and perpetuation of obesity; however, attention on the role of gliosis and microglia activation in other nuclei is still needed., Methods/results: Here, we demonstrate that early life consumption of high-fat/sucrose diet (HFSD) is sufficient to increase offspring body weight, hyperleptinemia and potentially maladaptive cytoarchitectural changes in the brainstem dorsal-vagal-complex (DVC), an essential energy balance processing hub, across postnatal development. Our data demonstrate that pre- and postnatal consumption of HFSD result in increased body weight, hyperleptinemia and dramatically affects the non-neuronal landscape, and therefore the plasticity of the DVC in the developing offspring., Conclusions: Current findings are very provocative, considering the importance of the DVC in appetite regulation, suggesting that HFSD-consumption during early life may contribute to subsequent obesity risk via DVC cytoarchitectural changes.

Skeletal muscle is sensitive to environmental cues that are first present in utero. Maternal overnutrition is a model of impaired muscle development leading to structural and metabolic dysfunction in adult life. In this study, we investigated the effect of an obesogenic maternal environment on growth and postnatal myogenesis in the offspring. Male C57BL/6J mice born to chow- or high-fat-diet-fed mothers were allocated to four different groups at the end of weaning. For the following 10 wk, half of the pups were maintained on the same diet as their mother and half of the pups were switched to the other diet (chow or high-fat). At 12 wk of age, muscle injury was induced using an intramuscular injection of barium chloride. Seven days later, mice were humanely killed and muscle tissue was harvested. A high-fat maternal diet impaired offspring growth patterns and downregulated satellite cell activation and markers of postnatal myogenesis 7 days after injury without altering the number of newly synthetized fibers over the whole 7-day period. Importantly, a healthy postnatal diet could not reverse any of these effects. In addition, we demonstrated that postnatal myogenesis was associated with a diet-independent upregulation of three miRNAs, mmu-miR-31-5p, mmu-miR-136-5p, and mmu-miR-296-5p. Furthermore, in vitro analysis confirmed the role of these miRNAs in myocyte proliferation. Our findings are the first to demonstrate that maternal overnutrition impairs markers of postnatal myogenesis in the offspring and are particularly relevant to today's society where the incidence of overweight/obesity in women of childbearing age is increasing.

Aging is associated with a decline in sex hormones, variable between sexes, that has an impact on many different body systems and might contribute to age-related disease progression. We aimed to characterize the sex differences in gut microbiota, and to explore the impact of depletion of gonadal hormones, alone or combined with postnatal overfeeding, in rats. Many of the differences in the gut microbiota between sexes persisted after gonadectomy, but removal of gonadal hormones shaped several gut microbiota features towards a more deleterious profile, the effect being greater in females than in males, mainly when animals were concurrently overfed. Moreover, we identified several intestinal miRNAs as potential mediators of the impact of changes in gut microbiota on host organism physiology. Our study points out that gonadal hormones contribute to defining sex-dependent differences of gut microbiota, and discloses a potential role of gonadal hormones in shaping gut microbiota, as consequence of the interaction between sex and nutrition. Our data suggest that the changes in gut microbiota, observed in conditions of sex hormone decline, as those caused by ageing in men and menopause in women, might exert different effects on the host organism, which are putatively mediated by gut microbiota-intestinal miRNA cross-talk.

Nutritional disorders during the perinatal period cause cardiometabolic dysfunction, which is observable in the early overfeeding (EO) experimental model. Therefore, severe caloric restriction has the potential of affecting homeostasis through the same epigenetic mechanisms, and its effects need elucidation. This work aims to determine the impact of food restriction (FR) during puberty in early overfed obese and non-obese animals in adult life. Three days after delivery (PN3), Wistar rats were separated into two groups: normal litter (NL; 9 pups) and small litter (SL; 3 pups). At PN30, some offspring were subjected to FR (50%) until PN60, or maintained with free access to standard chow. NL and SL animals submitted to food restriction (NLFR and SLFR groups) were kept in recovery with free access to standard chow from PN60 until PN120. Body weight and food intake were monitored throughout the experimental period. At PN120 cardiovascular parameters were analyzed and the animals were euthanized for sample collection. SLNF and SLFR offspring were overweight and had increased adiposity. Differences in blood pressure were observed only between obese and non-obese animals. Obese and FR animals have cardiac remodeling showing cardiomyocyte hypertrophy and the presence of interstitial and perivascular fibrosis. FR animals also show increased expression of AT1 and AT2 receptors and of total ERK and p-ERK. The present study showed that EO leads to the obese phenotype and cardiovascular disruptions. Interestingly, we demonstrated that severe FR during puberty leads to cardiac remodeling.

