Maternal obesity at conception programs obesity in the offspring

Risk of obesity in adult life is subject to programming during gestation. To examine whether in utero exposure to maternal obesity increases the risk of obesity in offspring, we developed an overfeeding-based model of maternal obesity in rats utilizing intragastric feeding of diets via total enteral nutrition. Feeding liquid diets to adult female rats at 220 kcal/kg(3/4) per day (15% excess calories/day) compared with 187 kcal/kg(3/4) per day for 3 wk caused substantial increase in body weight gain, adiposity, serum insulin, leptin, and insulin resistance. Lean or obese female rats were mated with ad libitum AIN-93G-fed male rats. Exposure to obesity was ensured to be limited only to the maternal in utero environment by cross-fostering pups to lean dams having ad libitum access to AIN-93G diets throughout lactation. Numbers of pups, birth weight, and size were not affected by maternal obesity. Male offspring from each group were weaned at postnatal day (PND)21 to either AIN-93G diets or high-fat diets (45% fat calories). Body weights of offspring from obese dams did not differ from offspring of lean dams when fed AIN-93G diets through PND130. However, offspring from obese dams gained remarkably greater (P < 0.005) body weight and higher % body fat when fed a high-fat diet. Body composition was assessed by NMR, X-ray computerized tomography, and weights of adipose tissues. Adipose histomorphometry, insulin sensitivity, and food intake were also assessed in the offspring. Our data suggest that maternal obesity at conception leads to fetal programming of offspring, which could result in obesity in later life.     

Effect of high-fat diet during gestation, lactation, or postweaning on physiological and behavioral indexes in borderline hypertensive rats

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or "junk food" diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance.     

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.     

Post-natal diet determines insulin resistance in fetally malnourished, low birthweight rats (F1) but diet does not modify the insulin resistance of their offspring (F2)

We examined the effects of prenatal and postnatal nutrition on birthweight and insulin sensitivity, indicated by the glucose/insulin (G/I) ratio, in adult rats (F1 generation) and in their adult offspring (F2 generation). Rat pups (F1) whose dams consumed low-protein diets during gestation (malnourished) consumed either nutritionally adequate (control) or high-fat diets ad libitum post-weaning. The offspring of these rats (F2) were maintained on the same diets as their respective dams. Separate pups (F1) whose dams consumed high-fat diets during gestation (over-nourished) were maintained on high-fat diets post-weaning, as were their offspring (F2). Birthweights were significantly reduced in all fetally malnourished F1 animals. At approximately 70 d of age, fasting insulin sensitivity in over-nourished F1 rats was significantly reduced compared to controls regardless of whether they were malnourished or over-nourished in utero; however, fetally malnourished F1 rats consuming control diets post-natally had significantly greater fasting insulin sensitivity than control animals. At 30 and 120 min post-glucose load, insulin sensitivity was reduced 12-65% in both groups of over-nourished F1 rats as compared to the fetally malnourished F1 rats consuming the control diet. Birthweights were significantly lower in F2 animals whose dams (F1) were fetally malnourished and weaned to high fat diets. Insulin sensitivity was significantly reduced in all F2 animals versus control animals, regardless of dietary treatment. Thus, post-natal diets alter insulin sensitivity in fetally malnourished, adult rats; and maternal malnutrition during gestation results in insulin resistance in offspring, irrespective of offsprings' birthweight or diet.     

