Diet-induced metabolic dysregulation in female mice causes osteopenia in adult offspring

Bone mass and quality in humans are controlled by numerous genetic and environmental factors that are not fully understood. Increasing evidence has indicated that maternal metabolic dysregulation impairs multiple physiological processes in the adult offspring, but a similar effect on bone health is yet to be established. Here, we have analyzed the bones of first-generation offspring from murine dams that present metabolic syndrome due to a high-fat and high-sugar (HF/HS) diet. Micro-CT analyses show that the long bones of HF/HS offspring possess lower cortical bone mass and weaker mechanical strength than normal, even though the trabecular bone is not affected. Histomorphometry and serum biochemistry indicate that both bone formation and resorption are diminished in the HF/HS offspring. In vitro, both osteoblast and osteoclast progenitors from the HF/HS offspring are deficient in differentiation, likely due to impairment of mitochondrial respiration. The study, therefore, identifies maternal metabolic health as an important environmental factor influencing bone volume and strength

Human Milk Oligosaccharide Concentrations and Infant Intakes Are Associated with Maternal Overweight and Obesity and Predict Infant Growth

Human milk oligosaccharides (HMOs) are bioactive molecules playing a critical role in infant health. We aimed to quantify the composition of HMOs of women with normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obesity (30.0–60.0 kg/m2) and determine the effect of HMO intake on infant growth. Human milk (HM) samples collected at 2 months (2 M; n = 194) postpartum were analyzed for HMO concentrations via high-performance liquid chromatography. Infant HM intake, anthropometrics and body composition were assessed at 2 M and 6 M postpartum. Linear regressions and linear mixed-effects models were conducted examining the relationships between maternal BMI and HMO composition and HMO intake and infant growth over the first 6 M, respectively. Maternal obesity was associated with lower concentrations of several fucosylated and sialylated HMOs and infants born to women with obesity had lower intakes of these HMOs. Maternal BMI was positively associated with lacto-N-neotetraose, 3-fucosyllactose, 3-sialyllactose and 6-sialyllactose and negatively associated with disialyllacto-N-tetraose, disialyllacto-N-hexaose, fucodisialyllacto-N-hexaose and total acidic HMOs concentrations at 2 M. Infant intakes of 3-fucosyllactose, 3-sialyllactose, 6-sialyllactose, disialyllacto-N-tetraose, disialyllacto-N-hexaose, and total acidic HMOs were positively associated with infant growth over the first 6 M of life. Maternal obesity is associated with changes in HMO concentrations that are associated with infant adiposity

A Mediterranean diet plan in lactating women with obesity reduces maternal energy intake and modulates human milk composition – a feasibility study

IntroductionMaternal obesity is associated with increased concentrations of human milk (HM) obesogenic hormones, pro-inflammatory cytokines, and oligosaccharides (HMOs) that have been associated with infant growth and adiposity. The objective of this pilot study was to determine if adherence to a Mediterranean meal plan during lactation modulates macronutrients and bioactive molecules in human milk from mothers with obesity.MethodsSixteen healthy, exclusively breastfeeding women with obesity (body mass index ≥30 kg/m2) enrolled between 4 and 5 months postpartum. The women followed a 4-week Mediterranean meal plan which was provided at no cost. Maternal and infant anthropometrics, HM composition, and infant intakes were measured at enrollment and at weeks 2 and 4 of the intervention. Thirteen mother-infant dyads completed the study. Additionally, participants from an adjacent, observational cohort who had obesity and who collected milk at 5 and 6 months postpartum were compared to this cohort.ResultsParticipants’ healthy eating index scores improved (+27 units, p < 0.001), fat mass index decreased (−4.7%, p < 0.001), and daily energy and fat intake were lower (−423.5 kcal/day, p < 0.001 and-32.7 g/day, p < 0.001, respectively) following the intervention. While HM macronutrient concentrations did not change, HM leptin, total human milk oligosaccharides (HMOs), HMO-bound fucose, Lacto-N-fucopentaose (LNFP)-II, LNFP-III, and difucosyllacto-N-tetrose (DFLNT) concentrations were lower following the intervention. Infant intakes of leptin, tumor necrosis factor (TNF)-α, total HMOs, HMO-bound fucose, LNFP-III and DFLNT were lower following the intervention. Specific components of the maternal diet (protein and fat) and specific measures of maternal diet quality (protein, dairy, greens and beans, fruit and vegetables) were associated with infant intakes and growth.DiscussionAdherence to a Mediterranean meal plan increases dietary quality while reducing total fat and caloric intake. In effect, body composition in women with obesity improved, HM composition and infants’ intakes were modulated. These findings provide, for the first time, evidence-based data that enhancing maternal dietary quality during lactation may promote both maternal and child health. Longer intervention studies examining the impact of maternal diet quality on HM composition, infant growth, and infant development are warranted

