Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice

Abstract

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 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 1 adult control (C) and UN mice and characterized metabolic phenotypes in F 2 offspring. RESULTS— We demonstrate that 1 ) reduced birth weight progresses to F 2 offspring through the paternal line (C♀-C♂ = 1.64 g; C♀-UN♂ = 1.57 g, P < 0.05; UN♀-C♂ = 1.64 g; UN♀-UN♂ = 1.60 g, P < 0.05), 2 ) obesity progresses through the maternal line (percent body fat: C♀-C♂ = 22.4%; C♀-UN♂ = 22.9%; UN♀-C♂ = 25.9%, P < 0.05; UN♀-UN♂ = 27.5%, P < 0.05), and 3 ) IGT progresses through both parental lineages (glucose tolerance test area under curve C♀-C♂ = 100; C♀-UN♂ = 122, P < 0.05; UN♀-C♂ = 131, P < 0.05; UN♀-UN♂ = 151, P < 0.05). Mechanistically, IGT in both F 1 and F 2 generations is linked to impaired β-cell function, explained, in part, by dysregulation of Sur1 expression. CONCLUSIONS— Maternal undernutrition during pregnancy (F 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 (transmaternal inheritance of obesity), gene expression mediated by developmental and epigenetic pathways (transpaternal inheritance of LBW), or both (IGT).

Intrauterine calorie restriction affects placental DNA methylation and gene expression

“…The placentas were collected after 10 days of CR, and therefore we hypothesize that the changes in expression and methylation between CR and CON are associated with this altered environment. From previous data we know that CR mice tend to develop increased fat mass and glucose intolerance compared with CON mice (30).…”

“…This model differs from previous mouse models of maternal diet effects, which primarily focused on overnutrition. Instead we model the effect of CR, which mimics the human IUGR phenotype encountered world-wide of low-birth-weight offspring that are predisposed to metabolic disorders (24,27,30).…”

A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations

“…To our knowledge, there is no direct evidence that fatty acid nutrition affects epigenetic gene regulation and that epigenetic mechanisms determining overweightness/obesity in an obesogenic environment have any relationship with those observed in malnourished fetuses ( 54 ). Among candidate genes, only sFRP4, a member of the Wnt signaling pathway known to exhibit epigenetic regulation through methylation, may be relevant to this observation ( 55 ).…”

Both Hepatic Lipogenesis and Beta-Oxidation are Altered in Offspring of Mothers Fed a High-Fat Diet in the First Two Generations (F1 and F2)

“…Evidence both from human and animal studies suggests that fetal programming may not be limited to the directly exposed F1 but may be transmitted to subsequent generations without re-exposure (Jimenez-Chillaron et al, 2009;Drake & Liu, 2010). These effects may be transmissible through both maternal and paternal lines (Jimenez-Chillaron et al; Pentinat et al, 2010;Dunn & Bale, 2011).…”