Effect of protein source in diets fed during gestation and lactation on food intake regulation in male offspring of Wistar rats

We hypothesized that protein source in the nutritionally adequate AIN-93G diets fed during gestation, lactation, and weaning influences food intake (FI) regulation in male offspring of Wistar rats. Pregnant rats were fed the recommended casein-based (C) or soy protein-based (S) diet during gestation (experiment 1) or during gestation and lactation (experiment 2). Pups (n = 12 per group) weaned to C or S diets were followed for 9 wk (experiment 1) or 14 wk (experiment 2). At termination, body weight was 5.4% and 9.4% higher, respectively, in offspring of dams fed the S diet. Altered FI regulation was shown by failure of devazepide (a CCK-A receptor blocker) to block FI reduction after protein preloads in offspring of S diet-fed dams, whereas it had a strong effect on offspring of C diet-fed dams (P < 0.005). Similarly, naloxone (an opioid receptor blocker) blocked FI reduction more after casein than after soy protein preloads (P < 0.01). In experiment 2, offspring of dams fed the S diet had higher hypothalamic gene expression of agouti related protein at weaning (P < 0.05), and higher FI was found throughout postweaning (P < 0.0001). FI reduction after protein preloads at week 7 and after glucose preloads at week 13 was greater in offspring of C diet-fed dams (P < 0.05). Plasma insulin at weaning and insulin, ghrelin, and glucagon-like peptide-1 at week 15 were higher in offspring of S diet-fed dams (all P < 0.05). In conclusion, nutritionally complete C and S diets consumed during gestation and lactation differ in their effects on body weight and FI regulation in the offspring. Extending the diet from gestation alone to throughout gestation and lactation exaggerated the adverse effects of the S diet. However, the diet consumed postweaning had little effect on the outcome.     

High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring

High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14 weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake.     

Accurate measurement of body weight and food intake in environmentally enriched male Wistar rats

Laboratory animals are crucial in the study of energy homeostasis. In particular, rats are used to study alterations in food intake and body weight. To accurately record food intake or energy expenditure it is necessary to house rats individually, which can be stressful for social animals. Environmental enrichment may reduce stress and improve welfare in laboratory rodents. However, the effect of environmental enrichment on food intake and thus experimental outcome is unknown. We aimed to determine the effect of environmental enrichment on food intake, body weight, behavior and fecal and plasma stress hormones in male Wistar rats. Singly housed 5–7‐week‐old male rats were given either no environmental enrichment, chew sticks, a plastic tube of 67 mm internal diameter, or both chew sticks and a tube. No differences in body weight or food intake were seen over a 7‐day period. Importantly, the refeeding response following a 24‐h fast was unaffected by environmental enrichment. Rearing, a behavior often associated with stress, was significantly reduced in all enriched groups compared to controls. There was a significant increase in fecal immunoglobulin A (IgA) in animals housed with both forms of enrichment compared to controls at the termination of the study, suggesting enrichment reduces hypothalamo‐pituitary‐adrenal (HPA) axis activity in singly housed rats. In summary, environmental enrichment does not influence body weight and food intake in singly housed male Wistar rats and may therefore be used to refine the living conditions of animals used in the study of energy homeostasis without compromising experimental outcome.     

The food intake of rats during pregnancy and lactation

Quantities of food required by Sprague-Dawley rats during gestation and lactation and in the post-lactation period were examined. Rats allowed to eat ad libitum during pregnancy consumed quantities of food only slightly greater than the amount reported to be the average intake of pregnant Sprague-Dawley rats (20 g/day). Rats delivered their pups on day 22 or day 23 of the gestation period, but regardless of the day of delivery, the food intake of each rat decreased on day 21 of pregnancy and then decreased a second time on the day of parturition. During lactation, food consumption of the rats soon exceeded the amount reported as the average intake of lactating rats (30-35 g/day). Food intake was found to escalate from 12.2 +/- 3.1 g/rat on day 0 of lactation, the lowest intake in the study, to 94.4 +/- 23.7 g on day 21 of lactation. However, in the latter part of the lactation period, the intake represented the combined food intake of dams and pups. Eight days in the post-lactation period were required for food intake of dams to return to a level near that recorded at the beginning of pregnancy.     

