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Parental Diabetes: The Akita Mouse as a Model of the Effects of Maternal and Paternal Hyperglycemia in Wildtype Offspring  [PDF]
Corinna Grasemann, Maureen J. Devlin, Paulina A. Rzeczkowska, Ralf Herrmann, Bernhard Horsthemke, Berthold P. Hauffa, Marc Grynpas, Christina Alm, Mary L. Bouxsein, Mark R. Palmert
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050210
Abstract: 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.
Additive Effects of Maternal High Fat Diet during Lactation on Mouse Offspring  [PDF]
Hisashi Masuyama, Yuji Hiramatsu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092805
Abstract: Recent reports indicated that nutrition in early infancy might influence later child health outcomes such as obesity and metabolic syndrome. Therefore, we examined the effects of maternal high fat diet (HFD) during lactation on the onset of a metabolic syndrome in their offspring. All offspring were cross-fostered by dams on the same or opposite diet to yield 4 groups: offspring from HFD-fed dams suckled by HFD-fed dams (OHH) and by control diet (CD)-fed dams (OHC) and CD-fed dams suckled by HFD-fed dams (OCH) and by CD-fed dams (OCC) mice. We examined several metabolic syndrome-related factors including body weight, blood pressure, glucose tolerance and adipocytokines. Mean body weights of OHH and OCH mice were significantly higher than those of OHC and OCC mice, respectively, with elevated systolic blood pressure. Moreover, OHH and OCH mice revealed significantly worse glucose tolerance compared with the OHC and OCC mice, respectively. Triglyceride and leptin levels were significantly increased and adiponectin levels were significantly reduced by the maternal HFD during lactation, with similar changes in leptin and adiponectin mRNA expression but without histone modifications in adipose tissues. In addition, maternal obesity induced by HFD during lactation increased and prolonged the leptin surge in the offspring and the gender differences of leptin surge were observed. Our data suggested that maternal HFD during lactation might have an additive effect on the onset of the metabolic syndrome in the offspring, irrespective of the nutritional status in utero through the modified leptin surge.
Maternal Deprivation Exacerbates the Response to a High Fat Diet in a Sexually Dimorphic Manner  [PDF]
Virginia Mela,álvaro Llorente-Berzal,Francisca Díaz,Jesús Argente,María-Paz Viveros,Julie A. Chowen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048915
Abstract: Maternal deprivation (MD) during neonatal life has diverse long-term effects, including affectation of metabolism. Indeed, MD for 24 hours during the neonatal period reduces body weight throughout life when the animals are maintained on a normal diet. However, little information is available regarding how this early stress affects the response to increased metabolic challenges during postnatal life. We hypothesized that MD modifies the response to a high fat diet (HFD) and that this response differs between males and females. To address this question, both male and female Wistar rats were maternally deprived for 24 hours starting on the morning of postnatal day (PND) 9. Upon weaning on PND22 half of each group received a control diet (CD) and the other half HFD. MD rats of both sexes had significantly reduced accumulated food intake and weight gain compared to controls when raised on the CD. In contrast, when maintained on a HFD energy intake and weight gain did not differ between control and MD rats of either sex. However, high fat intake induced hyperleptinemia in MD rats as early as PND35, but not until PND85 in control males and control females did not become hyperleptinemic on the HFD even at PND102. High fat intake stimulated hypothalamic inflammatory markers in both male and female rats that had been exposed to MD, but not in controls. Reduced insulin sensitivity was observed only in MD males on the HFD. These results indicate that MD modifies the metabolic response to HFD intake, with this response being different between males and females. Thus, the development of obesity and secondary complications in response to high fat intake depends on numerous factors.
