Fostering in mice induces cardiovascular and metabolic dysfunction in adulthood

Department of Hepatology and Gastroenterology, Guy's and St Thomas’ Hospital, London, UK
The Journal of Physiology (Impact Factor: 5.04). 08/2011; 589(16):3969 - 3981. DOI: 10.1113/jphysiol.2011.212324
Source: PubMed


Non-technical summary Cross-fostering of newborn pups to different dams is a method widely used in rodent studies of developmental ‘programming’ to determine whether pregnancy or the suckling period is more important in determining adult characteristics following changes to the maternal environment. We have investigated whether the process of fostering per se influences cardiovascular and metabolic development in mice. Compared with mice reared by their biological mother, fostered mice showed increased appetite, body weight, abdominal fatness and altered blood sugar metabolism. A marked increase in blood pressure was also apparent. This study demonstrates that the process of fostering can lead to profound effects in cardiovascular and metabolic function in otherwise normal mice. The findings have implications both for the interpretation of previous cross-fostering studies in mice and for studies investigating the hypothesis of developmental programming, in which early postnatal manipulation of litters is common practice.
Abstract Cross-fostering is widely used in developmental programming studies to determine the relative contribution of the in utero and suckling periods in establishing the adult offspring phenotype in response to an environmental challenge. We have investigated whether the process of fostering per se influences cardiovascular and metabolic function in adult offspring of C57BL/6J mice in comparison with animals suckled by their biological dams. Cross-fostered (CF) mice demonstrated juvenile onset hyperphagia and significantly higher body weight (from weaning to 12 weeks: male control (CON) vs. CF: P < 0.01, female CON vs. CF: P < 0.001; RM ANOVA) accompanied by increased abdominal adiposity in males only (white adipose tissue mass (mg): CON 280.5 ± 13.4 [mean ± SEM] (n= 7) vs. CF, 549.8 ± 99.3 (n= 8), P < 0.01). Both male and female CF mice demonstrated significantly enhanced glucose tolerance. A marked increase in systolic blood pressure (SBP) was observed in male CF mice (SBP (mmHg), day: CON 100.5 ± 1.4 (n= 6) vs. CF 114.3 ± 0.7 (n= 6), P < 0.001; night: CON 108.0 ± 2.0 (n= 6) vs. CF 123.2 ± 1.1 (n= 6), P < 0.001). Endothelium-dependent relaxation was enhanced in male CF mice, and renal noradrenaline was increased in female CF mice. Concentration of serum triglycerides, cholesterol, insulin and leptin were increased in CF vs. CON. The process of cross-fostering profoundly affects cardiovascular and metabolic phenotype in mice. The findings have implications for the inclusion of appropriate controls in the design of future studies and in the interpretation of previous cross-fostering studies in mice.