Nutritional imbalance in early life may disrupt the hypothalamic control of energy homeostasis and increase the risk of metabolic disease. The hypothalamic serotonin (5-hydroxytryptamine; 5-HT) system based in the hypothalamus plays an important role in the homeostatic control of energy balance, however the mechanisms underlying the regulation of energy metabolism by 5-HT remain poorly described. Several crucial mitochondrial functions are altered by mitochondrial stress. Adaptations to this stress include changes in mitochondrial multiplication (i.e, mitochondrial biogenesis). Due to the scarcity of evidence regarding the effects of serotonin reuptake inhibitors (SSRI) such as fluoxetine (FLX) on mitochondrial function, we sought to investigate the potential contribution of FLX on changes in mitochondrial function and biogenesis occurring in overfed rats. Using a neonatal overfeeding model, male Wistar rats were divided into 4 groups between 39 and 59 days of age based on nutrition and FLX administration: normofed + vehicle (NV), normofed + FLX (NF), overfed + vehicle (OV) and overfed + FLX (OF). We found that neonatal overfeeding impaired mitochondrial respiration and increased oxidative stress biomarkers in the hypothalamus. FLX administration in overfed rats reestablished mitochondrial oxygen consumption, increased mitochondrial uncoupling protein 2 (Ucp2) expression, reduced total reactive species (RS) production and oxidative stress biomarkers, and up-regulated mitochondrial biogenesis-related genes. Taken together our results suggest that FLX administration in overfed rats improves mitochondrial respiratory chain activity and oxidative balance and increases the transcription of genes employed in mitochondrial biogenesis favoring mitochondrial energy efficiency in response to early nutritional imbalance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The aim was to test the hypothesis that prenatal under- and overnutrition in late gestation can program small intestinal (SI) growth, angiogenesis, and endocrine function to predispose for a hyperabsorptive state, thereby increasing the susceptibility to the adverse effects of an early postnatal obesogenic diet. Twin-pregnant ewes were exposed to adequate (NORM), LOW (50% of NORM), or HIGH (150% energy and 110% protein of NORM) diets through the last trimester (term ~147 days). From 3 days to 6 months of age, their lambs were fed either a moderate (CONV) or a high-carbohydrate high-fat (HCHF) diet. At 6 months of age, responses in plasma metabolites and insulin to refeeding after fasting were determined and then different segments of the SI were sampled at autopsy. Prenatal overnutrition impacts were most abundant in the duodenum where HIGH had increased villus amplification factor and lowered villi thickness with increased IRS-1 and reduced GH-R expressions. In jejunum, HIGH lambs had an increased expression of Lactate gene and amplified when exposed to HCHF postnatally. Specifically, in LOW, sensitivity to HCHF was affected in ileum. Thus, the mismatching LOW-HCHF nutrition increased expressions of angiogenic genes (VEGF, VEGF-R1, ANGPT1, RTK) and increased mucosa layer (tunica mucosa) thickness but reduced muscle layer (Tunica muscularis) thickness. The SI is a target of prenatal nutritional programming, where late gestation overnutrition increased and shifted digestive capacity for carbohydrates toward the jejunum, whereas late gestation undernutrition predisposed for ileal angiogenesis and carbohydrate and fat hyperabsorptive capacity upon subsequent exposure to postnatal obesogenic diet., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Metabolic parameters ranging from circulating nutrient levels and substrate utilization to energy expenditure and thermogenesis are temporally modulated by the circadian timing system. During critical embryonic developmental periods, maternal over-nutrition could alter key elements in different tissues associated with the generation of circadian rhythmicity, compromising normal rhythmicity development. To address this issue, we determine whether maternal over-nutrition leads to alterations in the development of circadian rhythmicity at physiological and behavioral levels in the offspring. For this, female rabbits were fed a standard diet (SD) or high-fat and carbohydrate diet (HFCD) before mating and during gestation. Core body temperature and gross locomotor activity were continuously recorded in newborn rabbits, daily measurements of body weight and the amount of milk ingested was carried out. At the end of lactation, tissue samples, including brown adipose tissue (BAT) and white adipose tissue (WAT), were obtained for determining the expression of uncoupling protein-1 (UCP1) and cell death-inducing DNA fragmentation factor-like effector A (CIDEA) genes. HFCD pups exhibited conspicuous differences in the development of the daily rhythm of temperature and locomotor activity compared to the SD pups, including a significant increase in the daily mean core temperature, changes in the time when temperature or activity remains above the average, shifts in the acrophase, decrease in the duration and intensity of the anticipatory rise previous to nursing, and changes in frequency of the rhythms. HFCD pups exhibited a significant increase in BAT thermogenesis markers, and a decrease of these markers in WAT, indicating more heat generation by brown adipocytes and alterations in the browning process. These results indicate that maternal over-nutrition alters offspring homeostatic and chronostatic regulation at the physiological and behavioral levels. Further studies are needed to determine whether these alterations are associated with the changes in the organization of the circadian system of the progeny., Competing Interests: The authors have declared that no competing interests exist.

The maternal environment during pregnancy is critical for fetal development and perinatal perturbations can prime offspring disease risk. Here, we briefly review evidence linking two well-characterized maternal stressors - psychosocial stress and infection - to increased neuropsychiatric risk in offspring. In the current climate of increasing obesity and globalization of the Western-style diet, maternal overnutrition emerges as a pressing public health concern. We focus our attention on recent epidemiological and animal model evidence showing that, like psychosocial stress and infection, maternal overnutrition can also increase offspring neuropsychiatric risk. Using lessons learned from the psychosocial stress and infection literature, we discuss how altered maternal and placental physiology in the setting of overnutrition may contribute to abnormal fetal development and resulting neuropsychiatric outcomes. A better understanding of converging pathophysiological pathways shared between stressors may enable development of interventions against neuropsychiatric illnesses that may be beneficial across stressors., (Copyright © 2020. Published by Elsevier Inc.)

Childhood obesity is associated with metabolic and cardiovascular comorbidities. The development of these alterations may have its origin in early life stages such as the lactation period through metabolic programming. Insulin resistance is a common complication in obese patients and may be responsible for the cardiovascular alterations associated with this condition. This study analyzed the development of cardiovascular insulin resistance in a rat model of childhood overweight induced by overfeeding during the lactation period. On birth day, litters were divided into twelve (L12) or three pups per mother (L3). Overfed rats showed a lower increase in myocardial contractility in response to insulin perfusion and a reduced insulin-induced vasodilation, suggesting a state of cardiovascular insulin resistance. Vascular insulin resistance was due to decreased activation of phosphoinositide 3-kinase (PI3K)/Akt pathway, whereas cardiac insulin resistance was associated with mitogen-activated protein kinase (MAPK) hyperactivity. Early overfeeding was also associated with a proinflammatory and pro-oxidant state; endothelial dysfunction; decreased release of nitrites and nitrates; and decreased gene expression of insulin receptor (IR), glucose transporter-4 (GLUT-4), and endothelial nitric oxide synthase (eNOS) in response to insulin. In conclusion, overweight induced by lactational overnutrition in rat pups is associated with cardiovascular insulin resistance that could be related to the cardiovascular alterations associated with this condition.

