Pregestational diet transition to normal-fat diet avoids the deterioration of pancreatic β-cell function in male offspring induced by maternal high-fat diet

Novel progress has been made to understand the adverse pathophysiology in the pancreas of offspring exposed to overnutrition in utero. Our study is the first to evaluate whether the adverse effects of maternal overnutrition on offspring β-cell function are reversible or preventable through preconception maternal diet interventions. Herein, offspring mice were exposed in utero to one of the following: maternal normal-fat diet (NF group), maternal high-fat diet (HF group) or maternal diet transition from an HF to NF diet 9 weeks before pregnancy (H9N group). Offspring mice were subjected to postweaning HF diet for 12 weeks. HF offspring, but not H9N, displayed glucose intolerance and insulin resistance. HF male offspring had enlarged islet β-cells with reduced β-cell density, whereas, H9N male offspring did not show these changes. Co-immunofluorescent (Co-IF) staining of glucose transporter 2 (Glut2) and insulin (Ins) revealed significantly more Glut2⁺Ins⁻ cells, indicative of insulin degranulation, in HF male offspring but not H9N. In addition, Co-IF of insulin and p-H3S10 indicated that β cells of HF male offspring, but not H9N, had proliferation defects likely due to inhibited protein kinase B (AKT) phosphorylation. In summary, our study demonstrates that maternal H9N diet effectively prevents functional deterioration of β cells seen in HF male offspring by avoiding β-cell proliferation defects and degranulation.     

Protein-restriction diet during the suckling phase programs rat metabolism against obesity and insulin resistance exacerbation induced by a high-fat diet in adulthood

Protein restriction during the suckling phase can malprogram rat offspring to a lean phenotype associated with metabolic dysfunctions later in life. We tested whether protein-caloric restriction during lactation can exacerbate the effect of a high-fat (HF) diet at adulthood. To test this hypothesis, we fed lactating Wistar dams with a low-protein (LP; 4% protein) diet during the first 2 weeks of lactation or a normal-protein (NP; 23% protein) diet throughout lactation. Rat offspring from NP and LP mothers received a normal-protein diet until 60 days old. At this time, a batch of animals from both groups was fed an HF (35% fat) diet, while another received an NF (7% fat) diet. Maternal protein-caloric restriction provoked lower body weight and fat pad stores, hypoinsulinemia, glucose intolerance, higher insulin sensitivity, reduced insulin secretion and altered autonomic nervous system (ANS) function in adult rat offspring. At 90 days old, NP rats fed an HF diet in adulthood displayed obesity, impaired glucose homeostasis and altered insulin secretion and ANS activity. Interestingly, the LP/HF group also presented fat pad and body weight gain, altered glucose homeostasis, hyperleptinemia and impaired insulin secretion but at a smaller magnitude than the NP-HF group. In addition, LP/HF rats displayed elevated insulin sensitivity. We concluded that protein-caloric restriction during the first 14 days of life programs the rat metabolism against obesity and insulin resistance exacerbation induced by an obesogenic HF diet.     

Insulin sensitivity linked skeletal muscle Nr4a1 DNA methylation is programmed by the maternal diet and modulated by voluntary exercise in mice

Perinatal maternal high-fat consumption is known to increase the obesity and type 2 diabetes susceptibility and to impair exercise performance in the offspring. We hypothesize that epigenetic modifications in the skeletal muscle are partly responsible for this phenotype. To detect skeletal muscle genes affected by maternal nutrition, male offspring of low-fat (LF) and high-fat (HF) diet fed dams (BL6 mice) received LF diet upon weaning and were sacrificed at 6 or 25 weeks of age. Gene expression of Musculus quadriceps was investigated by microarray analysis revealing an up-regulation of the nuclear receptor Nr4a1 by maternal HF feeding. This was accompanied by promoter hypomethylation of CpG_-1408 which correlated with increased Nr4a1 gene expression at both ages. Offspring voluntary exercise training (by supplying running wheels from 7 to 25 weeks of age) normalized Nr4a1 methylation and gene expression respectively, and ameliorated the negative effects of maternal HF feeding on insulin sensitivity. Overall, Nr4a1 gene expression in skeletal muscle correlated with higher insulin levels during an oral glucose tolerance test and could, therefore, be involved in programming type 2 diabetes susceptibility in offspring exposed to perinatal high fat diet.     