Maternal obesity disrupts circadian rhythms of clock and metabolic genes in the offspring heart and liver

Early life nutritional adversity is tightly associated with the development of long-term metabolic disorders. Particularly, maternal obesity and high-fat diets cause high risk of obesity in the offspring. Those offspring are also prone to develop hyperinsulinemia, hepatic steatosis and cardiovascular diseases. However, the precise underlying mechanisms leading to these metabolic dysregulation in the offspring remain unclear. On the other hand, disruptions of diurnal circadian rhythms are known to impair metabolic homeostasis in various tissues including the heart and liver. Therefore, we investigated that whether maternal obesity perturbs the circadian expression rhythms of clock, metabolic and inflammatory genes in offspring heart and liver by using RT-qPCR and Western blotting analysis. Offspring from lean and obese dams were examined on postnatal day 17 and 35, when pups were nursed by their mothers or took food independently. On P17, genes examined in the heart either showed anti-phase oscillations (Cpt1b, Pparα, Per2) or had greater oscillation amplitudes (Bmal1, Tnf-α, Il-6). Such phase abnormalities of these genes were improved on P35, while defects in amplitudes still existed. In the liver of 17-day-old pups exposed to maternal obesity, the oscillation amplitudes of most rhythmic genes examined (except Bmal1) were strongly suppressed. On P35, the oscillations of circadian and inflammatory genes became more robust in the liver, while metabolic genes were still kept non-rhythmic. Maternal obesity also had a profound influence in the protein expression levels of examined genes in offspring heart and liver. Our observations indicate that the circadian clock undergoes nutritional programing, which may contribute to the alternations in energy metabolism associated with the development of metabolic disorders in early life and adulthood.     

Epigenetic programming of reward function in offspring: a role for maternal diet

Early life development, through gestation and lactation, represents a timeframe of extreme vulnerability for the developing fetus in general, and for the central nervous system in particular. An adverse perinatal environment can have a lasting negative impact on brain development, increasing the risk for developmental disorders and broader psychopathologies. A major determinant of the fetal developmental environment is maternal diet. The present review summarizes the current literature regarding the effect of poor maternal perinatal nutrition on offspring brain development, with an emphasis on reward-related neural systems and behaviors. Epigenetic mechanisms represent a likely link between maternal diet and persistent changes in offspring brain development, and these mechanisms are presented and discussed within the context of perinatal maternal nutrition.     

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain,Liver and Adipose Tissue of Adult Rat Offspring

Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.     

Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition

Maternal nutrient restriction results in intrauterine growth restriction (IUGR) newborns that develop obesity despite normal postweaning diet. The epidemic of metabolic syndrome is attributed to programmed "thrifty phenotype" and exposure to Western diets. We hypothesized that programmed IUGR newborns would demonstrate greater susceptibility to obesity and metabolic abnormalities in response to high-fat diet. From day 10 to term gestation and lactation, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% food restricted (FR). Cross-fostering techniques resulted in three offspring groups: control (AdLib/AdLib), FR during pregnancy (FR/AdLib), and FR during lactation (AdLib/FR). At 3 weeks, offspring were weaned to laboratory chow or high-fat calorie diet (9% vs. 17% calorie as fat). Body composition, appetite hormones, and glucose and lipid profiles were determined in 9-mo-old male and female offspring. High-fat diet had no effect on body weight of AdLib/AdLib, but significantly increased weights of FR/AdLib and AdLib/FR offspring. High-fat diet significantly increased body fat, reduced lean body mass, and accentuated plasma leptin but not ghrelin levels in both sexes in all groups. In males, high-fat diet caused a significant increase in glucose levels in all three groups with increased insulin levels in AdLib/AdLib and AdLib/FR, but not in FR/AdLib. In females, high-fat diet had no effect on glucose but significantly increased basal insulin among all three groups. High-fat diet caused hypertriglyceridemia in all three groups although only food-restricted females exhibited hypercholesterolemia. Sex and offspring phenotype-associated effects of high-fat diet indicate differing pathophysiologic mechanisms that require specific therapeutic approaches.     