Objectives: This investigation studied whether physical exercise could modulate cortical spreading depression (CSD) propagation velocity in adult rat offspring from dams that had received a high-fat (HF) diet during lactation. Methods: Wistar male rats suckled by dams fed either control (C) or HF diet ad libitum . After weaning, pups received standard laboratory chow. From 40 to 60 days of life, half of the animals exercised on a treadmill (group E); the other half remained sedentary (group S). Two additional HF groups (E and S) received fluoxetine (F; 10 mg/kg/day, orogastrically) from 40 to 60 days of life (groups HF/EF and HF/F). Results: At 40 days of life, rats from the maternal HF diet presented higher weight, thoracic circumference, and Lee Index than C animals and remained heavier at 60 days of life. Physical exercise decreased abdominal circumference. HF diet increased CSD propagation velocity (mean ± SD; mm/min) in sedentaries (HF/S 3.47 ± 0.31 versus C/S 3.24 ± 0.26). Treadmill exercise decelerated CSD propagation in both groups C/E (2.94 ± 0.28) and HF/E (2.97 ± 0.40). Fluoxetine alone decreased CSD propagation (HF/F 2.88 ± 0.45) compared with HF/S group. The combination of fluoxetine + exercise under HF condition (2.98 ± 0.27) was similar to HF/E group. Discussion: Physical exercise is able to reduce CSD propagation velocity in rat adult brains even when they have suffered over-nourishing during lactation. The effects of exercise alone or fluoxetine alone on CSD were similar to the effects of fluoxetine + exercise, under the HF condition. Data reinforce malnutrition during lactation modifies cortical electrophysiology even when the HF condition no longer exists.

Overweight/obesity has become a worldwide epidemic, and factors such as a sedentary lifestyle and inadequate eating habits directly contribute to the development of this condition. Studies indicate that rapid weight gain at critical development stages, such as the lactation period, is associated with the development of obesity, cardiovascular diseases, and diabetes in the long term. In addition to metabolic changes during adulthood, overweight/obesity may influence reproductive function of the population. In this context, the present study aimed to evaluate postnatal overfeeding effects on male and female Wistar rat reproductive parameters. Postnatal overfeeding was induced by applying the litter reduction method for both sexes. Forty animals were used, divided into four groups: two with normal litters (NL♂ and NL♀) and two with small litters (SL♂ and SL♀). The males were euthanized at 90 days of age, on the same date the females were mated. Females were also euthanized after the 20-day gestation. Metabolic and reproductive variables were analyzed. Regarding males, SL animals showed increased body weight, adiposity, and decreased relative weight of the seminal vesicle, prostate, and epididymis as well as changes in the ITT and OGTT glycemic tests. Concerning females, SL animals presented increased body weight, relative perigonadal fat weight, glucose intolerance as well as modify the vaginal opening and increased weight of female pup. The litter reduction method was efficient in leading to metabolic and reproductive alterations in male and female Wistar rat.

Maternal overnutrition during sensitive periods of early development increases the risk for obesity and neuropsychiatric disorders later in life. However, it still remains unclear during which phases of early development the offspring is more vulnerable. Here, we investigate the effects of maternal high-fat diet (MHFD) at different stages of pre- or postnatal development and characterize the behavioral, neurochemical and metabolic phenotypes. We observe that MHFD exposure at pre-conception has no deleterious effects on the behavioral and metabolic state of the offspring. Late gestational HFD exposure leads to more prominent addictive-like behaviors with reduced striatal dopamine levels compared to early gestational HFD. Conversely, offspring exposed to MHFD during lactation display the metabolic syndrome and schizophrenia-like phenotype. The latter, is manifested by impaired sensory motor gating, and latent inhibition as well as enhanced sensitivity to amphetamine. These effects are accompanied by higher striatal dopamine levels. Together, our data suggest that MHFD exposure during specific stages of development leads to distinct neuropathological alterations that determine the severity and nature of poor health outcome in adulthood, which may provide insight in identifying effective strategies for early intervention.

Aims/hypothesis: We previously showed that intrauterine exposure to gestational diabetes mellitus (GDM) increases selected markers of adiposity in pre-pubertal adolescents. In the present study, we examined these associations in adolescence, and explored whether they are strengthened as the participants transition through puberty., Methods: Data from 597 individuals (505 unexposed, 92 exposed) participating in the longitudinal Exploring Perinatal Outcomes among Children (EPOCH) study in Colorado were collected at two research visits when the participants were, on average, 10.4 and 16.7 years old. Adiposity measures included BMI, waist/height ratio, and visceral and subcutaneous adipose tissue (as determined by MRI). Separate general linear mixed models were used to assess the longitudinal relationships between exposure to maternal GDM and each adiposity outcome. We tested whether the effect changed over time by including an interaction term between exposure and age in our models, and whether the associations were explained by postnatal behaviours., Results: Compared with unexposed participants, those exposed to maternal GDM had higher BMI (β = 1.28; 95% CI 0.35, 2.21; p < 0.007), waist/height ratio (β = 0.03; 95% CI 0.01, 0.04; p = 0.0004), visceral adipose tissue (β = 4.81; 95% CI 1.08, 8.54; p = 0.01) and subcutaneous adipose tissue (β = 35.15; 95% CI 12.43, 57.87; p < 0.003). The magnitude of these differences did not change over time and the associations did not appear to be explained by postnatal behaviours., Conclusions/interpretation: Our data provide further evidence that intrauterine exposure to maternal GDM is associated with increased offspring adiposity, an effect that appears early in life and tracks throughout adolescence. Efforts to prevent childhood obesity following intrauterine exposure to maternal GDM should target the prenatal or early life periods.