High dietary intake of medium-chain fatty acids during pregnancy in rats prevents later-life obesity in their offspring

We investigated the effects of dietary fatty acids of different chain lengths during pregnancy in the rat on the susceptibility of offspring to later-life obesity and the underlying mechanisms. Pregnant rats were fed three different diets: standard (STD), high medium-chain fatty acids (MCFA); and high long-chain fatty acids (LCFA). The male offspring were assigned to three groups: STD control, MCFA and LCFA according to the maternal diets and suckled by dams fed with STD during pregnancy and lactation. After weaning, the offspring were fed with STD from 3 to 8 weeks of age. At the age of 8 weeks, rats in three groups: high-fat diet (HFD) control, MCFA and LCFA were fed with HFD until 14 weeks of age in an attempt to induce obesity, and rats in the HFD control group were selected randomly from the STD control group. Body weight and body fat content were decreased in the MCFA group accompanied by down-regulated mRNA expression of fatty acid synthase and acetyl-coA carboxylase 1, and increased mRNA and protein expression of adenosine monophosphate (AMP)-activated protein kinase (AMPK), carnitine palmitoyltransferase 1 and uncoupling protein 3 compared with the corresponding controls at 3, 8 and 14 weeks of age. The results suggested that the MCFA diet during pregnancy prevented later-life obesity in the offspring when they were exposed to HFD in later life, which might be related to programming of the expression of genes involved in fatty acid metabolism.     

CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats

The objective of the present study was to investigate in fed Wistar rats whether the cannabinoid-1 (CB1) receptor antagonist AVE1625 causes primary effects on metabolic blood and tissue parameters as well as metabolic rate, which are independent of reduced caloric intake. After single administration to rats postprandially, AVE1625 caused a slight dose-dependent increase in basal lipolysis. Six hours after single administration, liver glycogen content was dose-dependently reduced to approximately 60% of that of untreated controls. These findings demonstrate a primary acute effect of AVE1625 on induction of 1) lipolysis from fat tissue (increased FFA) and 2) glycogenolysis from the liver (reduced hepatic glycogen). Measured by indirect calorimetry, AVE1625 caused an immediate increase in total energy expenditure, a long-lasting increase of fat oxidation, and a transient increase of glucose oxidation, which were consistent with the acute findings on metabolic blood and tissue parameters. We conclude that, in addition to the well-investigated effects of CB1 receptor antagonists to reduce caloric intake and subsequently body weight, this pharmacological approach is additionally linked to inherently increased lipid oxidation. This oxidation is driven by persistently increased lipolysis from fat tissues, independently of reduced caloric intake, and might significantly contribute to the weight-reducing effect.     

High intensity exercise during pregnancy of rats. Effects on mother and offspring