Paternal exercise protects mouse offspring from high-fat-diet-induced type 2 diabetes risk by increasing skeletal muscle insulin signaling

Paternal obesity increases, while paternal exercise decreases, offspring obesity and type 2 diabetes (T2D) risk; however, no studies have determined whether a paternal high-fat (HF) diet and exercise interact to alter offspring body weight (BW), adiposity and T2D risk. Three-week-old male C57BL/6 mice were fed a normal-fat (NF) diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months prior to mating with NF-diet-fed dams. After weaning, male offspring were fed an NF or HF diet for an additional 3 months. F1 male mice whose fathers ate an HF diet had decreased % body fat accompanied by decreased gene expression of beige adipocyte marker FGF21. However, paternal HF-diet-induced reductions in F1 offspring % body fat normalized but did not reduce T2D risk. Exercise was protective against paternal HF-diet-induced insulin resistance by increasing the expression of insulin signaling (GLUT4, IRS1 and PI3K) markers in skeletal muscle resulting in normal T2D risk. When fathers were fed an HF diet and exercised, a postnatal HF diet increased beiging (PPARγ). Thus, these findings show that increases in T2D risk in male offspring when the father consumes an HF diet can be normalized when the father also exercises preconception and that this protection may occur by increases in insulin signaling potential within offspring skeletal muscle. Future studies should further determine the physiological mechanism(s) underlying the beneficial effects of exercise through the paternal lineage.     

Early exposure to a high-fat diet has more drastic consequences on metabolism compared with exposure during adulthood in rats

The aim of this study was determine whether the introduction of a high-fat diet during the peripubertal phase induces significant changes in body weight control, glucose homeostasis and the parasympathetic tonus compared with the administration of this diet to adult rats. High-fat diet was offered to male Wistar rats at weaning or during adulthood. A group of rats received high-fat diet for 60 days, from weaning to 81-day-old (HF81) or from 60 to 120-day-old (HF120), whereas 2 other groups received a normal-fat diet (i. e., NF81 and NF120). We analyzed adiposity, glucose homeostasis, insulin sensitivity, and vagal nerve activity. High-fat diet increased the accumulation of adipose tissue in all of the rats, but the difference was greater in the rats that were fed the high-fat diet since weaning (p<0.001). The HF rats showed glucose intolerance with high levels of insulin secretion during the glucose tolerance test (p<0.01). Rats that were fed the high-fat diet presented severe insulin resistance, indicated by a low K itt (p<0.01). Interestingly, the HF81 rats exhibited greater insulin resistance compared with the HF120 rats (p<0.05). The recordings of vagus nerve activity showed that the HF rats had higher parasympathetic activity than the NF rats irrespective of age (p<0.01). Our results show that a high-fat diet offered to rats just after weaning or in adulthood both cause impairment of glycemic homeostasis and imbalance in parasympathetic activity. Importantly, the consumption of high-fat diet immediately after weaning has more drastic consequences compared with the consumption of the same diet during adulthood.     

Maternal high-fat diet induces sex-specific endocannabinoid system changes in newborn rats and programs adiposity,energy expenditure and food preference in adulthood

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.     

Programming of Obesity and Comorbidities in the Progeny: Lessons from a Model of Diet-Induced Obese Parents

Aim

To determine the impact of paternal obesity, maternal obesity or the combination of two obese parents on markers of adult offspring metabolism, with a focus on body mass (BM), lipid and carbohydrate, components of lipogenesis and beta-oxidation in the liver, sex dimorphism in the offspring that received a SC diet during the postnatal period.

Materials and Methods

Male and female C57BL/6 mice were fed a high-fat diet (HF; 49% lipids) or standard chow (SC; 17% lipids) for 8 weeks before mating until lactation. The offspring were labeled according to sex, maternal diet (first letters), paternal diet (second letters), and received a SCdiet until 12-weeks of age when they were sacrificed. BM, eating behavior, glucose tolerance, plasma analysis, gene and protein expression of the components of lipogenesis and beta-oxidation in the liver of offspring were evaluated.