Objectives: Epidemiological studies have linked maternal obesity with metabolic as well as psychiatric disorders in the progeny. However, very little is known how maternal overnutrition may affect the cognitive abilities of the offspring. Methods: Here, we tested the hypothesis whether maternal high-fat diet (HFD) exposure in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the offspring during different age trajectories. Results: We found that maternal HFD led to cognitive disabilities in adult offspring compared to controls. It was mostly evident in a reference memory and in an associative learning paradigm. More severe and pervasive impairments were evident in the aged adult group across multiple cognitive domains. In addition, adult and aged adult HFD offspring showed potentiation of prepulse inhibition. The cognitive impairments observed at adulthood were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions. Discussion: Our results suggest that HFD offspring are at an increased risk to develop cognitive deficits, affecting learning and memory processes in adulthood. Furthermore, maternal HFD exposure may facilitate or even drive pathological brain aging mainly in the hippocampal and prefrontal cortex structures that may explain the cognitive deficits observed in the offspring.

Objective: This study aimed to analyze whether exposure to environmental enrichment (EE) during the juvenile phase of life interferes with the electrical activity of the adult rat brain. In addition, the present research also investigated whether this putative effect on brain electrical activity could be affected by prior overnutrition during lactation. Electrophysiology was measured through cortical spreading depression (CSD), a phenomenon related to brain excitability., Methods: Wistar rats were suckled in litters of either nine or three pups, forming the nourished (N) or overnourished (ON) groups, respectively. At 36 days old, half of the animals from each nutritional condition were exposed to EE. The other half was kept in the standard environment (SE). At 90-120 days of life, each animal was anesthetized for CSD recordings., Results: Overnutrition during lactation caused increases (p < 0.05) in body and brain weights. The EE decelerated CSD propagation velocity regardless of nutritional state during lactation (p < 0.001). The CSD deceleration in the N-EE group was 23.8% and in the ON-EE group was 15% in comparison with the N-SE and ON-SE groups, respectively., Conclusion: Our data demonstrated that EE exposure in the juvenile phase of the rat's life reduced brain excitability, and this effect was observed even if animals were overnourished during lactation. An EE could be considered an adjuvant therapeutic resource to modulate brain excitability.

The early-life environment is important in programming brain development, and metabolic disruptions at this time can have long-lasting effects. Previously, we have shown that rats overfed for the first 3 weeks of their neonatal life maintain obesity into adulthood. Neonatal overfeeding also leads to primed hypothalamic and hippocampal microglia that are hyper-responsive to an immune challenge in adulthood. However, whether this microglial priming contributes to the obese phenotype and whether it is possible to reverse either the obesity or the microglial priming are not clear. In the present study, we hypothesised that an intervention with minocycline during the juvenile period (postnatal day 21-42) would normalise both the microglial priming and obesity. To induce obesity in neonatal Wistar rats, we manipulated the litter sizes in which they were suckled, yielding litters of 12 (control-fed) or four (neonatally overfed). After weaning, we administered minocycline i.p. every second day for a 3-week period and examined body composition and microglial profiles 24 hours following an immune challenge with lipopolysaccharide. As demonstrated previously, neonatal overfeeding resulted in prolonged weight gain. However, minocycline failed to reverse this effect. Minocycline did reverse microglial priming in feeding-related regions of the hypothalamus, with minimal effects on pro-inflammatory cytokines and on microglial number and morphology in the hippocampus. Thus, the programming effect of neonatal overfeeding on microglial priming can be ameliorated by minocycline later in life. However, the persistent obesity seen after neonatal overfeeding is likely not driven by changes in hypothalamic inflammation and microglial activity., (© 2019 British Society for Neuroendocrinology.)

Modulation of the human gut microbiota through probiotics, prebiotics and dietary fibre are recognised strategies to improve health and prevent disease. Yet we are only beginning to understand the impact of these interventions on the gut microbiota and the physiological consequences for the human host, thus forging the way towards evidence-based scientific validation. However, in many studies a percentage of participants can be defined as 'non-responders' and scientists are beginning to unravel what differentiates these from 'responders;' and it is now clear that an individual's baseline microbiota can influence an individual's response. Thus, microbiome composition can potentially serve as a biomarker to predict responsiveness to interventions, diets and dietary components enabling greater opportunities for its use towards disease prevention and health promotion. In Part I of this two-part review, we reviewed the current state of the science in terms of the gut microbiota and the role of diet and dietary components in shaping it and subsequent consequences for human health. In Part II, we examine the efficacy of gut-microbiota modulating therapies at different life stages and their potential to aid in the management of undernutrition and overnutrition. Given the significance of an individual's gut microbiota, we investigate the feasibility of microbiome testing and we discuss guidelines for evaluating the scientific validity of evidence for providing personalised microbiome-based dietary advice. Overall, this review highlights the potential value of the microbiome to prevent disease and maintain or promote health and in doing so, paves the pathway towards commercialisation., Competing Interests: The authors declare no conflict of interest.

