A Maternal High Fat Diet Programmes Endothelial Function and Cardiovascular Status in Adult Male Offspring Independent of Body Weight,Which is Reversed by Maternal Conjugated Linoleic Acid (CLA) Supplementation

Maternal high fat intake during pregnancy and lactation can result in obesity and adverse cardio-metabolic status in offspring independent of postnatal diet. While it is clear that maternal high fat intake can cause hypertension in adult offspring, there is little evidence regarding the role of dietary interventions in terms of reversing these adverse effects. Conjugated linoleic acid (CLA) is an omega 6 fatty acid with beneficial effects in obesity and metabolic status. However, the impact of CLA supplementation in the context of pregnancy disorders and high fat diet-induced developmental programming of offspring cardio-metabolic dysfunction has not been investigated. We have utilised a model of maternal overnutrition to examine the effects of CLA supplementation on programmed endothelial dysfunction during adulthood. Female Sprague-Dawley rats were fed either a purified control diet (CON) or purified control diet supplemented with 1% CLA (of total fat), a purified high fat (HF) diet (45%kcal from fat) and a purified HF diet supplemented with 1% CLA (of total fat) (HFCLA). All dams were fed ad libitum throughout pregnancy and lactation. Offspring were fed a standard chow diet from weaning (day 21) until the end of the study (day 150). Systolic blood pressure (SBP) was measured at day 85 and 130 by tail cuff plethysmography. At day 150, offspring mesenteric vessels were mounted on a pressure myograph and vascular responses to agonist-induced constriction and endothelium-dependent vasodilators were investigated. SBP was increased at day 85 and 130 in HF and HFCLA adult male offspring compared to CON and CLA groups with no effect of CLA supplementation. An overall effect of a maternal HF diet was observed in adult male vessels with a reduced vasoconstrictor response to phenylephrine and blunted vasodilatory response to acetylcholine (ACh). Furthermore, HF and HFCLA offspring displayed a reduction in nitric oxide pathway function and an increased compensatory EDHF function when compared to CON and CLA groups. These data suggest that a maternal HF diet causes a developmental programming of endothelial dysfunction and hypertension in male offspring which can be partially improved by maternal CLA supplementation, independent of offspring body weight.     

Effects of Maternal Diet and Exercise during Pregnancy on Glucose Metabolism in Skeletal Muscle and Fat of Weanling Rats

Obesity during pregnancy contributes to the development of metabolic disorders in offspring. Maternal exercise may limit gestational weight gain and ameliorate these programming effects. We previously showed benefits of post-weaning voluntary exercise in offspring from obese dams. Here we examined whether voluntary exercise during pregnancy influences lipid and glucose homeostasis in muscle and fat in offspring of both lean and obese dams. Female Sprague-Dawley rats were fed chow (C) or high fat (F) diet for 6 weeks before mating. Half underwent voluntary exercise (CE/FE) with a running wheel introduced 10 days prior to mating and available until the dams delivered; others remained sedentary (CS/FS). Male and female pups were killed at postnatal day (PND)19 and retroperitoneal fat and gastrocnemius muscle were collected for gene expression. Lean and obese dams achieved similar modest levels of exercise. At PND1, both male and female pups from exercised lean dams were significantly lighter (CE versus CS), with no effect in those from obese dams. At PND19, maternal obesity significantly increased offspring body weight and adiposity, with no effect of maternal exercise. Exercise significantly reduced insulin concentrations in males (CE/FE versus CS/FS), with reduced glucose in male FE pups. In males, maternal obesity significantly decreased muscle myogenic differentiation 1 (MYOD1) and glucose transporter type 4 (GLUT4) mRNA expressions (FS vs CS); these were normalized by exercise. Maternal exercise upregulated adipose GLUT4, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α) mRNA expression in offspring of dams consuming chow. Modest voluntary exercise during pregnancy was associated with lower birth weight in pups from lean dams. Maternal exercise appeared to decrease the metabolic risk induced by maternal obesity, improving insulin/glucose metabolism, with greater effects in male than female offspring.     

Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice

Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D) and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of nonobese diabetic (NOD) mice. Four-week-old female NOD/ShiLtJ mice were fed with a control diet (CON; 10% energy from fat) or a high-fat diet (HFD; 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test, and then ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 and mature forms of interleukin (IL)-1β and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor α level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 was heightened in offspring ileum (P<.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might predispose them to the development of T1D and other gut permeability-associated diseases.     

Maternal obesity reverses the resistance to LPS-induced adverse pregnancy outcome and increases female offspring metabolic alterations in cannabinoid receptor 1 knockout mice

Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a “nutritional programming” of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.     

Maternal iodine supplementation improves motor coordination in offspring by modulating the mGluR1 signaling pathway in mild iodine deficiency-induced hypothyroxinemia rats

Iodine is an essential component for thyroid hormone synthesis. Epidemiological investigations have demonstrated that maternal mild iodine deficiency (ID)-induced hypothyroxinemia can affect intellectual and behavioral function in offspring. There is no definitive evidence demonstrating the effects of maternal iodine supplementation on neurobehavioral function in regional areas with mild ID. Thus, we aimed to clarify the effects of maternal mild ID and iodine supplementation on motor coordination in offspring and illuminate the underlying molecular mechanisms. Animal models of maternal mild ID and iodine supplementation were generated by providing Wistar rats an iodine-deficient diet and deionized water supplemented with potassium iodide during pregnancy and lactation. We found that mild ID-induced hypothyroxinemia led to a shorter latent time before falling down from the rotarod, a longer time to traverse the balance beam and poorer wire grip of the forelimbs, which imply motor coordination dysfunction. However, these impairments in the offspring were improved by iodine supplementation during pregnancy and lactation. We further observed that the ultrastructure and dendritic tree morphology of cerebellar Purkinje cells were altered in mild ID-induced hypothyroxinemia but that these changes could be reversed by iodine supplementation. Maternal mild ID and iodine supplementation also affected expression of the mGluR1 signaling pathway in offspring. Together, iodine supplementation during pregnancy and lactation can improve motor coordination in offspring by modulating the mGluR1 signaling pathway in mild ID-induced hypothyroxinemia rats.     

Effects of dietary n-3 PUFA levels in early life on susceptibility to high-fat-diet-induced metabolic syndrome in adult mice

The maternal nutritional status during pregnancy and lactation was closely related to the growth and development of the fetus and infants, which had a profound impact on the health of the offspring. N-3 polyunsaturated fatty acid (PUFA) had been proved to have beneficial effects on glucolipid metabolism. However, the effects of dietary different n-3 PUFA levels for mother during pregnancy and lactation on susceptibility to high-fat-diet-induced metabolic syndrome for offspring in adulthood are still unclear. The maternal mice were fed with control, n-3 PUFA-deficient or fish oil-contained n-3 PUFA-rich diets during pregnancy and lactation, and the weaned offspring were fed with high-fat or low-fat diet for 13 weeks, then were subjected to oral glucose tolerance tests. The results showed that dietary n-3 PUFA-deficiency in early life could aggravate the high-fat-diet-induced glucolipid metabolism disorders, including glucose intolerance, insulin resistance, obesity, and dyslipidemia, thus increased the susceptibility to metabolic syndrome of adult mice. Notably, nutritional supplementation with n-3 PUFA in early life could significantly alleviate the glucose metabolism disorders by increasing insulin sensitivity, inhibiting gluconeogenesis and promoting glycogenesis. In addition, administration with n-3 PUFA in early life remarkably reduced serum and hepatic lipid profiles by mediating the expression of genes related to lipogenesis and β-oxidation of fatty acids. Dietary n-3 PUFA-deficiency in early life increases the susceptibility to metabolic syndrome of adult offspring, and nutritional supplementation with n-3 PUFA enhances the tolerance to a high-fat diet of adult offspring.     