Maternal high-fat diet affects Msi/Notch/Hes signaling in neural stem cells of offspring mice

Numerous research have begun to reveal the importance of maternal nutrition in offspring brain development. Particularly, the maternal obesity or exposure to high-fat diet has been strongly suggested to exert irreversible impact on the structure and function of offspring's brain. However, it remains obscure about whether neonatal neural stem cells (NSCs) in offspring's brain are susceptible to maternal exposure to high-fat diet. Here we focused on the alternation in the Notch signaling in NSCs derived from neonatal mice, which had been given birth by female mice with a high-fat diet and found that, in fact, the high-fat diet administration imposed effects on not only maternal mice, indicated by the accumulation of viscera fat as well as the increase in body weight and serum total cholesterol, but also NSCs in the offspring’s brain, where significant increase was observed in the expression of genes, either downstream of Notch signaling or regulating this pathway, which have been shown essential for the maturation of NSCs. Therefore, our data provided the first evidence for the potential effect of maternal exposure to the high-fat diet on the Notch signaling pathway in offspring’s NSCs, indicating this altered signaling response might contribute to a profound change in offspring’s brains as a result of maternal high-fat diet prior to and during gestation.     

Embryonic programming of heart disease in response to obesity during pregnancy

Obesity during pregnancy programs adult-onset heart disease in the offspring. Clinical studies indicate that exposure to an adverse environment in utero during early, as compared to late, gestation leads to a higher prevalence of adult-onset heart disease. This suggests that the early developing heart is particularly sensitive to an adverse environment. Accordingly, growing evidence from clinical studies and animal models demonstrates that obesity during pregnancy alters the function of the fetal heart, programming a higher risk of cardiovascular disease later in life. Moreover, gene expression patterns and signaling pathways that promote initiation and progression of cardiovascular disease are altered in the hearts in offspring born to obese mothers. However, the mechanisms mediating the long-term effects of an adverse environment in utero on the developing heart leading to adult-onset disease are not clear. Here, we review clinical and experimental evidence documenting the effects of maternal obesity during pregnancy on the fetal and post-natal heart and emphasize on the potential mechanisms of disease programming.     

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.     

Protective effects of maternal methyl donor supplementation on adult offspring of high fat diet-fed dams

Obesity has become a global public health problem associated with metabolic dysfunction and chronic disorders. It has been shown that the risk of obesity and the DNA methylation profiles of the offspring can be affected by maternal nutrition, such as high-fat diet (HFD) consumption. The aim of this study was to investigate whether metabolic dysregulation and physiological abnormalities in offspring caused by maternal HFD can be alleviated by the treatment of methyl donors during pregnancy and lactation of dams. Female C57BL/6 mice were assigned to specific groups and given different nutrients (control diet, Control + Met, HFD and HFD + Met) throughout gestation and lactation. Offspring of each group were weaned onto a control diet at 3 weeks of age. Physiological (weight gain and adipose composition) and metabolic (plasma biochemical analyses) outcomes were assessed in male and female adult offspring. Expression and DNA methylation profiles of obesogenic-related genes including PPAR γ, fatty acid synthase, leptin and adiponectin were also detected in visceral fat of offspring. The results showed that dietary supplementation with methyl donors can prevent the adverse effects of maternal HFD on offspring. Changes in the expression and DNA methylation of obesogenic-related genes indicated that epigenetic regulation may contribute to the effects of maternal dietary factors on offspring outcomes.     

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.     

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.     

Animal models of in utero exposure to a high fat diet: A review

The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.     

Parental Diabetes: The Akita Mouse as a Model of the Effects of Maternal and Paternal Hyperglycemia in Wildtype Offspring

Aim/Hypothesis

Maternal diabetes and high-fat feeding during pregnancy have been linked to later life outcomes in offspring. To investigate the effects of both maternal and paternal hyperglycemia on offspring phenotypes, we utilized an autosomal dominant mouse model of diabetes (hypoinsulinemic hyperglycemia in Akita mice). We determined metabolic and skeletal phenotypes in wildtype offspring of Akita mothers and fathers.