Aims: Obesity is associated with innumerous comorbidities, including cardiovascular diseases, that occur by various mechanisms, including hyperactivation of the renin angiotensin system, oxidative stress and cardiovascular overload. Postnatal early overfeeding (PO) leads to metabolic imprinting that induces weight gain throughout life, and in this paper, we aimed to evaluate cardiovascular parameters and cardiac molecular changes due to obesity induced early in life by PO., Main Methods: Male Wistar rats (120-days-old), raised in normal (NL) or small litters (SL), were submitted to cardiac assessment by transthoracic echocardiography and blood pressure evaluation. Thereafter, the hearts and aorta rings from these animals were submitted to ex-vivo isolated assays. Still, cardiac morphological and molecular analyses were performed., Key Findings: PO induced ventricular hypertrophy, raised blood pressure, increased fibrosis, and ex-vivo cardiac dysfunction in the SL group. Furthermore, SL animals presented impaired vascular relaxation and increased vascular constriction responses. Besides functional alterations, SL animals presented augmented RAB-1b and SOD-1, despite no changes in RAS receptors expression or Akt/eNOS pathway., Significance: Taken together, our results consolidate the knowledge that the PO during lactation is critical for cardiometabolic programming, leading to oxidative stress and cardiac remodeling in later stages of life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Animal models have been indispensable in elucidating the potential causative mechanisms underlying the effects of maternal diet on offspring health. Of these, the mouse has been widely used to model maternal overnutrition and/or maternal obesity and to study its effects across one or more generations. This review discusses recent findings from mouse models, which resemble the human situation, i.e. overnutrition/obesity across pregnancy and lactation. It also highlights the importance of embryo transfer models in identifying critical developmental period(s) during which specific metabolic changes are programmed in the offspring. The mouse is also an excellent tool for maternal intervention studies aimed at elucidating the longer-term effects on the offspring and for defining possible maternal factors underling the programming of metabolic adversity in offspring. While knowledge of the mouse genome and the molecular tools available have allowed great progress to be made in the field, it is clear that we need to define if the effects on the offspring are mediated by maternal obesity per se or if specific components of the maternal metabolic environment are more important. We can then begin to identify at-risk offspring and to design more effective interventions for the mother and/or her child. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

Context: Iron overload has been associated with greater adipose tissue (AT) depots. We retrospectively studied the potential interactions between iron and AT during an experimental overfeeding in participants without obesity., Methods: Twenty-six participants (mean body mass index ± SD, 24.7 ± 3.1 kg/m2) underwent a 56-day overfeeding (+760 kcal/d). Serum iron biomarkers (ELISA), subcutaneous AT (SAT) gene expression, and abdominal AT distribution assessed by MRI were analyzed at the beginning and the end of the intervention., Results: Before intervention: SAT mRNA expression of the iron transporter transferrin (Tf) was positively correlated with the expression of genes related to lipogenesis (lipin 1, ACSL1) and lipid storage (SCD). SAT expression of the ferritin light chain (FTL) gene, encoding ferritin (FT), an intracellular iron storage protein, was negatively correlated to SREBF1, a gene related to lipogenesis. Serum FT (mean, 92 ± 57 ng/mL) was negatively correlated with the expression of SAT genes linked to lipid storage (SCD, DGAT2) and to lipogenesis (SREBF1, ACSL1). After intervention: Overfeeding led to a 2.3 ± 1.3-kg weight gain. In parallel to increased expression of lipid storage-related genes (mitoNEET, SCD, DGAT2, SREBF1), SAT Tf, SLC40A1 (encoding ferroportin 1, a membrane iron export channel) and hephaestin mRNA levels increased, whereas SAT FTL mRNA decreased, suggesting increased AT iron requirement. Serum FT decreased to 67 ± 43 ng/mL. However, no significant associations between serum iron biomarkers and AT distribution or expansion were observed., Conclusion: In healthy men, iron metabolism gene expression in SAT is associated with lipid storage and lipogenesis genes expression and is modulated during a 56-day overfeeding diet.

Background: Overnutrition due to a high-fat diet (HFD) can increase the vulnerability of the metabolic system to maladjustments. Estradiol has an inhibitory role on food intake and this hormone has demonstrated to be a crucial organizer during brain development., Objective: Our aim was to determine whether increased levels of estradiol in the early postnatal period modulate the alterations in metabolism and brain metabolic circuits produced by overnutrition., Methods: Twenty-four male and 24 female Wistar rats were submitted to a HFD (34.9% fat) or a control diet (5% fat) from gestational day 6. From postnatal (P) 6 to P13, both control and HFD groups were administered a s.c. injection of vehicle or estradiol benzoate (0.4 mg/kg), resulting in eight experimental groups (n = 6 in each group). Body weight, food intake and subcutaneous, visceral, and brown fat pads were measured. Agouti-related peptide, neuropeptide Y, orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay and plasma estradiol levels were measured by ELISA., Results: Males fed a HFD showed an increase in body weight and the amount of visceral and subcutaneous fat, which was coincident with an increase in the number of kilocalories ingested. Neonatal estradiol treatment restored the body weight and subcutaneous fat of HFD males to control levels. Hypothalamic POMC mRNA levels in HFD females were increased with respect to control females. This increase was reverted with estradiol treatment during development., Discussion: HFD and estradiol treatment have different effects on males and females. Overnutrition affects physiological parameters, such as body weight, visceral, and subcutaneous fat content, in males, while females present alterations in hypothalamic POMC mRNA levels. Hence, the increase in estradiol levels during a period that is critical for the programing of the feeding system can modulate some of the alterations produced by the continuous intake of high-fat content food.

Ample evidence from epidemiological studies has linked maternal obesity with metabolic disorders such as obesity, cardiovascular disease, and diabetes in the next generation. Recently, it was also shown that maternal obesity has long-term effects on the progeny's central nervous system. However, very little is known regarding how maternal overnutrition may affect, in particular, the cognitive abilities of the offspring. We reported that first-generation offspring exposed to a maternal high-fat diet (MHFD) displayed age-dependent cognitive deficits. These deficits were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions of MHFD offspring. Here, we tested the hypothesis that MHFD in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the second and third generations. We found that MHFD led to cognitive disabilities and an altered response to a noncompetitive receptor antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor in adult MHFD offspring in both second and third generations in a sex-specific manner. Our results suggest that maternal overnutrition leads to an increased risk of developing obesity in subsequent generations as well as to cognitive impairments, affecting learning and memory processes in adulthood. Furthermore, MHFD exposure may facilitate pathological brain aging which is not a consequence of obesity. Our findings shed light on the long-term effects of maternal overnutrition on the development of the central nervous system and the underlying mechanisms which these traits relate to disease predisposition.

