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: 4.38). 08/2011; 589(16):3969 - 3981. DOI: 10.1113/jphysiol.2011.212324
Source: PubMed

ABSTRACT 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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    European Journal of Nutrition 11/2013; · 3.13 Impact Factor
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    ABSTRACT: Background. Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1-P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome.
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