Effect of maternal vitamin and mineral restrictions on the body fat content and adipocytokine levels of WNIN rat offspring
Venu Lagishetty, Vijaya Nandiwada, Rajender Kalashikam, Raghunath Manchala
Nutrition & Metabolism , 2007, DOI: 10.1186/1743-7075-4-21
Abstract: Body fat percentage; glucose, insulin and adipocytokine levels in fasting plasma and fresh weights of epididymal fat pads were determined in the six months old male offspring of Wistar NIN rat dams on chronic 50 percent restriction of vitamins or minerals throughout their growth, gestation, lactation and weaned on to restricted diets or restricted mothers/offspring rehabilitated from different time points.In line with high body fat percent, chronic restriction of vitamins and minerals increased the epididymal fat pad weight. Maternal vitamin restriction decreased plasma adiponectin and increased leptin levels whereas mineral restriction decreased both. Both the treatments did not affect plasma TNF-α levels or insulin resistance status (HOMA-IR). Rehabilitation from parturition but not weaning, rescued the changes in the offspring.High body fat percentage in the offspring of vitamin restricted or mineral restricted rat dams was associated with increased abdominal adiposity (epididymal fat pad weight) and differential expression of adipocytokines but not insulin resistance. The changes could be mitigated by rehabilitation from birth but not weaning.Maternal under-nutrition impairs intrauterine development and increases adiposity, insulin resistance (IR) and associated metabolic disturbances in the later life of the offspring [1]. We reported earlier that chronic 50 percent restriction of minerals (MR) or vitamins (VR) in Wistar NIN (WNIN) rat dams increased the body fat percentage in offspring and decreased their insulin response to glucose challenge [2,3]. We also reported that increased oxidative stress and impaired antioxidant status were associated with maternal VR but not MR induced changes in offspring [2,3]. We now report whether or not increased body adiposity in the VR and MR offspring is associated with increased abdominal adiposity, altered expression of adipocytokines and insulin resistance.Adipocytokines, the adipocyte derived bioactive molecules, mediate
Maternal Manganese Restriction Increases Susceptibility to High-Fat Diet-Induced Dyslipidemia and Altered Adipose Function in WNIN Male Rat Offspring  [PDF]
Manisha Ganeshan,Pothaganti B. Sainath,Inagadapa J. Naga Padmavathi,Lagishetty Venu,Yedla Durga Kishore,Kalle Anand Kumar,Nemani Harishanker,J. Srinivasa Rao,Manchala Raghunath
Journal of Diabetes Research , 2011, DOI: 10.1155/2011/486316
Abstract: Growth in utero is largely a reflection of nutrient and oxygen supply to the foetus. We studied the effects of Mn restriction per se, maternal Mn restriction, and postnatal high-fat feeding in modulating body composition, lipid metabolism and adipocyte function in Wistar/NIN (WNIN) rat offspring. Female weanling, WNIN rats received ad libitum for 4 months, a control or Mn-restricted diet and were mated with control males. Some restricted mothers were rehabilitated with control diet from conception (MnRC) or parturition (MnRP), and their offspring were raised on control diet. Some restricted offspring were weaned onto control diet (MnRW), while others continued on restricted diet throughout (MnR). A set of offspring from each group was fed high-fat diet from 9 months onwards. Body composition, adipocytes function, and lipid metabolism were monitored in male rat offspring at regular intervals. Maternal manganese restriction increased the susceptibility of the offspring to high-fat-induced adiposity, dyslipidaemia, and a proinflammatory state but did not affect their glycemic or insulin status. 1. Introduction Tissues and organs of the developing foetus go through critical periods of development [1] which may coincide with periods of rapid cell division. Exposure of the foetus to maternal malnutrition causes intrauterine growth retardation (IUGR) [2] leading to low birth weight whose prevalence varies from 13% to 30% in India. However, most animal models that studied the mechanistic basis of this relationship considered only the maternal deficiency of macronutrients. Micronutrients, especially minerals, play an important role in the structure and metabolic activities of animals and are important in their reproduction [3]. Despite this, the role of maternal micronutrient deficiencies in the etiology of adiposity and lipid metabolism in the offspring has not been studied well. We showed earlier that maternal mineral restriction induced irreversible alterations in body fat% and lipid metabolism in rat offspring, whereas maternal vitamin restriction induced similar but reversible changes [4, 5]. Manganese (Mn), an essential micronutrient for humans and animals, is an enzyme cofactor and a constituent of metalloenzymes [6]. It activates enzymes of fatty acid synthesis [7], hepatic gluconeogenesis [8], and is a critical component of manganese superoxide dismutase (MnSOD) involved in mitochondrial oxidant defense system. Although reports on Mn restriction per se are limited, many epidemiological studies have reported the importance of Mn as a supplement in
Vascular Dysfunction Induced in Offspring by Maternal Dietary Fat Involves Altered Arterial Polyunsaturated Fatty Acid Biosynthesis  [PDF]
Christopher J. Kelsall, Samuel P. Hoile, Nicola A. Irvine, Mojgan Masoodi, Christopher Torrens, Karen A. Lillycrop, Philip C. Calder, Geraldine F. Clough, Mark A. Hanson, Graham C. Burdge
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034492
Abstract: Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG ?394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis.