Nutrient overload occurs worldwide as a consequence of the modern diet pattern and the physical inactivity that sometimes accompanies it. Cells initiate multiple protective mechanisms to adapt to elevated intracellular metabolites and restore metabolic homeostasis, but irreversible injury to the cells can occur in the event of prolonged nutrient overload. Many studies have advanced the understanding of the different detrimental effects of nutrient overload; however, few reports have made connections and given the full picture of the impact of nutrient overload on cellular metabolism. In this review, detailed changes in metabolic and energy homeostasis caused by chronic nutrient overload, as well as their associations with the development of metabolic disorders, are discussed. Overnutrition-induced changes in key organelles and sensors rewire cellular bioenergetic pathways and facilitate the shift of the metabolic state toward biosynthesis, thereby leading to the onset of various metabolic disorders, which are essentially the downstream manifestations of a misbalanced metabolic equilibrium. Based on these mechanisms, potential therapeutic targets for metabolic disorders and new research directions are proposed.

Background and Aims: The prevalence of obesity is increasing worldwide at an alarming rate. Altered early nutrition, in particular postnatal overfeeding (PNOF), is a risk factor for impaired cardiac function in adulthood. In the understanding of the initiation or progression of heart diseases, NLRP3 inflammasome and non-coding RNAs have been proposed as key players. In this context, the aim of this study was to decipher the role of NLRP3 inflammasome and its post transcriptional control by micro-RNAs in the regulation of cardiac metabolic function induced by PNOF in mice., Methods and Results: Based on a model of mice exposed to PNOF through litter size reduction, we observed increased cardiac protein expression levels of NLRP3 and ETS-1 associated with alterations in insulin signaling. Additionally, miR-193b levels were down-regulated in the adult hearts of overfed animals. In a cardiomyocyte cell line, transfection with miR-193b induced down-regulation of ETS-1 and NLRP3 and improved insulin signaling., Conclusions: These findings suggest that the miR-193b could be involved in cardiac phenotypic changes observed in adulthood induced by PNOF likely through the regulation of ETS-1 and NLRP3 expression, and through this of insulin signaling., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Maternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring's hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition., Methods: Eight-week-old female Sprague-Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet., Results: With maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet., Conclusion: Maternal overnutrition programs long-term epigenetic alterations in the offspring's hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.

Neonatal nutritional changes induce long-lasting effects on energy homeostasis. Adiponectin influences food intake and body weight. The aim of this study was to investigate the effects of neonatal nutritional programming on the central stimulation of adiponectin. Male Wistar rats were divided on postnatal (PN) day 3 in litters of 3 (small litter, SL), 10 (normal litter, NL), or 16 pups/dam (large litter, LL). We assessed body weight gain for 60 days, adiponectin concentration, and white adipose tissue weight. We examined the response of SL, NL, and LL rats on body weight gain, food intake, oxygen consumption (V̇o 2 ), respiratory exchange ratio (RER), calorimetry, locomotor activity, phosphorylated-AMP-activated protein kinase (AMPK) expression in the hypothalamus, and uncoupling protein (UCP)-1 in the brown adipose tissue after central stimulus with adiponectin. After weaning, SL rats maintained higher body weight gain despite similar food intake compared with NL rats. LL rats showed lower body weight at weaning, with a catch up afterward and higher food intake. Both LL and SL groups had decreased plasma concentrations of adiponectin at PN60. SL rats had increased white adipose tissue. Central injection of adiponectin decreased body weight and food intake and increased V̇o 2 , RER, calorimetry, p-AMPK and UCP- 1 expression in NL rats, but it had no effect on SL and LL rats, compared with the respective vehicle groups. In conclusion, neonatal under- and overfeeding induced an increase in body weight gain in juvenile and early adult life. Unresponsiveness to central effects of adiponectin contributes to the imbalance of the energy homeostasis in adult life induced by neonatal nutritional programming.

Background: Short-term overfeeding combined with reduced physical activity impairs metabolic function and alters the expression of key genes within adipose tissue. We have shown that daily vigorous-intensity running can prevent these changes independent of any net effect on energy imbalance. However, which type, intensity and/or duration of exercise best achieves these benefits remains to be ascertained., Methods/design: Forty-eight healthy young men will be recruited and randomly allocated to one of four experimental conditions for 1 week: (1) to ingest 50% more energy than normal by over-consuming their habitual diet whilst simultaneously restricting their physical activity below 4000 steps day -1 (i.e. energy surplus; SUR group); (2) the same regimen but with a daily 45-min bout of vigorous-intensity arm crank ergometry at 70% of maximum oxygen uptake (SUR + ARM group); (3) the same regimen but with a daily 45-min bout of moderate-intensity treadmill walking at 50% of maximum oxygen uptake (SUR + MOD group); (4) the same regimen but with the addition of intermittent short bouts of walking during waking hours (SUR + BREAKS group). Critically, all exercise groups will receive additional dietary energy intake to account for the energy expended by exercise, thus maintaining a matched energy surplus. At baseline and follow-up, fasted blood samples, abdominal subcutaneous adipose tissue and skeletal muscle biopsies will be obtained and oral glucose tolerance tests conducted., Discussion: This study will establish the impact of different forms of daily exercise on metabolic function at the whole-body level as well as within adipose tissue and skeletal muscle in the context of a standardised energy surplus., Trial Registration: ISRCTN, ISRCTN18311163 . Registered on 24 June 2015.

Adipose tissue plays a significant role in whole body energy homeostasis. Obesity-associated diabetes, fatty liver and metabolic syndrome are closely linked to adipose stress and dysfunction. Genetic predisposition, overeating and physical inactivity influence the expansion of adipose tissues. Under conditions of constant energy surplus, adipocytes become hypertrophic and adipose tissues undergo hyperplasia so as to increase their lipid storage capacity, thereby keeping circulating blood glucose and fatty acids below toxic levels. Nonetheless, adipocytes have a saturation point where they lose capacity to store more lipids. At this stage, when adipocytes are fully lipid-engorged, they express stress signals. Adipose depots (particularly visceral compartments) from obese individuals with a severe metabolic phenotype are characterized by the high proportion of hypertrophic adipocytes. This review focuses on the mechanisms of adipocyte enlargement in relation to adipose fatty acid and cholesterol metabolism, and considers how this may be related to adipose dysfunction., (© 2017 World Obesity Federation.)