A long-term maternal diet intervention is necessary to avoid the obesogenic effect of maternal high-fat diet in the offspring

Although a pre-pregnancy dietary intervention is believed to be able to prevent offspring obesity, research evidence is absent. We hypothesize that a long period of pre-pregnancy maternal diet transition from a high-fat (HF) diet to a normal-fat (NF) diet effectively prevents offspring obesity, and this preventive effect is independent of maternal body weight change. In our study, female mice were either continued on an NF diet (NF group) or an HF diet (HF group) until weaning, or switched from an HF to an NF for 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group) before pregnancy. After weaning, the offspring were given the HF diet for 12 weeks to promote obesity. The mothers, regardless of which group, did not display maternal body weight change and glucose intolerance either before pregnancy or after weaning. Compared to the HF group, the H1N and H5N, but not the H9N, offspring developed glucose intolerance earlier, with more severely imbalanced glucose homeostasis. These offspring also displayed hepatocyte degeneration and significant adipocyte hypertrophy associated with higher expression of lipogenesis genes. The molecular mechanistic study showed blunted insulin signaling, overactivated adipocyte Akt signaling and hepatic AMPK signaling with enhanced lipogenesis genes in the H1N and H5N versus the NF offspring. However, maternal H9N diets normalized glucose and lipid metabolism of the offspring via resensitized insulin signaling and normalized Akt and AMPK signaling. In summary, we showed that a long-term maternal diet intervention effectively released the intergenerational obesogenic effect of maternal HF diet independent of maternal weight management.     

Maternal supplementation with n-3 long chain polyunsaturated fatty acids during perinatal period alleviates the metabolic syndrome disturbances in adult hamster pups fed a high-fat diet after weaning

Perinatal nutrition is thought to affect the long-term risk of the adult to develop metabolic syndrome. We hypothesized that maternal supplementation with eicosapentaenoic acid and docosahexaenoic acid during pregnancy and lactation would protect offspring fed a high-fat diet from developing metabolic disturbances. Thus, two groups of female hamsters were fed a low-fat control diet, either alone (LC) or enriched with n-3 long chain polyunsaturated fatty acids (LC-PUFA) (LO), through the gestational and lactation periods. After weaning, male pups were randomized to separate groups that received either a control low-fat diet (LC) or a high-fat diet (HC) for 16 weeks. Four groups of pups were defined (LC-LC, LC-HC, LO-LC and LO-HC), based on the combinations of maternal and weaned diets. Maternal n-3 LC-PUFA supplementation was associated with reduced levels of basal plasma glucose, hepatic triglycerides secretion and postprandial lipemia in the LO-HC group compared to the LC-HC group. Respiratory parameters were not affected by maternal supplementation. In contrast, n-3 LC-PUFA supplementation significantly enhanced the activities of citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase compared to the offspring of unsupplemented mothers. Sterol regulatory element binding protein-1c, diacylglycerol O-acyltransferase 2, fatty acid synthase, stearoyl CoA desaturase 1 and tumor necrosis factor α expression levels were not affected by n-3 LC-PUFA supplementation. These results provide evidence for a beneficial effect of n-3 LC-PUFA maternal supplementation in hamsters on the subsequent risk of metabolic syndrome. Underlying mechanisms may include improved lipid metabolism and activation of the mitochondrial oxidative pathway.     