Results

HF diet-fed mothers and fathers were overweight, hyperglycemic and glucose intolerant and had a deteriorating lipid profile. The adult male and female offspring of HF-mothers were overweight, with an increased adiposity index, hyperphagic, had an impaired glucose metabolism, increased total cholesterol and triacylglycerol levels, increased lipogenesis concomitant with decreased beta-oxidation resulting in liver steatosis. The male and female offspring of HF-father had impaired glucose metabolism, exacerbated lipogenesis without influencing beta-oxidation and enhanced hepatic steatosis. These findings are independent of BM. Male and female offspring of a mother and father that received a HF diet demonstrated these effects most prominently in adult life.

Conclusion

Paternal obesity leads to alterations in glucose metabolism, increase in components of lipogenesis and liver steatosis. In contrast, maternal obesity leads to overweight and changes in the metabolic profile and liver resulting from activation of hepatic lipogenesis with impaired beta-oxidation. When both parents are obese, the effects observed in the male and female offspring are exacerbated.     

Maternal green tea polyphenol intake during lactation attenuates kidney injury in high-fat-diet-fed male offspring programmed by maternal protein restriction in rats

Maternal malnutrition is known to increase the risk of obesity in offspring. We investigated whether green tea extract (GTE) intake during lactation affects obesity-related fibrosis and inflammation in the kidney of high-fat-diet-fed adult offspring of protein-restricted-diet-fed dams during pregnancy and lactation. Pregnant Wistar rats received diets containing 20% (normal-protein, NP) or 8% (low-protein, LP) casein, and they received 0%-, 0.12%- or 0.24%-GTE-containing LP diets (LP/LP, LP/LGT and LP/HGT, respectively) during lactation. At weaning, the pups that received a diet providing 13% (normal-fat, NF) or 45% (high-fat, HF) energy from fat were divided into five groups: NP/NP/NF, LP/LP/NF, LP/LP/HF, LP/LGT/HF and LP/HGT/HF. At week 45, the degree of fibrosis; macrophage infiltration; protein expression levels of TGF-β; and mRNA levels of TNF-α, DNMT, UHRF1 and histone lysine methyltransferase (G9a) in the kidneys of male offspring were examined. The area of fibrosis and TGF-βlevels increased in the LP/LP/HF group. Conversely, the fibrotic areas and TGF-β levels in the LP/HGT/HF group decreased (33% and 31%, respectively) compared with those in the LP/LP/HF group. The number of macrophages and mRNA levels of TNF-α in the LP/HGT/HF group decreased (34% and 29%, respectively) compared with those in the LP/LP/HF group. DNMT1, UHRF1 and G9a mRNA levels in the LP/HGT/HF group decreased compared with those in the LP/LP/HF group. In conclusion, GTE intake during lactation attenuated tubulointerstitial fibrosis and macrophage infiltration by down-regulating epigenetic modulators such as DNMT1, UHRF1 and G9a in the kidney of HF-diet-fed adult offspring programmed by maternal protein restriction.     

母鼠营养不良导致子代在生命早期出现糖脂代谢紊乱及其机制探讨

为了探讨母鼠孕期和哺乳期营养不良对子代生命早期糖脂代谢的影响及其机制,文章对孕期和哺乳期母鼠分别喂养高脂饮食、低蛋白饮食和正常饮食,观察其子鼠断乳时(3周龄)糖脂代谢指标,并采用荧光定量PCR方法检测子鼠肝组织氧化物酶增殖物激活受体γ(PPARγ)基因的表达情况。结果表明：子鼠在3周龄时,与正常饮食组相比,低蛋白饮食组子鼠出生体重(7.36±0.91 vs 8.94±1.39,P<0.0001)较低,体长较短(12.27±0.53 vs 13.44±0.36,P<0.0001);高脂饮食组子鼠体重(9.53±0.68 vs 7.36±0.91,P<0.0001)和体长(13.22±0.35 vs 12.27±0.53,P<0.0001)均高于低蛋白饮食组;另外,高脂饮食组子鼠腹腔糖耐量实验30 min和60 min血糖明显高于正常饮食组(P<0.001),且高脂饮食组30 min血糖水平也明显高于低蛋白饮食组(P<0.001),高脂饮食组子鼠糖耐量曲线下面积明显大于正常饮食组(P<0.001)。另外,与正常饮食组相比,高脂饮食组子鼠空腹胆固醇水平明显升高(1.64±0.21 vs 1.18±0.16,P<0.01),低蛋白饮食组空腹胆固醇水平明显下降(0.96±0.09 vs 1.18±0.16,P<0.05)。荧光定量PCR结果显示,在低蛋白饮食组和高脂饮食组,其子鼠肝组织PPARγ基因表达量均明显高于正常饮食组(P<0.05)。结果显示,母鼠妊娠期和哺乳期高脂饮食与低蛋白饮食均可以诱导子鼠在发育早期出现糖脂代谢紊乱,PPARγ基因可能在其中参与了重要的调控作用。     