Inflammation may be a mechanism of maternal programming because it has the capacity to alter the maternal environment and can persist postnatally in offspring tissues. This study evaluated the effects of restricted- and over-feeding on maternal and offspring inflammatory gene expression using reverse transcription (RT)-PCR arrays. Pregnant ewes were fed 60% (Restricted), 100% (Control), or 140% (Over) of National Research Council requirements beginning on day 30.2 ± 0.2 of gestation. Maternal (n = 8-9 ewes per diet) circulating nonesterified fatty acid (NEFA) and expression of 84 inflammatory genes were evaluated at five stages during gestation. Offspring (n = 6 per diet per age) inflammatory gene expression was evaluated in the circulation and liver at day 135 of gestation and birth. Throughout gestation, circulating NEFA increased in Restricted mothers but not Over. Expression of different proinflammatory mediators increased in Over and Restricted mothers, but was diet-dependent. Maternal diet altered offspring systemic and hepatic expression of genes involved in chemotaxis at late gestation and cytokine production at birth, but the offspring response was distinct from the maternal. In the perinatal offspring, maternal nutrient restriction increased hepatic chemokine (CC motif) ligand 16 and tumor necrosis factor expression. Alternately, maternal overnutrition increased offspring systemic expression of factors induced by hypoxia, whereas expression of factors regulating hepatocyte proliferation and differentiation were altered in the liver. Maternal nutrient restriction and overnutrition may differentially predispose offspring to liver dysfunction through an altered hepatic inflammatory microenvironment that contributes to immune and metabolic disturbances postnatally.

Rigorous nutritional care during early life leads to healthy adulthood. Cardiovascular and metabolic disorders, the most prevalent clinical challenges worldwide, are epidemiologically linked to poor nutritional habits throughout life. We aimed to understand whether postnatal overnutrition (PO) initiated during lactation affects metabolic markers and vascular function later in life. To test this hypothetical effect, we studied a PO Wistar rat model based on adjusting litter size at the third day of age to three pups and eight for the control group (C). Systemic parameters such as body weight and food intake were significantly increased in adult rats, measured up to 36 weeks. Moreover, fat mass, triglycerides, insulin and systolic blood pressure were all significantly increased in the PO group. Furthermore, we assessed whether these alterations would affect morphological and functional parameters in isolated vessels. Consistent with systemic alterations of the vasculature, contraction of thoracic aortic rings, determined by dose-response curves to norepinephrine (NE), was significantly reduced in PO rats. Histological stains revealed that the relative area of collagen was higher and the elastic fiber density was lower in the distal rings of PO rats. Altogether, our results highlight the critical importance of having a healthy neonatal nutrition to prevent harmful metabolic and vascular alterations during adulthood.

BackgroudEarly life nutrition may have a role in the regulation of metabolism in adulthood. The present study aimed to evaluate the effects of postnatal overfeeding and a postweaning fish oil diet on energy expenditure.MethodsOn postnatal day 3, rat litters were adjusted to a litter size of three (small litters, SLs) or ten (normal litters, NLs). After weaning, SLs were fed the standard diet or a fish oil diet enriched with polyunsaturated fatty acids (SL-FOs) for 10 weeks. The metabolic parameters of rats were monitored using the TSE LabMaster at postnatal week 3 (W 3 ) and postnatal week 13 (W 13 ).ResultsAt W 3 , the O 2 consumption and heat production in SLs were lower than those in NLs, while the respiratory exchange ratio (RER) was higher than NLs. SLs showed obesity, dyslipidemia, and impaired glucose tolerance at W 13 . The postweaning fish oil diet in SLs not only increased O 2 consumption, CO 2 production, heat production, and reduced the RER but it also reduced weight gain, serum triglycerides, and improved glucose tolerance at W 13 .ConclusionPostnatal overfeeding can decrease the level of body energy expenditure and induce obesity, but a fish oil diet can increase the energy expenditure and prevent the development of metabolic dysregulation in adults.

Aims: To examine the associations of intrauterine exposure to maternal diabetes and obesity with offspring insulin resistance, β-cell function and oral disposition index in a longitudinal observational study of ethnically diverse offspring., Methods: A total of 445 offspring who were exposed (n=81) or not exposed (n=364) to maternal diabetes in utero completed two fasting blood measurements at mean (sd) ages of 10.5 (1.5) and 16.5 (1.2) years, respectively, and an oral glucose tolerance test at the second visit. We used linear mixed models and general linear univariate models to evaluate the associations of maternal diabetes and pre-pregnancy BMI with offspring outcomes., Results: Maternal diabetes in utero predicted increased insulin resistance [18% higher updated homeostatic model assessment of insulin resistance (HOMA2-IR), P=0.01; 19% lower Matsuda index, P=0.01 and 9% greater updated homeostatic model assessment of β-cell function (HOMA2-β), P=0.04]. Each 5-kg/m 2 increase in pre-pregnancy BMI predicted increased insulin resistance (11% greater HOMA2-IR, P<0.001; 10% lower Matsuda index, P<0.001; 6% greater HOMA2-β, P<0.001). Similar results were obtained in a combined model with both exposures. After adjustment for offspring BMI, only maternal diabetes was associated with higher HOMA2-IR (β=1.12, P=0.03) and lower Matsuda index (β=0.83, P=0.01). Neither exposure was associated with early insulin response or oral disposition index., Conclusions: Intrauterine exposure to diabetes or obesity is associated with greater offspring insulin resistance than non-exposure, supporting the hypothesis that fetal overnutrition results in metabolic abnormalities during childhood and adolescence., (© 2017 Diabetes UK.)

