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OBJECTIVE- Low birth weight (LBW) is associated with increased risk of obesity, diabetes, and cardiovascular disease during adult life. Moreover, this programmed disease risk can progress to subsequent generations. We previously described a mouse model of LBW, produced by maternal caloric undernutrition (UN) during late gestation. LBW offspring (F^sub 1^-UN generation) develop progressive obesity and impaired glucose tolerance (IGT) with aging. We aimed to determine whether such metabolic phenotypes can be transmitted to subsequent generations in an experimental model, even in the absence of altered nutrition during the second pregnancy.
RESEARCH DESIGN AND METHODS- We intercrossed female and male F^sub 1^ adult control (C) and UN mice and characterized metabolic phenotypes in F^sub 2^ offspring.
RESULTS- We demonstrate that 1) reduced birth weight progresses to F^sub 2^ offspring through the paternal line (C[female] -C[male] = 1.64 g; C[female]-UN[male] = 1.57 g, P < 0.05; UN[female] -C[male] = 1.64 g; UN[female] -UN[male] = 1.60 g, P < 0.05), 2) obesity progresses through the maternal line (percent body fat: C[female] -C[male] = 22.4%; C[female] -UN[male] = 22.9%; UN[female] - C[male]= 25.9%, P < 0.05; UN[female] -UN[male] = 27.5%, P < 0.05), and 3) IGT progresses through both parental lineages (glucose tolerance test area under curve C[female] -C[male] = 100; C[female] -UN[male] = 122, P < 0.05; UN[female] -C[male] = 131, P < 0.05; UN[female] -UN[male] = 151,P< 0.05). Mechanistically, IGT in both F^sub 1^ and F^sub 2^ generations is linked to impaired ß-cell function, explained, in part, by dysregulation of Sur1 expression.
CONCLUSIONS - Maternal undernutrition during pregnancy (F^sub 0^) programs reduced birth weight, IGT, and obesity in both first- and second-generation offspring. Sex-specific transmission of phenotypes implicates complex mechanisms including alterations in the maternal metabolic environment (transmaternai inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT). Diabetes 58:460-468, 2009
Human and animal studies have demonstrated a strong association between intrauterine growth retardation/low birth weight (LBW) and increased susceptibility to cardiovascular disease, obesity, and type 2 diabetes during adult life (1-5). This association has been conceptualized by the developmental programming hypothesis, which proposes that environmental stimuli acting during critical windows of development, including fetal and/or early postnatal periods, can induce permanent alterations in cell/tissue structure and function...