Maternal obesity enhances collagen accumulation and cross-linking in skeletal muscle of ovine offspring

Maternal obesity (MO) has harmful effects on both fetal development and subsequent offspring health. We previously demonstrated that MO enhances collagen accumulation in fetal skeletal muscle, but its impact on mature offspring muscle collagen accumulation is unknown. Ewes were fed either a control diet (Con, fed 100% of NRC nutrient recommendations) or obesogenic diet (OB, fed 150% of NRC nutrient recommendations) from 60 days before conception to birth. All ewes received the Con diet during lactation. Male offspring were euthanized at 2.5 years (mean) and the left Longissimus dorsi (LD) muscle and semitendinosus (ST) muscle were sampled. Collagen concentration increased by 37.8 ± 19.0% (P<0.05) in LD and 31.2 ± 16.0% (P<0.05) in ST muscle of OB compared to Con offspring muscle. Mature collagen cross-linking (pyridinoline concentration) was increased for 22.3 ± 7.4% and 36.3 ± 9.9% (P<0.05) in LD and ST muscle of OB group respectively. Expression of lysyl oxidase, lysyl hydroxylase-2b (LH2b) and prolyl 4-hydroxylase (P4HA) was higher in OB LD and ST muscle. In addition, the expression of metalloproteinases (MMPs) was lower but tissue inhibitor of metalloproteinases (TIMPs) was higher in OB offspring muscle, indicating reduced collagen remodeling. MO enhanced collagen content and cross-linking in offspring muscle, which might be partially due to reduced collagen remodeling. Our observation that the collagen content and cross-linking are enhanced in MO offspring muscle is significant, because fibrosis is known to impair muscle functions and is a hallmark of muscle aging.     

Maternal obesogenic diet enhances cholestatic liver disease in offspring

Human and animal model data show that maternal obesity promotes nonalcoholic fatty liver disease in offspring and alters bile acid (BA) homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS) diet and then bred them with lean males. Offspring were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 2 weeks to induce cholestasis, and a subgroup was then fed CON for an additional 10 days. Additionally, to evaluate the role of the gut microbiome, we fed antibiotic-treated mice cecal contents from CON or HF/HS offspring, followed by DDC for 2 weeks. We found that HF/HS offspring fed DDC exhibited increased fine branching of the bile duct (ductular reaction) and fibrosis but did not differ in BA pool size or intrahepatic BA profile compared to offspring of mice fed CON. We also found that after 10 days recovery, HF/HS offspring exhibited sustained ductular reaction and periportal fibrosis, while lesions in CON offspring were resolved. In addition, cecal microbiome transplant from HF/HS offspring donors worsened ductular reaction, inflammation, and fibrosis in mice fed DDC. Finally, transfer of the microbiome from HF/HS offspring replicated the cholestatic liver injury phenotype. Taken together, we conclude that maternal HF/HS diet predisposes offspring to increased cholestatic injury after DDC feeding and delays recovery after returning to CON diets. These findings highlight the impact of maternal obesogenic diet on hepatobiliary injury and repair pathways during experimental cholestasis.     

Pre-Weaning Growth Hormone Treatment Reverses Hypertension and Endothelial Dysfunction in Adult Male Offspring of Mothers Undernourished during Pregnancy

Maternal undernutrition results in elevated blood pressure (BP) and endothelial dysfunction in adult offspring. However, few studies have investigated interventions during early life to ameliorate the programming of hypertension and vascular disorders. We have utilised a model of maternal undernutrition to examine the effects of pre-weaning growth hormone (GH) treatment on BP and vascular function in adulthood. Female Sprague-Dawley rats were fed either a standard control diet (CON) or 50% of CON intake throughout pregnancy (UN). From neonatal day 3 until weaning (day 21), CON and UN pups received either saline (CON-S, UN-S) or GH (2.5 ug/g/day)(CON-GH, UN-GH). All dams were fed ad libitum throughout lactation. Male offspring were fed a standard diet until the end of the study. Systolic blood pressure (SBP) was measured at day 150 by tail cuff plethysmography. At day 160, intact mesenteric vessels mounted on a pressure myograph. Responses to pressure, agonist-induced constriction and endothelium-dependent vasodilators were investigated to determine vascular function. SBP was increased in UN-S groups and normalised in UN-GH groups (CON-S 121±2 mmHg, CON-GH 115±3, UN-S 146±3, UN-GH 127±2). Pressure mediated dilation was reduced in UN-S offspring and normalised in UN-GH groups. Vessels from UN-S offspring demonstrated a reduced constrictor response to phenylephrine and reduced vasodilator response to acetylcholine (ACh). Furthermore, UN-S offspring vessels displayed a reduced vasodilator response in the presence of L-NG-Nitroarginine Methyl Ester (L-NAME), carbenoxolone (CBX), L-NAME and CBX, Tram-34 and Apamin. UN-GH vessels showed little difference in responses when compared to CON and significantly increased vasodilator responses when compared to UN-S offspring. Pre-weaning GH treatment reverses the negative effects of maternal UN on SBP and vasomotor function in adult offspring. These data suggest that developmental cardiovascular programming is potentially reversible by early life GH treatment and that GH can reverse the vascular adaptations resulting from maternal undernutrition.     

