The nutritional sins of the mother…: Prenatal exposures of a mother can affect the health of her offspring, but how? Radford et al. found that the male progeny of undernourished pregnant mice had altered DNA chemistry in their sperm. In addition, the offspring displayed compromised metabolic health. The specific affected genes not only lost DNA methylation but also lacked the normal sperm DNA packaging factors (protamines) and instead were enriched in nucleosomes. Thus, when subjected to a suboptimal prenatal environment, offspring feel the effects of the maternal assault. Science , this issue p. 10.1126/science.1255903

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 (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).

Rates of obesity and insulin resistance have climbed sharply over the past 30 years. These epidemics are temporally related to a dramatic rise in consumption of fast food; until recently, it was not known whether the fast food was driving the obesity, or vice versa. We review the unique properties of fast food that make it the ideal obesigenic foodstuff, and elucidate the mechanisms by which fast food intake contributes to obesity, emphasizing its effects on energy metabolism and on the central regulation of appetite. After examining the epidemiology of fast food consumption, obesity, and insulin resistance, we review insulin’s role in the central nervous system’s (CNS) regulation of energy balance, and demonstrate the role of CNS insulin resistance as a cause of leptin resistance and in the promotion of the pleasurable or “hedonic” responses to food. Finally, we analyze the characteristics of fast food, including high-energy density, high fat, high fructose, low fiber, and low dairy intake, which favor the development of CNS insulin resistance and obesity.

Objective To identify metabolite patterns associated with childhood obesity, to examine relations of these patterns with measures of adiposity and cardiometabolic risk, and to evaluate associations with maternal peripartum characteristics. Methods Untargeted metabolomic profiling was used to quantify metabolites in plasma of 262 children (6‐10 years). Principal components analysis was used to consolidate 345 metabolites into 18 factors and identified two that differed between obese (BMI ≥ 95‰; n = 84) and lean children (BMI < 85‰; n = 150). The relations of these factors with adiposity (fat mass, BMI, skinfold thicknesses) and cardiometabolic biomarkers (HOMA‐IR, triglycerides, leptin, adiponectin, hsCRP, IL‐6) using multivariable linear regression was then investigated. Finally, the associations of maternal prepregnancy obesity, gestational weight gain, and gestational glucose tolerance with the offspring metabolite patterns was examined. Results A branched‐chain amino acid (BCAA)‐related pattern and an androgen hormone pattern were higher in obese vs. lean children. Both patterns were associated with adiposity and worse cardiometabolic profiles. For example, each increment in the BCAA and androgen pattern scores corresponded with 6% (95% CI: 1, 13%) higher HOMA‐IR. Children of obese mothers had 0.61 (0.13, 1.08) higher BCAA score than their counterparts. Conclusions BCAA and androgen metabolites were associated with adiposity and cardiometabolic risk during mid‐childhood. Maternal obesity may contribute to altered offspring BCAA metabolism.

Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

Phthalates are ubiquitous endocrine disrupting chemicals associated with diabetes. Although women and minorities are more likely to be exposed to phthalates, no prior studies have examined phthalate exposure and markers of diabetes risk evaluating effect modification by gender and race/ethnicity.