We see in this study the effect of high intensity exercise (90% VO₂ max) in pregnant rats and their offspring depending on the length of pregnancy. The findings were compared with those obtained for sedentary pregnant rats and non-pregnant rats for similar exercise. This allowed for analysing the isolated effects of exercise (against the sedentary non-pregnant rat control group), of pregnancy and of the interaction between the two factors. For checking the effect of the length of pregnancy, each group of rats was subdivided into those with pregnancy terminated or sacrificed on the seventh, fourteenth or twentieth day of the experiment. VO₂ max, post-exertion blood lactic acid level, body weight gain, food intake, feed efficiency, glucose, triglyceride, total cholesterol, total protein and albumin plasmatic concentrations in adult rats, and weight and number of offspring of pregnant rats were determined. Pregnancy increased weight gain and feed efficiency from the first week of the study, accompanied by a greater food intake (from the twelfth day). In the group of pregnant rats subjected to exercise, there was a reduction in weight gain percentage and feed efficiency in the first and third weeks, staying the same in the second week. A greater food intake during the period accompanied this recovery in the second week. In the group of non-pregnant rats subjected to exercise, food intake did not vary. As the weight gain percentage was less in relation to the non-pregnant control group, feed efficiency decreased. Pregnancy induced a drop in blood sugar level starting in the second week, and the exercise performed during pregnancy did not change this behavior. Pregnancy produced, however, an increase in plasmatic concentration of triglycerides and total cholesterol during the third week of pregnancy. Exercise performed by pregnant rats also did not change this behavior, but the increase observed in the third week was less. Exercise performed by non-pregnant rats did not change the blood sugar level and plasmatic concentration of triglycerides and total cholesterol during the entire experiment. Plasmatic concentration of total proteins and albumin showed a drop in the third week of pregnancy, probably due to high fetal use of proteins in this stage. Exercise performed by the pregnant group caused a lower protein drop in the third week, and in the non-pregnant group, determined an increase in plasmatic protein concentrations. The weight of the offspring of mother rats exercised until the end of the second and third weeks of pregnancy was found to be reduced in relation to the sedentary pregnant group. The group exercised until the third week showed a reduction in the number of offspring, indicating a possible fetal reabsorption. These findings confirmed that high intensity exercise can produce deleterious effects on the mother and fetus, especially when applied up to the last stage of pregnancy.     

Maternal zinc intake of Wistar rats has a protective effect in the alloxan-induced diabetic offspring

Zinc has a role in the synthesis, storage, and secretion of insulin, and has been suggested to be beneficial when used in the diabetic state. Effect of zinc intake in pregnant rats has been studied here on diabetized offspring. Pregnant rats were divided in two groups; the control group received normal food and water, and the experimental group received zinc sulfate during pregnancy and 3 weeks after offspring birth. Male offspring from the control (C) and experimental (E) groups were divided each in three groups: C1, fed with normal food and water; C2, diabetized with alloxan; C3, received zinc sulfate; E1, fed with normal food and water; E2, diabetized with alloxan; and E3, receiving zinc sulfate. After 30 days, the histological changes of pancreatic tissues were investigated by light microscopy. Body weight, blood glucose, serum insulin levels, food intake, water intake, and urine quantity were also compared between the groups. Water intake and urine quantity were decreased significantly (p?<?0.01and p?<?0.001) in E2 (experimental diabetic group) in comparison with C2 (control diabetic group), but there was no significant difference in the body weight in C2 in comparison with E2, while blood glucose was decreased significantly (p?<?0.001) and blood insulin level was increased significantly (p?<?0.01) in E2 in comparison with C2. Microscopic evaluation of pancreas showed that E2 were protected against alloxan-induced beta-cell degeneration. In conclusion, this work showed that maternal zinc intake may influence subsequent deleterious effects of diabetes on alloxan-diabetized offspring.     

Altered health outcomes in adult offspring of Sprague Dawley and Wistar rats undernourished during early or late pregnancy

BACKGROUND: Birth weight in humans has been inversely associated with adult disease risk. Results of animal studies have varied depending on species, strain, and treatment. METHODS: We compared birth weight and adult health in offspring following 50% maternal undernutrition on gestation days (GD) 1–15 (UN1–15) or GD 10–21 (UN10–21) in Sprague Dawley and Wistar rats. Offspring from food‐deprived dams were weighed and cross‐fostered to control dams. Litters were weighed during lactation and initiating at weaning males were fed either control or a high‐fat diet. Young and mature adult offspring were evaluated for obesity, blood pressure (BP), insulin response to oral glucose, and serum lipids. Nephron endowment, renal glucocorticoid receptor, and renin–aldosterone–angiotensin system components were measured. RESULTS: The UN10–21 groups had birth weights lower than controls and transient catch up growth by weaning. Neither strain demonstrated obesity or dyslipidemia following prenatal undernutrition, but long‐term body weight deficits occurred in the UN groups of both strains. High‐fat diet fed offspring gained more weight than control offspring without an effect of prenatal nutrition. Sprague Dawley were slightly more susceptible than Wistar rats to altered insulin response and increased BP following gestational undernutrition. Nephron endowment in Sprague Dawley but not Wistar offspring was lower in the UN10–21 groups. Glucocorticoid and renin–aldosterone–angiotensin system pathways were not altered. CONCLUSIONS: The most consistent effect of maternal undernutrition was elevated BP in offspring. Long‐term health effects occurred with undernutrition during either window, but the UN10–21 period resulted in lower birth weight and more severe adult health effects. Birth Defects Res (Part B) 89:396–407, 2010. © 2010 Wiley‐Liss, Inc.     