Effects of the Use of Assisted Reproductive Technologies and an Obesogenic Environment on Resistance Artery Function and Diabetes Biomarkers in Mice Offspring

Maternal obesity affects the incidence of cardiovascular disease and diabetes in offspring. Also the use of assisted reproductive technologies (ART) has been associated with cardiovascular deficiencies in offspring. Obese women often suffer from infertility and use ART to achieve a pregnancy, but the combined effects of maternal obesity and ART on cardiovascular health and incidence of diabetes in the offspring is not known. Here, we report the effects of the use of ART within an obesogenic environment, consisting of feeding a western diet (WD) to dams and offspring, on resistance artery function and presence of diabetes biomarkers in juvenile mice offspring. Our results indicate that WD and ART interacted to induce endothelial dysfunction in mesenteric resistance arteries isolated from 7-week-old mice offspring. This was determined by presence of a reduced acetylcholine-induced dilation compared to controls. The arteries from these WD-ART mice also had greater wall cross-sectional areas and wall to lumen ratios indicative of vascular hypertrophic remodeling. Of the diabetes biomarkers measured, only resistin was affected by a WD×ART interaction. Serum resistin was significantly greater in WD-ART offspring compared to controls. Diet and sex effects were observed in other diabetes biomarkers. Our conclusion is that in mice the use of ART within an obesogenic environment interacts to favor the development of endothelial dysfunction in the resistance arteries of juvenile offspring, while having marginal effects on diabetes biomarkers.     

Maternal obesogenic diet combined with postnatal exposure to high-fat diet induces metabolic alterations in offspring

Maternal obesity has been shown to impact the offspring health during childhood and adult life. This study aimed to evaluate whether maternal obesity combined with postnatal exposure to an obesogenic diet could induce metabolic alterations in offspring. Female CD1 mice were fed a control diet (CD, 11.1% of energy from fat) or with a high-fat diet (HFD, 44.3% of energy from fat) for 3 months. After weaning, pups born from control and obese mothers were fed with CD or HFD for 3 months. Both mothers and offspring were weighted weekly and several blood metabolic parameters levels were evaluated. Here, we present evidence that the offspring from mothers exposed to a HFD showed increased acetylation levels of histone 3 on lysine 9 (H3K9) in the liver at postnatal Day 1, whereas the levels of acetylation of H4K16, dimethylation of H3K27, and trimethylation of H3K9 showed no change. We also observed a higher perinatal weight and increased blood cholesterol levels when compared to the offspring on postnatal Day 1 born from CD-fed mothers. When mice born from obese mothers were fed with HFD, we observed that they gained more weight, presented higher blood cholesterol levels, and abdominal adipose tissue than mice born to the same mothers but fed with CD. Collectively, our results point toward maternal obesity and HFD consumption as a risk factor for epigenetic changes in the liver of the offspring, higher perinatal weight, increased weight gain, and altered blood cholesterol levels.     

