Intergenerational Transmission of Glucose Intolerance and Obesity by In Utero Undernutrition in Mice
Jimenez-Chillaron, Josep C.
Faucette, Ryan R.
Otis, Jessica P.
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CitationJimenez-Chillaron, Josep C., Elvira Isganaitis, Marika Charalambous, Stephane Gesta, Thais Pentinat-Pelegrin, Ryan R. Faucette, Jessica P. Otis, et al. 2009. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58(2): 460-468.
AbstractOBJECTIVE—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 (F1-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 F1 adult control (C) and UN mice and characterized metabolic phenotypes in F2 offspring. RESULTS—We demonstrate that 1) reduced birth weight progresses to F2 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 F1 and F2 generations is linked to impaired β-cell function, explained, in part, by dysregulation of Sur1 expression. CONCLUSIONS—Maternal undernutrition during pregnancy (F0) 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).
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