孕期应激下调成年雄性子代大鼠海马HDAC2表达

目的明确母代大鼠孕期应激对雄性子代海马中组蛋白去乙酰化酶2(histone deacetylase 2, HDAC2)表达变化的影响。方法将16只SD孕鼠随机分为应激组和对照组,每组8只,应激组在孕16-21天进行限制性应激,对照组不做任何处理。ELISA检测成年子代外周血血浆糖皮质激素,用旷场、高架十字迷宫、新物体识别及巴恩斯迷宫四种行为学评估成年子代认知功能,免疫组织化学、Western blot、RT-PCR 检测成年雄性子代海马HDAC2表达变化。结果母代孕期应激成年子代糖皮质激素升高,旷场与高架十字迷宫中表现出焦虑样行为,新物体识别与Barnes迷宫表现出学习记忆与空间记忆能力下降,海马HDAC2 mRNA和蛋白水平均下调。结论孕期应激对子代成年的认知功能损害可能与子代海马HDAC2的表达下调有关。     

Sucrose feeding during pregnancy and lactation elicits distinct metabolic response in offspring of an inbred genetic model of metabolic syndrome

The importance of early environment, including maternal diet during pregnancy, is suspected to play a major role in pathogenesis of metabolic syndrome and related conditions. One of the proposed mechanisms is a mismatch between the prenatal and postnatal environments, leading to misprogramming of the metabolic and signaling pathways of the developing fetus. We assessed whether the exposure to high-sucrose diet (HSD) alleviates the detrimental effects of sucrose feeding in later life (predictive adaptive hypothesis) in a highly inbred model of metabolic syndrome, the PD/Cub rat. Rat dams were continuously fed either standard or HSD (70% calories as sucrose) starting 1 wk before breeding, throughout pregnancy, at birth, and until weaning of the offspring. After weaning, all male offspring were fed HSD until the age of 20 wk, when detailed metabolic and morphometric profiles were ascertained. The early life exposure to a sucrose-rich diet resulted in distinct responses to longtime postnatal HSD feeding. Offspring of the sucrose-fed mothers displayed higher adiposity and substantial increases in triglyceride liver content together with unfavorable distribution of cholesterol into lipoprotein subfractions. On the other hand, their adiponectin concentrations were significantly higher, and insulin sensitivity of skeletal muscle was enhanced compared with the offspring of standard diet-fed mothers. Triglycerides, free fatty acids, overall glucose tolerance, and the insulin sensitivity of adipose tissue were comparable in both groups. In the genetically identical animals, maternal HSD feeding elicited a variety of subtle effects but did not lead to predictive adaptive protection from most HSD-induced metabolic derangements.     

Effect of the Japanese diet during pregnancy and lactation or post-weaning on the risk of metabolic syndrome in offspring

We examined the effects on offspring of ingestion of the 1975 Japanese diet during pregnancy and lactation and after weaning in mice. Pregnant dams were divided into groups that were fed the Japanese diet or a control diet and raised until offspring were weaned. The offspring after weaning were further divided into groups that were raised on the Japanese diet or the control diet. Ingestion of the Japanese diet after weaning suppressed accumulation of visceral fat in offspring, and reduced the amount of lipids in serum and liver. This effect was weakened if the Japanese diet was only ingested during pregnancy and lactation. Therefore, it was suggested that ingestion of the Japanese diet of mothers during pregnancy and lactation weakens the lipid accumulation inhibitory effect of the Japanese diet in children.     

