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.     

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.     

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.     

The hypothalamic POMC mRNA expression is upregulated in prenatally undernourished male rat offspring under high-fat diet

Epidemiological studies demonstrated that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to increased risk of metabolic syndrome. In rats, we previously demonstrated that adult male IUGR offspring from prenatal 70% food-restricted dams throughout gestation (FR30) were predisposed to energy balance dysfunctions such as impaired glucose intolerance, hyperleptinemia, hyperphagia and adiposity. We investigated whether postweaning moderate high-fat (HF) diet would amplify the phenotype focusing on the hypothalamus gene expression profile. Prenatally undernourished rat offspring were HF-fed from weaning until adulthood while body weight and food intake were measured. Tissue weights, glucose tolerance and plasma endocrine parameters levels were determined in 4-month-old rats. Hypothalamic gene expression profiling of adult FR30 rat was performed using Illumina microarray analysis and the RatRef-12 Expression BeadChip that contains 21,792 rat genes. Under HF diet, contrary to C animals, FR30 rats displayed increased body weight. However, most of the endocrine disorders observed in chow diet-fed adult FR30 were alleviated. We also observed very few gene expression changes in hypothalamus of FR30 rat. Amongst factors involved in hypothalamic energy homeostasis programming system, only the POMC and transthyretin mRNA expression levels were preferentially increased under HF diet. Both elevated gene expression levels may be seen as adaptive mechanisms counteracting against deleterious effects of HF feeding in FR30 animals. This study shows that the POMC gene expression is a key target of long-term developmental programming in prenatally undernourished male rat offspring, specifically within an obesogenic environment.     

Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet

Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11β-HSD1, 11β-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11β-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition.     

Unexpected long-term protection of adult offspring born to high-fat fed dams against obesity induced by a sucrose-rich diet

Background

Metabolic and endocrine environment during early life is crucial for metabolic imprinting. When dams were fed a high fat diet (HF diet), rat offspring developed hypothalamic leptin resistance with lean phenotype when weaned on a normal diet. Interestingly, when grown on the HF diet, they appeared to be protected against the effects of HF diet as compared to offspring of normally fed dams. The mechanisms involved in the protective effect of maternal HF diet are unclear.

Methodology/Principal Findings

We thus investigated the impact of maternal high fat diet on offspring subjected to normal or high palatable diet (P diet) on metabolic and endocrine parameters. We compared offspring born to dams fed P or HF diet. Offspring born to dams fed control or P diet, when fed P diet exhibited a higher body weight, altered hypothalamic leptin sensitivity and metabolic parameters suggesting that maternal P diet has no protective effect on offspring. Whereas, maternal HF diet reduces body weight gain and circulating triglycerides, and ameliorates corpulence index of offspring, even when subjected to P diet. Interestingly, this protective effect is differently expressed in male and female offspring. Male offspring exhibited higher energy expenditure as mirrored by increased hypothalamic UCP-2 and liver AdipoR1/R2 expression, and a profound change in the arcuate nucleus astrocytic organization. In female offspring, the most striking impact of maternal HF diet is the reduced hypothalamic expression of NPY and POMC.

Conclusions/Significance

HF diet given during gestation and lactation protects, at least partially, offspring from excessive weight gain through several mechanisms depending upon gender including changes in arcuate nucleus astrocytic organization and increased hypothalamic UCP-2 and liver AdipoR1/2 expression in males and reduced hypothalamic expression of NPY and POMC in females. Taken together our results reveal new mechanisms involved in the protective effect of maternal HF diet.     

Maternal flaxseed oil intake during lactation changes body fat,inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism

We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil + 2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1β and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1β expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.     

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

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

Fatty-acid-mediated hypothalamic inflammation and epigenetic programming

A high-fat diet is the main environmental cue that has been studied in the hypothalamus since the discovery of its connection with hypothalamic inflammation. Current evidence shows hypothalamic inflammation as a likely mechanism for the dysregulation on the homeostatic control of energy balance, which leads to metabolic alterations and obesity. Although this mechanism seems to be reversible when set during adulthood, we argue whether dietary fatty acids, during critical periods of development, could affect hypothalamic function permanently and set an increased susceptibility to obesity. We found few experimental studies that looked at programming induced by different fatty acids on the hypothalamus. They clearly showed a connection between maternal fat diet, hypothalamic inflammation and metabolic alterations in the offspring. We found that not only a high-fat diet but also a normolipidic diet with unbalanced quantities of different fatty acids produced diverse inflammatory responses on the hypothalamus. Therefore, strategies of manipulating dietary fatty acids in pregnant and lactating women may have great impact on the population's future health. However, more research is still needed on the effects of fatty acids and the hypothalamic inflammation on programming.     