Third-Trimester Glucose Homeostasis in Healthy Women Is Differentially Associated with Human Milk Oligosaccharide Composition at 2 Months Postpartum by Secretor Phenotype

Human milk oligosaccharides (HMOs) are bioactive molecules in human milk that play a critical role in infant health. Obesity and associated metabolic aberrations can negatively impact lactation and alter milk composition. Here, the relationship between maternal glucose homeostasis and HMO composition from 136 healthy women was examined. Maternal glucose homeostasis (fasting plasma glucose and insulin, homeostatic model assessment for insulin resistance, and insulin sensitivity index) was evaluated at 30 weeks of gestation in healthy women (body mass index = 18.5–35 kg/m2). Human milk samples were collected at two months postpartum. HMO concentrations were measured via high performance liquid chromatography. Women were categorized into “secretor” and “non-secretor” groups based on 2′-Fucosyllactose concentrations (<100 nmol/mL, non-secretor). Pearson’s correlation analysis and linear models were used to assess the relationships between maternal glucose homeostasis and HMO concentrations. In non-secretors, third trimester fasting plasma glucose and insulin were negatively associated with total HMO-bound sialic acid and concentrations of the sialylated HMOs 3′-sialyllactose and disialylacto-N-tetraose. In secretors, difucosyllactose and lacto-N-fucopentaose-II concentrations increased and sialyllacto-N-tetraose c and sialyllacto-N-tetraose b decreased as insulin sensitivity increased. This study is the first to demonstrate a relationship between obesity-associated maternal factors and HMO composition in both secretor and non-secretor populations

Maternal fructose drives placental uric acid production leading to adverse fetal outcomes

Maternal metabolic diseases increase offspring risk for low birth weight and cardiometabolic diseases in adulthood. Excess fructose consumption may confer metabolic risks for both women and their offspring. However, the direct consequences of fructose intake per se are unknown. We assessed the impact of a maternal high-fructose diet on the fetal-placental unit in mice in the absence of metabolic syndrome and determined the association between maternal serum fructose and placental uric acid levels in humans. In mice, maternal fructose consumption led to placental inefficiency, fetal growth restriction, elevated fetal serum glucose and triglyceride levels. In the placenta, fructose induced de novo uric acid synthesis by activating the activities of the enzymes AMP deaminase and xanthine oxidase. Moreover, the placentas had increased lipids and altered expression of genes that control oxidative stress. Treatment of mothers with the xanthine oxidase inhibitor allopurinol reduced placental uric acid levels, prevented placental inefficiency, and improved fetal weights and serum triglycerides. Finally, in 18 women delivering at term, maternal serum fructose levels significantly correlated with placental uric acid levels. These findings suggest that in mice, excess maternal fructose consumption impairs placental function via a xanthine oxidase/uric acid-dependent mechanism, and similar effects may occur in humans

Maternal Obesity Reduces Milk Lipid Production in Lactating Mice by Inhibiting Acetyl-CoA Carboxylase and Impairing Fatty Acid Synthesis