Infradian rhythmics of markers of physiologic and metabolic processes in Wistar male rats

This work presents the results of the amplitude-phase structure of the physiological rhythms (locomotor activity) and steroid hormones production (common testosterone and cortisole) in gelded and intact Wistar male rats as well as rats exposed to an information load. The markers have been shown to depend on the social state of the animal. It was proved that there was a phase coincidence of the periods of the biological rhythms of common testosterone (intact rats), cortisole and locomotor activity for animals with different individualand typological features. It was shown that the oscillation period of infradian rhythms of the measured markers of physiologic and metabolic processes in the animals of all groups amounted to 4 days. It was found that infradian rhythms were not sensitive to factors of various genesis.     

Postparturitional testosterone surge in male offspring of rats stressed and/or fed ethanol during late pregnancy

Male offspring of rats exposed to restraint stress and/or alcohol during late pregnancy show aberrant patterns of sexual behavior masculinization and defeminization that vary as a function of treatment. The impact of these treatments on the postparturitional testosterone (T) surge that contributes to sexual behavior differentiation was investigated. Plasma T was measured using radioimmunoassay in individual males sampled on day 21 of gestation within 10 min of cesarean delivery or 1, 2, or 4 h thereafter. Neonatal T in the group exposed only to stress did not differ from that in the control group. T was lower than control levels at birth in both alcohol groups. The magnitude of the T surge that occurred during the first hour of birth in the control group was diminished by 50% in both alcohol groups, whose T pattern was very similar. There was no common alteration in postparturitional T associated with the increased lordotic behavior potential that males in all three treatment groups typically share, nor were there idiosyncratic endocrine abnormalities linked to the very different male copulatory pattern each exhibits. Exposure to an abnormal T milieu during fetal as well as neonatal ontogeny may underlie the etiology of the different sexual behavior patterns exhibited by males exposed to stress and/or alcohol. Possible unique effects each treatment exerts on perinatal plasma T and it's aromatization to estradiol in hypothalamic targets are discussed.     

Effect of different iodide intake during pregnancy and lactation on thyroid and cardiovascular function in maternal and offspring rats