Moderate caloric restriction in lactating rats programs their offspring for a better response to HF diet feeding in a sex-dependent manner

We aimed to assess the lasting effects of moderate caloric restriction in lactating rats on the expression of key genes involved in energy balance of their adult offspring (CR) and their adaptations under high-fat (HF) diet. Dams were fed with either ad libitum normal-fat (NF) diet or a 30% caloric restricted diet throughout lactation. After weaning, the offspring were fed with NF diet until the age of 15 weeks and then with an NF or a HF diet until the age of 28 weeks, when they were sacrificed. Body weight and food intake were followed. Blood parameters and the expression of selected genes in hypothalamus and white adipose tissue (WAT) were analysed. CR ate fewer calories and showed lower body weight gain under HF diet than their controls. CR males were also resistant to the increase of insulin and leptin occurring in their controls under HF diet, and HF diet exposed CR females showed lower circulating fasting triglyceride levels than controls. In the hypothalamus, CR males had higher ObRb mRNA levels than controls, and CR females displayed greater InsR mRNA levels than controls and decreased neuropeptide Y mRNA levels when exposed to HF diet. CR males maintained WAT capacity of fat uptake and storage and of fatty-acid oxidation under HF diet, whereas these capacities were impaired in controls; female CR showed higher WAT ObRb mRNA levels than controls. These results suggest that 30% caloric restriction in lactating dams ameliorates diet-induced obesity in their offspring by enhancing their sensitivity to insulin and leptin signaling, but in a gender-dependent manner.     

Maternal cigarette smoke exposure contributes to glucose intolerance and decreased brain insulin action in mice offspring independent of maternal diet

Background

Maternal smoking leads to intrauterine undernutrition and is associated with low birthweight and higher risk of offspring obesity. Intrauterine smoke exposure (SE) may alter neuroendocrine mediators regulating energy homeostasis as chemicals in cigarette smoke can reach the fetus. Maternal high-fat diet (HFD) consumption causes fetal overnutrition; however, combined effects of HFD and SE are unknown. Thus we investigated the impact of combined maternal HFD and SE on adiposity and energy metabolism in offspring.

Method

Female Balb/c mice had SE (2 cigarettes/day, 5 days/week) or were sham exposed for 5 weeks before mating. Half of each group was fed HFD (33% fat) versus chow as control. The same treatment continued throughout gestation and lactation. Female offspring were fed chow after weaning and sacrificed at 12 weeks.

Results

Birthweights were similar across maternal groups. Faster growth was evident in pups from SE and/or HFD dams before weaning. At 12 weeks, offspring from HFD-fed dams were significantly heavier than those from chow-fed dams (chow-sham 17.6±0.3 g; chow-SE 17.8±0.2 g; HFD-sham 18.7±0.3 g; HFD-SE 18.8±0.4 g, P<0.05 maternal diet effect); fat mass was significantly greater in offspring from chow+SE, HFD+SE and HFD+sham dams. Both maternal HFD and SE affected brain lactate transport. Glucose intolerance and impaired brain response to insulin were observed in SE offspring, and this was aggravated by maternal HFD consumption.

Conclusion

While maternal HFD led to increased body weight in offspring, maternal SE independently programmed adverse health outcomes in offspring. A smoke free environment and healthy diet during pregnancy is desirable to optimize offspring health.     