Maternal Omega-3 Supplementation Increases Fat Mass in Male and Female Rat Offspring  [PDF]
Beverly Sara Muhlhausler,Dijana Miljkovic,Cory J. Xian,Emmanuelle Duthoit
Frontiers in Genetics , 2011, DOI: 10.3389/fgene.2011.00048
Abstract: Adipogenesis and lipogenesis are highly sensitive to the nutritional environment in utero and in early postnatal life. Omega-3 long chain polyunsaturated fatty acids (LCPUFA) inhibit adipogenesis and lipogenesis in adult rats, however it is not known whether supplementing the maternal diet with omega-3 LCPUFA results in reduced fat deposition in the offspring. Female Albino Wistar rats were fed either a standard chow (Control, n = 10) or chow designed to provide ~15 mg/kg/day of omega-3 LCPUFA, chiefly as docosahexaenoic acid (DHA), throughout pregnancy and lactation (Omega-3, n = 11) and all pups were weaned onto a commercial rat chow. Blood and tissues were collected from pups at 3 and 6 weeks of age and weights of visceral and subcutaneous fat depots recorded. The expression of adipogenic and lipogenic genes in the subcutaneous and visceral fat depots were determined using quantitative real time reverse transcription-PCR. Birth weight and postnatal growth were not different between groups. At 6 weeks of age, total percentage body fat was significantly increased in both male (5.09 ± 0.32% vs. 4.56 ± 0.2%, P < 0.04) and female (5.15 ± 0.37% vs. 3.89 ± 0.36%, P < 0.04) offspring of omega-3 dams compared to controls. The omega-3 LCPUFA content of erythrocyte phospholipids (as a% of total fatty acids) was higher in omega-3 offspring (6.7 ± 0.2% vs. 5.6 ± 0.2%, P < 0.001). There was no effect of maternal omega-3 LCPUFA supplementation on the expression of adipogenic or lipogenic genes in the offspring in either the visceral or subcutaneous fat depots. We have therefore established that an omega-3 rich environment during pregnancy and lactation in a rodent model increases fat accumulation in both male and female offspring, particularly in subcutaneous depots, but that this effect is not mediated via upregulation adipogenic/lipogenic gene transcription. These data suggest that maternal n?3 LCPUFA supplementation during pregnancy/lactation may not be an effective strategy for reducing fat deposition in the offspring.
High Fat Diet and In Utero Exposure to Maternal Obesity Disrupts Circadian Rhythm and Leads to Metabolic Programming of Liver in Rat Offspring  [PDF]
Sarah J. Borengasser, Ping Kang, Jennifer Faske, Horacio Gomez-Acevedo, Michael L. Blackburn, Thomas M. Badger, Kartik Shankar
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084209
Abstract: The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER) and metabolic (PPARα, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARα expression prior to obesity development.
Methyl Donor Supplementation Blocks the Adverse Effects of Maternal High Fat Diet on Offspring Physiology  [PDF]
JesseLea Carlin, Robert George, Teresa M. Reyes
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063549
Abstract: Maternal consumption of a high fat diet during pregnancy increases the offspring risk for obesity. Using a mouse model, we have previously shown that maternal consumption of a high fat (60%) diet leads to global and gene specific decreases in DNA methylation in the brain of the offspring. The present experiments were designed to attempt to reverse this DNA hypomethylation through supplementation of the maternal diet with methyl donors, and to determine whether methyl donor supplementation could block or attenuate phenotypes associated with maternal consumption of a HF diet. Metabolic and behavioral (fat preference) outcomes were assessed in male and female adult offspring. Expression of the mu-opioid receptor and dopamine transporter mRNA, as well as global DNA methylation were measured in the brain. Supplementation of the maternal diet with methyl donors attenuated the development of some of the adverse effects seen in offspring from dams fed a high fat diet; including weight gain, increased fat preference (males), changes in CNS gene expression and global hypomethylation in the prefrontal cortex. Notable sex differences were observed. These findings identify the importance of balanced methylation status during pregnancy, particularly in the context of a maternal high fat diet, for optimal offspring outcome.
Interaction between Maternal and Offspring Diet to Impair Vascular Function and Oxidative Balance in High Fat Fed Male Mice  [PDF]
Christopher Torrens, Priya Ethirajan, Kimberley D. Bruce, Felino R. A. Cagampang, Richard C. M. Siow, Mark A. Hanson, Christopher D. Byrne, Giovanni E. Mann, Geraldine F. Clough
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050671
Abstract: Aims To determine the impact of maternal and post-weaning consumption of a high fat diet on endothelium-dependent vasorelaxation and redox regulation in adult male mouse offspring. Methods Female C57BL6J mice were fed an obesogenic high fat diet (HF, 45% kcal fat) or standard chow (C, 21% kcal fat) pre-conception and throughout pregnancy and lactation. Post-weaning, male offspring were continued on the same diet as their mothers or placed on the alternative diet to give 4 dietary groups (C/C, HF/C, C/HF and HF/HF) which were studied at 15 or 30 weeks of age. Results There were significant effects of maternal diet on offspring body weight (p<0.004), systolic blood pressure (p = 0.026) and endothelium-dependent relaxation to ACh (p = 0.004) and NO production (p = 0.005) measured in the femoral artery. With control for maternal diet there was also an effect of offspring post-weaning dietary fat to increase systolic blood pressure (p<0.0001) and reduce endothelium-dependent relaxation (p = 0.022) and ACh-mediated NO production (p = 0.007). There was also a significant impact of age (p<0.005). Redox balance was perturbed, with altered regulation of vascular enzymes involved in ROS/NO signalling. Conclusions Maternal consumption of a HF diet is associated with changes in vascular function and oxidative balance in the offspring of similar magnitude to those seen with consumption of a high fat diet post-weaning. Further, this disadvantageous vascular phenotype is exacerbated by age to influence the risk of developing obesity, raised blood pressure and endothelial dysfunction in adult life.
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