<div><p>Maternal metabolic and nutrient trafficking adaptations to lactation differ among lean and obese mice fed a high fat (HF) diet. Obesity is thought to impair milk lipid production, in part, by decreasing trafficking of dietary and <i>de novo</i> synthesized lipids to the mammary gland. Here, we report that <i>de novo</i> lipogenesis regulatory mechanisms are disrupted in mammary glands of lactating HF-fed obese (HF-Ob) mice. HF feeding decreased the total levels of acetyl-CoA carboxylase-1 (ACC), and this effect was exacerbated in obese mice. The relative levels of phosphorylated (inactive) ACC, were elevated in the epithelium, and decreased in the adipose stroma, of mammary tissue from HF-Ob mice compared to those of HF-fed lean (HF-Ln) mice. Mammary gland levels of AMP-activated protein kinase (AMPK), which catalyzes formation of inactive ACC, were also selectively elevated in mammary glands of HF-Ob relative to HF-Ln dams or to low fat fed dams. These responses correlated with evidence of increased lipid retention in mammary adipose, and decreased lipid levels in mammary epithelial cells, of HF-Ob dams. Collectively, our data suggests that maternal obesity impairs milk lipid production, in part, by disrupting the balance of <i>de novo</i> lipid synthesis in the epithelial and adipose stromal compartments of mammary tissue through processes that appear to be related to increased mammary gland AMPK activity, ACC inhibition, and decreased fatty acid synthesis.</p></div

Maternal Metabolic Syndrome Programs Mitochondrial Dysfunction via Germline Changes across Three Generations

Maternal obesity impairs offspring health, but the responsible mechanisms are not fully established. To address this question, we fed female mice a high-fat/high-sugar diet from before conception until weaning and then followed the outcomes in the next three generations of offspring, all fed a control diet. We observed that female offspring born to obese mothers had impaired peripheral insulin signaling that was associated with mitochondrial dysfunction and altered mitochondrial dynamic and complex proteins in skeletal muscle. This mitochondrial phenotype persisted through the female germline and was passed down to the second and third generations. Our results indicate that maternal programming of metabolic disease can be passed through the female germline and that the transfer of aberrant oocyte mitochondria to subsequent generations may contribute to the increased risk for developing insulin resistance

Effects of HF feeding and obesity on ACC and P-ACC levels in mammary glands of lactating dams.

<p>ACC and P-ACC levels in mammary glands of LF-fed, HF-Ln and HF-Ob dams at L10. (A) Representative immunoblots of ACC, P-ACC and β-actin in mammary gland extracts. (B–G) Chemiluminescence quantification of ACC (B, C) and P-ACC (D, E) relative to β-actin, and the P-ACC/ACC ratio (F, G) in mammary gland extracts. The values are means ± SEM (N = 5). Panels B, D and F compare the effects of HF feeding (LF-fed vs HF-Ln+HF-Ob) on relative mammary gland levels of ACC (B), P-ACC (D) and P-ACC/ACC (F). Panels C, E and G compare the effects of obesity (HF-Ln vs HF-Ob) on relative mammary gland levels of ACC (C), P-ACC (E) and P-ACC/ACC (G). Statistically significant differences are indicate by the following symbols: *<i>p</i><0.05; ♦p<0.03; ‡‡p<0.004.</p

Effects of HF feeding and obesity on mammary gland tissue morphology and composition.

<p>Glandular morphologies, and relative epithelial and adipose contents of mammary glands are shown for LF-fed, HF-Ln and HF-Ob dams at L10. (A) Representative images of H&E stained mammary glands. Higher magnification images taken from areas outlined by the black boxes are shown in the lower panels. Arrowheads in higher magnification images indicate mammary epithelium and stars indicate adipocytes. Graphs in B–D compare the effects of HF feeding (LF-fed vs HF-Ln+HF-Ob) and obesity (HF-Ln vs HF-Ob) on mammary gland weights (B), epithelial (white bars) and adipose (grey bars) compositions of mammary glands (C), and adipocyte diameters (D). (E) Shows the size distribution range of mammary gland adipocytes expressed as percentage of adipocytes with diameters in the ranges of 0–20 µm, 20–40 µm, 40–60 µm, 60–80 µm, and 80–100 µm. For panel B, values are means ± SEM for 5 mice per group. For panels C and D, values are means ± SEM, of 5 sections per animal and 5 animals per group. Statistically significant differences are indicate by the following symbols: ♦<i>p</i><0.03; **p<0.01; ††p<0.001.</p