Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.

Prader–Willi syndrome (PWS) is a rare genetic disorder characterized by a wide range of clinical manifestations, including obesity, hyperphagia, and behavioral problems. Bifidobacterium animalis subsp. lactis strain BPL1 has been shown to improve central adiposity in adults with simple obesity. To evaluate BPL1′s effects in children with PWS, we performed a randomized crossover trial among 39 patients (mean age 10.4 years). Participants were randomized to placebo–BPL1 (n = 19) or BPL1–placebo (n = 20) sequences and underwent a 12-week period with placebo/BPL1 treatments, a 12-week washout period, and a 12-week period with the crossover treatment. Thirty-five subjects completed the study. The main outcome was changes in adiposity, measured by dual-energy X-ray absorptiometry. Secondary outcomes included lipid and glucose metabolism, hyperphagia, and mental health symptoms. Generalized linear modeling was applied to assess differences between treatments. While BPL1 did not modify total fat mass compared to placebo, BPL1 decreased abdominal adiposity in a subgroup of patients older than 4.5 years (n = 28). BPL1 improved fasting insulin concentration and insulin sensitivity. Furthermore, we observed modest improvements in some mental health symptoms. A follow-up trial with a longer treatment period is warranted to determine whether BPL1 supplementation can provide a long-term therapeutic approach for children with PWS (ClinicalTrials.gov NCT03548480).

Prader–Willi syndrome is a rare genetic disorder associated with impaired body composition, hyperphagia, and excessive weight gain. Strict dietary restrictions from an early age is crucial to prevent or delay the early onset of obesity, which is the main driver of comorbidities in these patients. The aim of this study was to identify dietary and gut microbiota components closely linked to weight status of these patients. We studied a cohort of children and adolescents with genetic diagnosis of Prader–Willi syndrome (N = 31), in which we determined adiposity by Dual-energy X-ray absorptiometry (DXA) and dietary composition with 4-day food records. Furthermore, we obtained fecal samples to assess microbiota composition by 16S sequencing. Multivariate regression models showed that body mass index standard deviation score (BMI-SDS) and body fat mass were directly associated with saturated fat intake and meat consumption, and inversely associated with fruit consumption. Furthermore, the gut microbiome from normal weight patients was characterized by higher phylogenetic diversity compared to those overweight or obese, with differential abundance of several genera, including Alistipes, Klebsiella, and Murimonas. Notably, Alistipes abundance was inversely correlated to adiposity, lipid and glucose homeostasis parameters, and meat intake. Our results suggest that limiting meat and increasing fruit intake might be beneficial for body weight management in children and adolescents with Prader–Willi syndrome.

Very preterm infants (VPI, born at or before 32 weeks of gestation) are at risk of adverse health outcomes, from which they might be partially protected with appropriate postnatal nutrition and growth. Metabolic processes or biochemical markers associated to extrauterine growth restriction (EUGR) have not been identified. We applied untargeted metabolomics to plasma samples of VPI with adequate weight for gestational age at birth and with different growth trajectories (29 well-grown, 22 EUGR) at the time of hospital discharge. A multivariate analysis showed significantly higher levels of amino-acids in well-grown patients. Other metabolites were also identified as statistically significant in the comparison between groups. Relevant differences (with corrections for multiple comparison) were found in levels of glycerophospholipids, sphingolipids and other lipids. Levels of many of the biochemical species decreased progressively as the level of growth restriction increased in severity. In conclusion, an untargeted metabolomic approach uncovered previously unknown differences in the levels of a range of plasma metabolites between well grown and EUGR infants at the time of discharge. Our findings open speculation about pathways involved in growth failure in preterm infants and the long-term relevance of this metabolic differences, as well as helping in the definition of potential biomarkers.

Although bariatric and metabolic surgery (BS) has proved effective in the treatment of obesity based on the reduction in fat mass and the remission of comorbidities, there is also loss of lean mass after BS which could compromise muscle functionality. According to the European Working Group on Sarcopenia in Older People (EWGSOP), sarcopenia is a disease associated with loss of muscle mass, strength, and function. Through a comprehensive review of the literature, we identified a range of studies focusing on evaluating sarcopenia-related parameters according to the EWGSOP2 consensus criteria, before and after BS. Although most studies reported reductions in skeletal muscle mass and absolute muscle strength after surgery, improvements in muscle functionality were generally achieved, independent of the type of BS.

Childhood obesity increases the risk of developing metabolic syndrome later in life. Moreover, metabolic dysfunction may be inherited into the following generation through non-genomic mechanisms, with epigenetics as a plausible candidate. The pathways involved in the development of metabolic dysfunction across generations in the context of childhood obesity remain largely unexplored. We have developed a mouse model of early adiposity by reducing litter size at birth (small litter group, SL: 4 pups/dam; control group, C: 8 pups/dam). Mice raised in small litters (SL) developed obesity, insulin resistance and hepatic steatosis with aging. Strikingly, the offspring of SL males (SL-F1) also developed hepatic steatosis. Paternal transmission of an environmentally induced phenotype strongly suggests epigenetic inheritance. We analyzed the hepatic transcriptome in C-F1 and SL-F1 mice to identify pathways involved in the development of hepatic steatosis. We found that the circadian rhythm and lipid metabolic process were the ontologies with highest significance in the liver of SL-F1 mice. We explored whether DNA methylation and small non-coding RNAs might be involved in mediating intergenerational effects. Sperm DNA methylation was largely altered in SL mice. However, these changes did not correlate with the hepatic transcriptome. Next, we analyzed small non-coding RNA content in the testes of mice from the parental generation. Two miRNAs (miR-457 and miR-201) appeared differentially expressed in the testes of SL-F0 mice. They are known to be expressed in mature spermatozoa, but not in oocytes nor early embryos, and they may regulate the transcription of lipogenic genes, but not clock genes, in hepatocytes. Hence, they are strong candidates to mediate the inheritance of adult hepatic steatosis in our murine model. In conclusion, litter size reduction leads to intergenerational effects through non-genomic mechanisms. In our model, DNA methylation does not seem to play a role on the circadian rhythm nor lipid genes. However, at least two paternal miRNAs might influence the expression of a few lipid-related genes in the first-generation offspring, F1.