Results

Both maternal and paternal diabetes resulted in phenotypic changes in wildtype offspring. Phenotypic changes were more pronounced in male offspring than in female offspring. Maternal hyperglycemia resulted in metabolic and skeletal phenotypes in male wildtype offspring. Decreased bodyweight and impaired glucose tolerance were observed as were reduced whole body bone mineral density and reduced trabecular bone mass.Phenotypic changes in offspring of diabetic fathers differed in effect size from changes in offspring of diabetic mothers. Male wildtype offspring developed a milder metabolic phenotype, but a more severe skeletal phenotype. Female wildtype offspring of diabetic fathers were least affected.

Conclusions

Both maternal and paternal diabetes led to the development of metabolic and skeletal changes in wildtype offspring, with a greater effect of maternal diabetes on metabolic parameters and of paternal diabetes on skeletal development. The observed changes are unlikely to derive from Mendelian inheritance, since the investigated offspring did not inherit the Akita mutation. While fetal programming may explain the phenotypic changes in offspring exposed to maternal diabetes in-utero, the mechanism underlying the effect of paternal diabetes on wildtype offspring is unclear.     

Respective contributions of maternal insulin resistance and diet to metabolic and hypothalamic phenotypes of progeny

Maternal obesity can influence susceptibility to obesity and type 2 diabetes in progeny. We examined the relationship of maternal insulin resistance (IR), a metabolically important consequence of increased adiposity, to adverse consequences of obesity for fetal development. We used mice heterozygous for a null allele of the insulin receptor (Insr) to study the contributions of maternal IR to offspring phenotype without the potential confound of obesity per se, and how maternal consumption of high-fat diet (HFD) may, independently and interactively, affect progeny. In progeny fed a 60% HFD, body weight and adiposity were transiently (5-7 weeks) increased in wild-type (+/+) offspring of Insr(+/-) HFD-fed dams compared to offspring of wild-type HFD-fed dams. Offspring of HFD-fed wild-type dams had increased body weight, blood glucose, and plasma insulin concentrations compared to offspring of chow-fed wild-type dams. Quantification of proopiomelanocortin (POMC) and neuropeptide-Y (NPY) populations in the arcuate nucleus of the hypothalamus (ARH) of offspring of wild-type vs. Insr(+/-) dams was performed to determine whether maternal IR affects the formation of central feeding circuits. We found a 20% increase in the number of Pomc-expressing cells at postnatal day 9 in offspring of Insr(+/-) dams. In conclusion, maternal HFD consumption-distinct from overt obesity per se-was a major contributor to increased body weight, adiposity, IR, and liver triglyceride (TG) phenotypes in progeny. Maternal IR played a minor role in predisposing progeny to obesity and IR, though it acted synergistically with maternal HFD to exacerbate early obesity in progeny.     

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.     

Interactive effects of maternal and weaning high linoleic acid intake on hepatic lipid metabolism,oxylipins profile and hepatic steatosis in offspring

Non-alcoholic fatty liver disease (NAFLD) has been described as a hepatic manifestation of the metabolic syndrome. When several studies correlated maternal linoleic acid (LA) intake with the development of obesity, only few links have been made between n-6 fatty acid (FA) and NAFLD. Herein, we investigated the influence of both maternal and weaning high LA intake on lipid metabolism and susceptibility to develop later metabolic diseases in offspring. Pregnant rats were fed a control-diet (2% LA) or a LA-rich diet (12% LA) during gestation and lactation. At weaning, offspring was assigned to one of the two diets, i.e., either maintained on the same maternal diet or fed the other diet for 6 months. Physiological, biochemical parameters and hepatic FA metabolism were analyzed. We demonstrated that the interaction between the maternal and weaning LA intake altered metabolism in offspring and could lead to hepatic steatosis. This phenotype was associated with altered hepatic FA content and lipid metabolism. Interaction between maternal and weaning LA intake led to a specific pattern of n-6 and n-3 oxylipins that could participate to the development of hepatic steatosis in offspring. Our findings highlight the significant interaction between maternal and weaning high LA intake to predispose offspring to later metabolic disease and support the predictive adaptive response hypothesis.