Increased maternal fat consumption during pregnancy alters body composition in neonatal mice

Maternal overnutrition prior to and during gestation causes pronounced metabolic dysfunction in the adult offspring. However, less is known about metabolic adaptations in the offspring that occur independently of postnatal growth and nutrition. Therefore, we evaluated the impact of excess maternal dietary lipid intake on the in utero programming of body composition, hepatic function, and hypothalamic development in newborn (P0) offspring. Female mice were fed a low-fat (LF) or high-fat (HF) diet and were mated after 4, 12, and 23 wk. A subset of the obese HF dams was switched to the LF diet during the second (DR2) or third (DR3) pregnancies. The HF offspring accrued more fat mass than the LF pups, regardless of duration of maternal HF diet consumption or prepregnancy maternal adiposity. Increased neonatal adiposity was not observed in the DR3 pups. Liver weights were reduced in the HF offspring but not in the DR2 or DR3 pups. Offspring hepatic triglyceride content was reduced in the HF pups, but hepatic inflammation and expression of lipid metabolism genes were largely unaffected by maternal diet. Maternal diet did not alter the hypothalamic expression of orexigenic and anorexigenic neuropeptides in the offspring. Thus, the intrauterine programming of increased neonatal adiposity and reduced liver size by maternal overnutrition is evident in mice at birth and occurs prior to the development of maternal obesity. These observations demonstrate that dietary intervention during pregnancy minimizes the deleterious effects of maternal obesity on offspring body composition, potentially reducing the offsprings' risk of developing obesity and related diseases later in life.     

母代高脂饮食诱导子代在小鼠生命早期出现糖脂代谢紊乱且具有雄性易感性

目的：探讨孕期和哺乳期的高脂饮食能否导致子代在生命早期出现糖脂代谢紊乱。方法成年雌性C57BL/6J小鼠与正常饮食雄性小鼠进行交配,孕鼠随机分为高脂饮食组和正常饮食组,在孕期和哺乳期喂养高脂饲料或正常饲料,至交配后第一代鼠断乳时（3周龄）观察其糖脂代谢相关性指标以及肝脏病理表现。结果较正常饮食组子鼠相比,高脂饮食子鼠出生体重更低（ P＜0.05）。在断乳时,高脂饮食组雄性子鼠体重较重（ P ＝0.038）,腹腔糖耐量实验30 min和60 min血糖明显升高（P值分别为＜0.001和＜0.01）,糖耐量曲线下面积较大（P＝0.0016）,HOMA-IR值较大（P＜0.05）,雌性子鼠腹腔糖耐量实验在30 min血糖高于正常组（P＜0.01）,而糖耐量曲线下面积和HOMA-IR值在两组之间无明显统计学意义。雄性和雌性子代小鼠空腹胆固醇水平高脂饮食组均高于正常饮食组（ P值分别为＜0.0001和0.0004）,而两组雄性和雌性子代小鼠空腹胰岛素和甘油三酯水平差异均无显著性（ P均＞0.05）。另外,在断乳时高脂饮食子鼠出现肝脏脂肪变性,雌性和雄性子鼠无明显差异。结论母鼠孕期和哺乳期高脂饮食能够诱导子代在生命早期就能出现糖脂代谢紊乱并且雄性子鼠更易出现肥胖、糖耐量异常、胰岛素抵抗。     

Maternal diet-induced obesity during suckling period programs offspring obese phenotype and hypothalamic leptin/insulin resistance