Choline prevents fetal overgrowth and normalizes placental fatty acid and glucose metabolism in a mouse model of maternal obesity

Maternal obesity increases placental transport of macronutrients, resulting in fetal overgrowth and obesity later in life. Choline participates in fatty acid metabolism, serves as a methyl donor and influences growth signaling, which may modify placental macronutrient homeostasis and affect fetal growth. Using a mouse model of maternal obesity, we assessed the effect of maternal choline supplementation on preventing fetal overgrowth and restoring placental macronutrient homeostasis. C57BL/6J mice were fed either a high-fat (HF, 60% kcal from fat) diet or a normal (NF, 10% kcal from fat) diet with a drinking supply of either 25 mM choline chloride or control purified water, respectively, beginning 4 weeks prior to mating until gestational day 12.5. Fetal and placental weight, metabolites and gene expression were measured. HF feeding significantly (P<.05) increased placental and fetal weight in the HF-control (HFCO) versus NF-control (NFCO) animals, whereas the HF choline-supplemented (HFCS) group effectively normalized placental and fetal weight to the levels of the NFCO group. Compared to HFCO, the HFCS group had lower (P<.05) glucose transporter 1 and fatty acid transport protein 1 expression as well as lower accumulation of glycogen in the placenta. The HFCS group also had lower (P<.05) placental 4E-binding protein 1 and ribosomal protein s6 phosphorylation, which are indicators of mechanistic target of rapamycin complex 1 activation favoring macronutrient anabolism. In summary, our results suggest that maternal choline supplementation prevented fetal overgrowth in obese mice at midgestation and improved biomarkers of placental macronutrient homeostasis.     

Grape skin extract protects against programmed changes in the adult rat offspring caused by maternal high-fat diet during lactation

Maternal overnutrition during suckling period is associated with increased risk of metabolic disorders in the offspring. We aimed to assess the effect of Vitis vinifera L. grape skin extract (ACH09) on cardiovascular and metabolic disorders in adult male offspring of rats fed a high-fat (HF) diet during lactation. Four groups of female rats were fed: control diet (7% fat), ACH09 (7% fat plus 200 mg kg^?1 d^?1 ACH09 orally), HF (24% fat), and HF+ACH09 (24% fat plus 200 mg kg^?1 d^?1 ACH09 orally) during lactation. After weaning, all male offspring were fed a control diet and sacrificed at 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams and ACH09 prevented the hypertension. Increased adiposity, plasma triglyceride, glucose levels and insulin resistance were observed in offspring from both ages, and those changes were reversed by ACH09. Expression of insulin cascade proteins IRS-1, AKT and GLUT4 in the soleus muscle was reduced in the HF group of both ages and increased by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric arteries antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase in the HF group. In conclusion, the treatment of HF-fed dams during lactation with ACH09 provides protection from later-life hypertension, body weight gain, insulin resistance and oxidative stress. The protective effect ACH09 may involve NO synthesis, antioxidant action and activation of insulin-signaling pathways.     

Maternal high-fat diet during pregnancy and lactation affects hepatic lipid metabolism in early life of offspring rat

We investigated whether maternal over-nutrition during pregnancy and lactation affects the offspring’s lipid metabolism at weaning by assessing liver lipid metabolic gene expressions and analysing its mechanisms on the development of metabolic abnormalities. Female Sprague–Dawley rats were fed with standard chow diet (CON) or high-fat diet (HFD) for 8 weeks, and then continued feeding during gestation and lactation. The offspring whose dams were fed with HFD had a lower birth weight but an increased body weight with impaired glucose tolerance, higher serum cholesterol, and hepatic steatosis at weaning. Microarray analyses showed that there were 120 genes differently expressed between the two groups. We further verified the results by qRT-PCR. Significant increase of the lipogenesis (Me1, Scd1) gene expression was found in HFD (P<0.05), and up-regulated expression of genes (PPAR-α, Cpt1α, Ehhadh) involved in β-oxidation was also observed (P<0.05), but the Acsl3 gene was down-regulated (P<0.05). Maternal over-nutrition could not only primarily induce lipogenesis, but also promote lipolysis through an oxidation pathway as compensation, eventually leading to an increased body weight, impaired glucose tolerance, elevated serum cholesterol and hepatic steatosis at weaning. This finding may provide some evidence for a healthy maternal diet in order to reduce the risk of metabolic diseases in the early life of the offspring.     

Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring

Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+17%) with hyperleptinemia and hyperinsulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood.     