ObjectiveWe aimed to investigate the impact of different iodide intake during pregnancy and lactation on iodine concentration in urine and serum, fatty acid metabolism, thyroid and cardiovascular function in maternal and offspring rats.MethodsPregnant rats were randomly assigned to four groups: normal adult iodide intake (NAI, 7.5 μg/d), normal pregnant iodide intake (NPI, 12.5 μg/d), 5 times (5 HI, 62.5 μg/d) and 10 times higher-than-normal pregnant iodide intake (10 HI, 125 μg/d). The maternal rats were continuously administered potassium iodide until postnatal day 16 (PN16). Thyroid function was measured by enzyme-linked immunosorbent assay (ELISA). The iodine concentration in urine and serum were detected by inductively coupled plasma mass spectrometry (ICP-MS). The messenger ribonucleic acid (mRNA) expressions of Krüppel-like factor 9 (KLF9) and thioredoxin reductase 2 (Txnrd2) were measured using quantitative real-time polymerase chain reaction (RT-qPCR). Characteristic distribution of KLF9 expression and its interaction with TRβ was assessed by immunohistochemical and immunofluorescence staining. Serum fatty acids were analyzed by Liquid Chromatography-Mass Spectrometry (LC-MS). Cardiac function and blood pressure were measured by echocardiography and a non-invasive tail-cuff system.ResultsHigh iodide intake (5 HI and 10 HI) during pregnancy and lactation results in increased urinary iodine concentration (UIC), serum total iodine concentration (STIC) and serum non-protein-bound iodine concentration (SNBIC) in both maternal and offspring rats, along with significantly increased FT3 and its target gene expression of KLF9. In maternal rats of both 5 HI and 10 HI groups, systolic blood pressure (SBP) was significantly higher, the increased SBP was significantly correlated with the increased UIC (r = 0.968, p = 0.002; r = 0.844, p = 0.035), KLF9 (r = 0.935, p = 0.006; r = 0.954, p = 0.003) and the decreased Txnrd2 (r = −0.909, p = 0.012; r = −0.912, p = 0.011). In maternal rats of 10 HI group, cardiac hyperfunction with increased LVEF, LVFS and decreased LVESD were observed. The increased LVEF and decreased LVESD were significantly correlated with UIC, STIC and SNBIC (r = 0.976, p = 0.001; r = 0.945, p = 0.005; r = 0.953, p = 0.003; r = −0.917, p = 0.01; r = −0.859, p = 0.028; r = −0.847, p = 0.033), LVEF, LVFS and LVESD were significant correlated with KLF9 (r = 0.950, p = 0.004; r = 0.963, p = 0.002; r = −0.990, p = 0.0002) and Txnrd2 expression (r = −0.979, p = 0.001; r = −0.915, p = 0.01; r = 0.933, p = 0.007), and the decreased LVESD was correlated with decreased epoxyeicosatrienoic acid (EET) metabolites: 5,6-EET, 8,9-DHET and 11,12-DHET (r = 0.999, p = 0.034; r = 1.000, p = 0.017; r = 1.000, p = 0.017). While in offspring rats, no significant change in SBP and cardiac function was found. STIC and SNBIC were much lower than those in maternal rats, and eicosapentaenoic acid (EPA) metabolites (9-HEPE, 15-HEPE and 14,15 DiHETE) were significantly increased.ConclusionIn addition to thyroid hormones, STIC, SNBIC, KLF9, Txnrd2, EET and EPA metabolites might be promising biomarkers in high iodide intake-induced thyroid and cardiovascular function.     

The role of time of food intake on upcoming liver disease in male Wistar rat

Interventions against obesity, are mainly around changing calorie intake and energy expenditure. Recently, some studies focused on the influence of circadian time of food intake on metabolic status. Here, we compare the role of calorie restriction and time restricted feeding followed by high-fat diet started post weaning, First, 52 male Wistarrats (3 weeks old) were divided into two groups: the high-fat diet (HFD, n = 42) and the control group (CON1, n = 11). After 17 weeks, five rats were randomly selected from each group for sample preparation. In the second phase, the animals in HFD group were assigned into four groups (n = 9): (1) 30% calorie restriction (CR), (2) day intermittent fasting (DIF), (3) night intermittent fasting (NIF), (4) adlibitum food intake (AL), (5) remained animal from the first phase control (CON2). Seventeen weeks of HFD started post-weaning did not cause fatty liver but it caused a significant difference in the body and the adipose tissue weight (P0.05). The results showed that longtime HFD did not lead to liver steatosis while the incorrect time of food intake predisposes the animal to the upcoming liver disease. This data indicate a significant role of timing of food intake rather than nutrition composition itself.     

Adult offspring long-term effects of high salt and water intake during pregnancy

Offspring from dams subjected to hypereninemia, hyperdipsia, and natriophilia by partial aortic ligation (PAL) showed a long-term modification of their ingestive behavior. These rats, upon reaching adulthood, showed an increased appetite for low-concentration saline solutions (0.1 M) when compared to control rats. They also presented a high intake of a medium concentration NaCl solution (0.45 M) after having been offered a very aversive highly concentrated NaCl solution (1.0 M) along with water for 2 days. An increase was also observed in their salt/water intake ratio following two different thirst challenges, 24-h fluid deprivation or sodium depletion by furosemide treatment. The demonstration of the long-term effect of pregnancy history on salt preference in adult offspring draws attention to the possible physiopathological aspects that may be of relevance, considering the well-established relationship between salt intake and hypertension, a disease most commonly occurring in the adult and aged population.     

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.