During the early post-natal period, offspring are vulnerable to environmental insults, such as nutritional and hormonal changes, which increase risk to develop metabolic diseases later in life. Our aim was to understand whether maternal obesity during lactation programs offspring to metabolic syndrome and obese phenotype, in addition we aimed to assess the peripheral glucose metabolism and hypothalamic leptin/insulin signaling pathways. At delivery, female Wistar rats were randomly divided in two groups: Control group (CO), mothers fed a standard rodent chow (Nuvilab); and Diet-induced obesity group (DIO), mothers who had free access to a diet performed with 33% ground standard rodent chow, 33% sweetened condensed milk (Nestlé), 7% sucrose and 27% water. Maternal treatment was performed throughout suckling period. All offspring received standard rodent chow from weaning until 91-day-old. DIO dams presented increased total body fat and insulin resistance. Consequently, the breast milk from obese dams had altered composition. At 91-day-old, DIO offspring had overweight, hyperphagia and higher adiposity. Furthermore, DIO animals had hyperinsulinemia and insulin resistance, they also showed pancreatic islet hypertrophy and increased pancreatic β-cell proliferation. Finally, DIO offspring showed low ObRb, JAK2, STAT-3, IRβ, PI3K and Akt levels, suggesting leptin and insulin hypothalamic resistance, associated with increased of hypothalamic NPY level and decreased of POMC. Maternal obesity during lactation malprograms rat offspring to develop obesity that is associated with impairment of melanocortin system. Indeed, rat offspring displayed glucose dyshomeostasis and both peripheral and central insulin resistance.     

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.     

Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers

Absence of leptin is known to disrupt the development of energy balance regulatory mechanisms. We investigated whether administration of leptin to normally nourished rats affects energy balance in their offspring. Leptin (2 mg.kg(-1).day(-1)) was administered from day 14 of pregnancy and throughout lactation. Male and female offspring were fed either on chow or on high-fat diets that elicited similar levels of obesity in the sexes from 6 wk to 15 mo of age. Treatment of the dams with leptin prevented diet-induced increases in the rate of weight gain, retroperitoneal fat pad weight, area under the intraperitoneal glucose tolerance curve, and fasting plasma insulin concentration in female offspring. In the male offspring, the diet-induced increase in weight gain was prevented and increased fat pad weight was reduced. Energy intake per rat was higher in response to the obesogenic diet in male offspring of saline-treated but not leptin-treated dams. A similar trend was seen in 3-mo-old female offspring. Energy expenditure at 3 mo of age was higher for a given body weight in female offspring of leptin-treated compared with saline-treated dams when these animals were fed on the obesogenic diet. A similar trend was seen for male rats fed on the obesogenic diet. Thus leptin levels during pregnancy and lactation can affect the development of energy balance regulatory systems in their offspring.     

Supplementation with polyunsaturated fatty acids in pregnant rats with mild diabetes normalizes placental PPARγ and mTOR signaling in female offspring developing gestational diabetes

Maternal diabetes impairs fetoplacental development and programs metabolic diseases in the offspring. We have previously reported that female offspring of pregnant rats with mild diabetes develop gestational diabetes mellitus (GDM) when they become pregnant. Here, we studied the effects of supplementation with polyunsaturated fatty acids (PUFAs) in pregnant mild diabetic rats (F0) by feeding a 6% safflower-oil-enriched diet from day 1 to 14 followed by a 6% chia-oil-enriched diet from day 14 of pregnancy to term. We analyzed maternal metabolic parameters and placental signaling at term in pregnant offspring (F1). The offspring of both PUFAs-treated and untreated mild diabetic rats developed GDM. Although gestational hyperglycemia was not prevented by dietary PUFAs treatment in F0, triglyceridemia and cholesterolemia in F1 mothers were normalized by F0 PUFAs dietary treatment. In the placenta of F1 GDM rats, PPARγ levels were reduced and lipoperoxidation was increased, changes that were prevented by the maternal diets enriched in PUFAs in the F0 generation. Moreover, fetal overgrowth and placental activation of mTOR signaling pathways were reduced in F1 GDM rats whose mothers were treated with PUFAs diets. These results suggest that F0 PUFAs dietary treatment in pregnancies with mild diabetes improves maternal dyslipidemia, fetal overgrowth and placental signaling in female offspring when they become pregnant. We speculate that an increased PUFAs intake in pregnancies complicated by diabetes may prove effective to ameliorate metabolic programming in the offspring, thereby improving the health of future generations.