A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring

Epidemiological and animal studies suggest that diet-induced epigenetic modifications in early life can contribute to development of the metabolic syndrome in adulthood. We previously reported features of the metabolic syndrome in adult offspring of rats fed a diet rich in animal fat during pregnancy and suckling. We now report a study to compare the relative effects of high-fat feeding during 1) pregnancy and 2) the suckling period in the development of these disorders. As observed previously, 6-mo-old female offspring of fat-fed dams suckled by the same fat-fed dams (OHF) demonstrated raised blood pressure, despite being fed a balanced diet from weaning. Female offspring of fat-fed dams "cross fostered" to dams consuming a control diet during suckling (OHF/C) demonstrated raised blood pressure compared with controls (OC) [systolic blood pressure (SBP; mmHg) means +/- SE: OHF/C, 132.5 +/- 3.0, n = 6 vs. OC, 119.0 +/- 3.8, n = 7, P < 0.05]. Female offspring of controls cross fostered to dams consuming the fat diet (OC/HF) were also hypertensive [SBP (mmHg) 131.0 +/- 2.5 mmHg, n = 6 vs. OC, P < 0.05]. Endothelium-dependent relaxation (EDR) of male and female OHF and OHF/C mesenteric small arteries was similar and blunted compared with OC (P < 0.001). OC/HF arteries showed profoundly impaired EDR (OC/HF vs. OHF, P < 0.001). OHF/C and OC/HF demonstrated hyperinsulinemia and increased adiposity. Features of the metabolic syndrome in adult offspring of fat-fed rats can be acquired both antenatally and during suckling. However, exposure during pregnancy confers adaptive protection against endothelial dysfunction induced by maternal fat feeding during suckling.     

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

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

Both Food Restriction and High-Fat Diet during Gestation Induce Low Birth Weight and Altered Physical Activity in Adult Rat Offspring: The “Similarities in the Inequalities” Model

We have previously described a theoretical model in humans, called “Similarities in the Inequalities”, in which extremely unequal social backgrounds coexist in a complex scenario promoting similar health outcomes in adulthood. Based on the potential applicability of and to further explore the “similarities in the inequalities” phenomenon, this study used a rat model to investigate the effect of different nutritional backgrounds during gestation on the willingness of offspring to engage in physical activity in adulthood. Sprague-Dawley rats were time mated and randomly allocated to one of three dietary groups: Control (Adlib), receiving standard laboratory chow ad libitum; 50% food restricted (FR), receiving 50% of the ad libitum-fed dam’s habitual intake; or high-fat diet (HF), receiving a diet containing 23% fat. The diets were provided from day 10 of pregnancy until weaning. Within 24 hours of birth, pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, and HF_Adlib. Maternal chow consumption and weight gain, and offspring birth weight, growth, physical activity (one week of free exercise in running wheels), abdominal adiposity and biochemical data were evaluated. Western blot was performed to assess D2 receptors in the dorsal striatum. The “similarities in the inequalities” effect was observed on birth weight (both FR and HF groups were smaller than the Adlib group at birth) and physical activity (both FR_Adlib and HF_Adlib groups were different from the Adlib_Adlib group, with less active males and more active females). Our findings contribute to the view that health inequalities in fetal life may program the health outcomes manifested in offspring adult life (such as altered physical activity and metabolic parameters), probably through different biological mechanisms.     

Early hypothalamic FTO overexpression in response to maternal obesity--potential contribution to postweaning hyperphagia

Background

Intrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.

Methods

Female Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.

Results

At weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P = 0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.

Significance

Maternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.     

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.     

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to “developmental origins of health and disease.”     

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.     

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.     

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

Aim

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

Materials and Methods

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

Results

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

Conclusion

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

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

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

Maternal resveratrol intake during lactation attenuates hepatic triglyceride and fatty acid synthesis in adult male rat offspring

Resveratrol (3,5,4-trihydroxystilbene) is a natural polyphenolic compound found in grapes and red wine and has been shown to exert protective effects on the liver preventing lipid accumulation induced by a high-fat diet. However, no studies have shown that the nutritional resveratrol intake by the parental generation has modified lipogenesis in an adult offspring. The aim of this study was to investigate whether maternal resveratrol intake during lactation affects lipogenesis in adult male rat offspring, and if it does, what is the molecular mechanistic basis. Six male pups born from mothers given a control diets during lactation (CC group) and six male pups born from mothers given a control diet as well as resveratrol during lactation (CR group) were fed a standard diet until sacrifice at 36 weeks. Adult male offspring from mothers given resveratrol during lactation (CR group) had lower body weight from the fourth week of lactation until adulthood, but no significant change was observed in the relative food intake. Low levels of plasma triacylglycerol were found in the CR group compared to the CC group. Histopathological analysis of the livers of adult male rat offspring revealed lipid accumulation in hepatocytes in the CC group, whereas lipid droplets were rare in the CR group. Hepatic protein levels of AMPK-phosphorylated at ser403, Sirt1, and Nampt in the CR group were upregulated significantly compared to the CC group. These results indicated the maternal resveratrol intake during lactation-induced activation of AMPK through Sirt1 upregulation. In this study, significant upregulation of the levels of precursor of sterol regulatory element binding protein-1c (SREBP-1c) and downregulation of the ratio of active-SREBP-1c/precusor-SREBP-1c were observed in the CR group compared to the CC group. These results suggested that proteolytic processing of SREBP-1c was suppressed by AMPK in the livers of the CR group. It is well known that SREBP-1c regulates the lipogenic pathway by activating genes involved in triglyceride and fatty acid synthesis. The present study showed significant downregulation of hepatic fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) levels in the CR group. These results indicated that maternal resveratrol intake during lactation suppressed SREBP-1c cleavage and nuclear translocation and repressed SREBP-1c target gene expression such as FAS and ACC in the livers of adult male offspring. These changes attenuate hepatic triacylglycerol and fatty acid synthesis in adult male offspring.