Background and Aims: The aim of this study was to analyze the effects of early overnutrition (EON) on the expression of the renin angiotensin aldosterone system (RAAS) components in renal cortex, renal arteries and renal perivascular adipose tissue (PVAT), as well as the vascular response of renal arteries to Angiotensin II (Ang II)., Methods and Results: On birth day litters were adjusted to twelve (L12-control) or three (L3-overfed) pups per mother. Half of the animals were sacrificed at weaning (21 days old) and the other half at 5 months of age. Ang II-induced vasoconstriction of renal artery segments increased in young overfed rats and decreased in adult overfed rats. EON decreased the gene expression of angiotensinogen (Agt), Ang II receptors AT1 and AT2 and eNOS in renal arteries of young rats, while it increased the mRNA levels of AT-2 and ET-1 in adult rats. In renal PVAT EON up-regulated the gene expression of COX-2 and TNF-α in young rats and the mRNA levels of renin receptor both in young and in adult rats. On the contrary, Ang II receptors mRNA levels were downregulated at both ages. Renal cortex of overfed rats showed increased gene expression of Agt in adult rats and of AT1 in young rats. However the mRNA levels of AT1 were decreased in the renal cortex of overfed adult rats., Conclusion: EON is associated with alterations in the vascular response of renal arteries to Ang II and changes in the gene expression of RAAS components in renal tissue., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Objective: The suckling period is a critical phase of development, in which maternal overnutrition may program the susceptibility of developing chronic diseases and disorders, such as obesity and metabolic alterations, in adult life. Here, we questioned whether the consumption of a cafeteria diet throughout lactation in rats affects the macronutrient composition of milk and whether it results in permanent metabolic effects in the offspring., Methods: Nursing rats were fed a control diet or a cafeteria diet during lactation. Milk was obtained at different time points of lactation. Offspring (males and females) were weaned onto a control diet until the age of 6 months. Circulating parameters were measured under ad libitum feeding and under 12-h fasting conditions at weaning and at 3 and 6 months of age. An oral glucose tolerance test (OGTT) was performed at 3 and 6 months of age., Results: Rats fed a cafeteria diet during lactation consumed an unbalanced diet, with lower protein and higher fat content versus controls, which was reflected in the composition of the milk. The offspring of rats fed a cafeteria diet during lactation showed lower body weight and lower lean mass, but greater fat accumulation, compared with controls. They also displayed hyperleptinaemia, altered lipid profile and impaired response to an OGTT., Conclusion: Maternal consumption of a cafeteria diet throughout lactation in rats produces lasting effects in the metabolic health of their offspring, which are not associated with a higher body weight but with a greater fat accumulation, similarly to the thin-outside-fat-inside phenotype.

The optimal nutritional support in Acute Kidney Injury (AKI) still remains an open issue. The present study was aimed at evaluating the validity of conventional predictive formulas for the calculation of both energy expenditure and protein needs in critically ill patients with AKI. A prospective, multicenter, observational study was conducted on adult patients hospitalized with AKI in three different intensive care units (ICU). Nutrient needs were estimated by different methods: the Guidelines of the European Society of Parenteral and Enteral Nutrition (ESPEN) for both calories and proteins, the Harris-Benedict equation, the Penn-State and Faisy-Fagon equations for energy. Actual energy and protein needs were repeatedly measured by indirect calorimetry (IC) and protein catabolic rate (PCR) until oral nutrition start, hospital discharge or renal function recovery. Forty-two patients with AKI were enrolled, with 130 IC and 123 PCR measurements obtained over 654 days of artificial nutrition. No predictive formula was precise enough, and Bland-Altman plots wide limits of agreement for all equations highlight the potential to under- or overfeed individual patients. Conventional predictive formulas may frequently lead to incorrect energy and protein need estimation. In critically ill patients with AKI an increased risk for under- or overfeeding is likely when nutrient needs are estimated instead of measured., Competing Interests: The authors declare no conflict of interest.

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Background/objective: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance., Subjects/methods: Twenty-nine healthy men (27±5 years old; body mass index 25.5±2.3 kg m -2 ) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6±2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp., Results: Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P=0.001 and P=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day -1 (P=0.003) and tended to increase fat oxidation by 6±16 g day -1 (P=0.07) but did not affect carbohydrate oxidation (P=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, P=8 × 10 -5 ) but not fat oxidation rates (P=0.09)., Conclusions: The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Bisphenol-A (BPA) is a widely used endocrine-disrupting chemical. Prenatal exposure to BPA is known to affect birth weight, but its impact on the cardiovascular system has not been studied in detail. In this study, we investigated the effects of prenatal BPA treatment and its interaction with postnatal overfeeding on the cardiovascular system. Pregnant sheep were given daily subcutaneous injections of corn oil (control) or BPA (0.5 mg/kg/day in corn oil) from day 30 to day 90 of gestation. A subset of female offspring of these dams were overfed to increase body weight to ~30% over that of normal fed controls. Cardiovascular function was assessed using non-invasive echocardiography and cuff blood pressure (BP) monitoring at 21 months of age. Ventricular tissue was analyzed for gene expression of cardiac markers of hypertrophy and collagen at the end of the observation period. Prenatal BPA exposure had no significant effect on BP or morphometric measures. However, it increased atrial natriuretic peptide gene expression in the ventricles and reduced collagen expression in the right ventricle. Overfeeding produced a marked increase in body weight and BP. There were compensatory increases in left ventricular area and internal diameter. Prenatal BPA treatment produced a significant increase in interventricular septal thickness when animals were overfed. However, it appeared to block the increase in BP and left ventricular area caused by overfeeding. Taken together, these results suggest that prenatal BPA produces intrinsic changes in the heart that are capable of modulating morphological and functional parameters when animals become obese in later life.