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    • "We have previously shown that offspring exposure to MO throughout pregnancy and lactation induces a significant increase in markers indicative of a NAFPD phenotype, when compared to offspring exposed to a normal intrauterine and perinatal environment [1]. Here, we corroborate these results using a more pathophysiologically relevant model not involving cross-fostering which has since been shown to influence metabolic phenotype [35]. In addition to the previous findings of increased pancreatic triglycerides, collagen and TGF-β expression [1], our results show that MO in conjunction with a post-weaning OD (Ob_Ob) significantly impacts upon pancreas weight, pancreatic triglycerides concentration and macrovesicular fat concentration. "
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    ABSTRACT: Emerging evidence suggests that maternal obesity (MO) predisposes offspring to obesity and the recently described non-alcoholic fatty pancreas disease (NAFPD) but involved mechanisms remain unclear. Using a pathophysiologically relevant murine model, we here investigated a role for the biological clock - molecular core circadian genes (CCG) in the generation of NAFPD. Female C57BL6 mice were fed an obesogenic diet (OD) or standard chow (SC) for 6 weeks, prior to pregnancy and throughout gestation and lactation: resulting offspring were subsequently weaned onto either OD (Ob_Ob and Con_Ob) or standard chow (Ob_Con and Con_Con) for 6 months. Biochemical, pro-inflammatory and pro-fibrogenic markers associated with NAFPD were then evaluated and CCG mRNA expression in the pancreas determined. Offspring of obese dams weaned on to OD (Ob_Ob) had significantly increased (p≤0.05): bodyweight, pancreatic triglycerides, macrovesicular pancreatic fatty-infiltration, and pancreatic mRNA expression of TNF-α, IL-6, α-SMA, TGF-β and increased collagen compared to offspring of control dams weaned on to control chow (Con_Con). Analyses of CCG expression demonstrated a phase shift in CLOCK (-4.818, p<0.01), REV-ERB-α (-1.4,p<0.05) and Per2 (3.27,p<0.05) in association with decreased amplitude in BMAL-1 (-0.914,p<0.05) and PER2 (1.18,p<0.005) in Ob_Ob compared to Con_Con. 2-way ANOVA revealed significant interaction between MO and post-weaning OD in expression of CLOCK (p<0.005), PER1 (p<0.005) and PER2 (p<0.05) whilst MO alone influenced the observed rhythmic variance in expression of all 5 measured CCG. Fetal and neonatal exposure to a maternal obesogenic environment interacts with a post-natal hyper-calorific environment to induce offspring NAFPD through mechanisms involving perturbations in CCG expression.
    PLoS ONE 03/2014; 9(3):e89505. DOI:10.1371/journal.pone.0089505 · 3.23 Impact Factor
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    • "We are aware, however, that suckling of pups from obese dams on lean fosters and subsequent feeding with control diet may cause a disadvantageous mismatch between the pre-and postnatal environment that might influence offspring outcome via epigenetic mechanisms [51]. The process of fostering itself has recently been reported to lead to sex-specific cardiovascular and metabolic alterations and increased white adipose tissue accumulation specifically in males [52]. Thus, as we carried out fostering of all offspring of both the HFD-fed and CD-fed experimental group of dams, we cannot completely exclude that an interaction between the prenatal maternal HFD and the " fostered " phenotype might have contributed to adult adiposity and metabolic phenotypes observed in our study. "
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    ABSTRACT: Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized NMRI mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features not being observed in females. Instead, those showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet*sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition.
    Biochimica et Biophysica Acta 11/2013; 1842(2). DOI:10.1016/j.bbadis.2013.11.021 · 4.66 Impact Factor
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    • "For example, between-strain fostering alters anxiety behaviors [51], autoimmune disease [52], and body weight [48]. Importantly, within-strain fostering also influences anxiety, juvenile social behaviors [22], [53], [54], and body weight [47], [55]. Taken together with the data shown here, we propose that fostering itself alters the maternal environment and mediates permanent changes in offspring phenotypes. "
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    ABSTRACT: It is well known that genes and environment interact to produce behavioral phenotypes. One environmental factor with long-term effects on gene transcription and behavior is maternal care. A classic paradigm for examining maternal care and genetic interactions is to foster pups of one genetic strain to dams of a different strain ("between-strain fostering"). In addition, fostering to a dam of the same strain ("within-strain fostering") is used to reduce indirect effects, via behavioral changes in the dams, of gestation treatments on offspring. Using within-and between-strain fostering we examined the contributions of genetics/prenatal environment, maternal care, and the effects of fostering per se, on adult aggressive behavior in two inbred mouse strains, C57BL/6J (B6) and DBA/2J (DBA). We hypothesized that males reared by dams of the more aggressive DBA strain would attack intruders faster than those reared by B6 dams. Surprisingly, we found that both methods of fostering enhanced aggressive behavior, but only in B6 mice. Since all the B6 offspring are genetically identical, we asked if maternal behavior of B6 dams was affected by the relatedness of their pups. In fact, B6 dams caring for foster B6 pups displayed significantly reduced maternal behaviors. Finally, we measured vasopressin and corticotrophin releasing hormone mRNA in the amygdalae of adult B6 males reared by foster or biological dams. Both genes correlated with aggressive behavior in within-strain fostered B6 mice, but not in mice reared by their biological dams. In sum, we have demonstrated in inbred laboratory mice, that dams behave differently when rearing their own newborn pups versus pups from another dam of the same strain. These differences in maternal care affect aggression in the male offspring and transcription of Avp and Crh in the brain. It is likely that rearing by foster dams has additional effects and implications for other species.
    PLoS ONE 09/2013; 8(9):e75037. DOI:10.1371/journal.pone.0075037 · 3.23 Impact Factor
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