Resveratrol treatment improves the altered metabolism and related dysbiosis of gut programed by prenatal high-fat diet and postnatal high-fat diet exposure

A maternal high-fat (HF) diet sensitizes offspring to the adverse effects of postnatal HF intake and can lead to metabolic dysregulation. Resveratrol, a natural polyphenolic compound found in grapes and red wine, could help to relieve metabolic syndrome dysregulation. Since the gut microbiota is known to be closely related to metabolic homeostasis, this study aimed to investigate the impact of a combination of maternal and postweaning HF diets on the gut microbiota and whether resveratrol could relieve the gut dysbiosis associated with metabolic dysregulation. Sprague–Dawley dams were sustained on either a chow or HF diet before mating, during pregnancy and during lactation. Their offspring were randomly fed chow or a HF diet after weaning. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal HF/postnatal chow diet), CH (maternal chow/postnatal high-fat diet) and HH (maternal/postnatal HF diet). A fifth group consisted of HH with resveratrol treatment. We found that both maternal and postnatal HF exposure has a distinct effect on the gut microbiota metagenome of offspring. Maternal HF diet exposure decreased plasma acetate, propionate and butyrate level, while postnatal HF diet exposure decreased plasma acetate level in adult life. The metabolic dysregulation programed by the maternal and postnatal HF diets was related to the relevant gut microbiota. Resveratrol treatment ameliorated the altered plasma propionate level related to maternal HF and postnatal HF diet treatment. Resveratrol treatment also improved most of the altered metabolic dysregulation and related dysbiosis programmed by maternal and postnatal HF diet exposure.     

Maternal postnatal high-fat diet,rather than gestational diet,affects morphology and mTOR pathway in skeletal muscle of weaning rat

The positive regulation of insulin pathway in skeletal muscle results in increased activity of the mammalian target of rapamycin (mTOR), a positive effector of mRNA translation rate and protein synthesis. Studies that assess the activity of this protein in response to chronic high-fat diet (HFD) are scarce and controversial, and to date, there are no studies evaluating the mTOR pathway in infants exposed to gestational and postgestational HFD. This study investigated the effect of maternal HFD on skeletal muscle morphology and on phosphorylation of proteins that comprise the intracellular mTOR signaling pathway in soleus muscle of offspring at weaning. For this purpose, 10 days prior to conception, 39 female Wistar rats were randomly assigned to either control diet (CTL) or HFD. Later, rats were distributed into four groups according to gestational and postpregnancy diet: CTL/CTL (n=10), CTL/HF (n=11), HF/HF (n=10) and HF/CTL (n=8). After 21 days of lactation, pups were killed, and blood samples and soleus and gastrocnemius skeletal muscle were collected for analysis. We observed an influence of maternal postgestational diet, rather than gestational diet, in promoting an obese phenotype, characterized by body fat accumulation, insulin resistance and high serum leptin, glucose, triglycerides and cholesterol levels (P<.05). We have also detected alterations on skeletal muscle morphology — with reduced myofiber density — and impairment on S6 kinase 1 and 4E binding protein-1 phosphorylation (P<.05). These results emphasize the importance of maternal diet during lactation on muscle morphology and on physiological adaptations of infant rats.     

Involvement of the GHSR in the developmental programming and metabolic disturbances induced by maternal undernutrition

The mismatch between maternal undernutrition and adequate nutrition after birth increases the risk of developing metabolic diseases. We aimed to investigate whether the hyperghrelinemia during maternal undernourishment rewires the hypothalamic development of the offspring and contributes to the conversion to an obese phenotype when fed a high-fat diet (HFD). Pregnant C57BL/6 J, wild type (WT) and ghrelin receptor (GHSR)^−/− mice were assigned to either a normal nourished (NN) group, or an undernutrition (UN) (30% food restricted) group. All pups were fostered by NN Swiss mice. After weaning, pups were fed a normal diet, followed by a HFD from week 9. Plasma ghrelin levels peaked at postnatal day 15 (P15) in both C57BL/6 J UN and NN pups. Hypothalamic Ghsr mRNA expression was upregulated at P15 in UN pups compared to NN pups and inhibited agouti-related peptide (AgRP) projections. Adequate lactation increased body weight of UN WT but not of GHSR^−/− pups compared to NN littermates. After weaning with a HFD, body weight and food intake was higher in WT UN pups but lower in GHSR^−/− UN pups than in NN controls. The GHSR prevented a decrease in ambulatory activity and oxygen consumption in UN offspring during ad libitum feeding. Maternal undernutrition triggers developmental changes in the hypothalamus in utero which were further affected by adequate feeding after birth during the postnatal period by affecting GHSR signaling. The GHSR contributes to the hyperphagia and the increase in body weight when maternal undernutrition is followed by an obesity prone life environment.