Reducing maternal weight improves offspring metabolism and alters (or modulates) methylation

The rapid rise in obesity over the past few decades worldwide challenges our generation to develop effective strategies to prevent and treat obesity and associated metabolic complications, such as type 2 diabetes and cardiovascular disease. Obesity is clearly aggravated by our increasingly sedentary lifestyle, decreased physical fitness, and increased intake of calorie-dense foods during both childhood and adult life, all of which promote energy excess. However, despite this obesogenic environment, not all individuals develop obesity. Such differences in susceptibility can be linked, in part, to interindividual variation in DNA sequence (1). Some individuals may have a permissive genetic landscape favoring energy storage, a beneficial phenotype when energy supply was limited or intermittent (as in previous human history throughout the millennia), but which has now become counterproductive in modern society. Guénard et al. now provide striking evidence that intrauterine environmental exposures are critical—and potentially modifiable—mediators of obesity risk in humans (2). Specifically, surgically induced reduction in body weight in a woman of reproductive age can reduce obesity in her children, potentially via epigenetic mechanisms.

A large body of evidence indicates that early-life environmental exposures, both during intrauterine and early postnatal life, can be potent mediators of risk for obesity, a concept termed “developmental origins of disease” or disease “programming.” Both human and animal models have demonstrated that exposure of a growing fetus or baby to a suboptimal intrauterine environment, induced by factors such as maternal overnutrition or undernutrition, diabetes, insulin resistance, placental dysfunction, glucocorticoids, or hypoxia, can increase risk for obesity, cardiovascular disease, and type 2 diabetes during adult life (3). This effect has been demonstrated most clearly in the case of maternal diabetes in humans, in which exposure to hyperglycemia during pregnancy increases adiposity in offspring and increases their risk for obesity and type 2 diabetes during adult life, compared with siblings born before maternal diabetes developed (4). Similar relationships have been observed for maternal obesity, excessive gestational weight gain, excessive neonatal growth and adiposity, and risk for type 2 diabetes (5). Some estimates suggest that nearly half of type 2 diabetes in youth may be attributable to exposure to maternal diabetes and obesity (5). Thus, maternal obesity may fuel a vicious cycle of risk for children and even grandchildren, accelerating the obesity epidemic.

An important question is whether interventions that reduce obesity and improve the metabolic health of the mother will have long-lasting impact on the health of the child. One strategy would be to promote maternal weight loss before conception, to reduce fetal exposure to an obesogenic maternal environment. Unfortunately, traditional “diet and exercise” approaches do not often achieve robust and sustained weight loss. In contrast, surgical approaches have emerged as an effective (yet admittedly complex) strategy to promote durable weight loss, improve insulin resistance, and improve or reverse type 2 diabetes (6), and thus provide a population in which we can evaluate the impact of maternal weight loss before pregnancy.

Biliopancreatic diversion with duodenal switch (BPD) is a highly effective procedure that combines elements of restriction and extensive bypass of the proximal and midgut. Although chronic micronutrient malabsorption has reduced implementation of this procedure in favor of gastric bypass, adjustable gastric banding, and sleeve gastrectomy, the analysis of women who underwent BPD in the past provides a unique opportunity to study the impact of this procedure on the health of their children. Kral et al. previously compared the prevalence of overweight and obesity among siblings born to mothers before or after they were treated with biliopancreatic diversion (7). Children born a mean of 6 y after obesity surgery had a 52% relative decrease in the prevalence of obesity, compared with children born before maternal surgery; these relationships remained even when only age-matched children were examined. Offspring obesity was related to maternal presurgical body mass index (BMI), consistent with high penetrance of obesity in families, and tended to be linked to gestational weight gain. Reductions in obesity and overweight in children born after maternal surgery were also observed, even in a subgroup of women who had lost substantial weight but remained severely obese at the time of conception (BMI 41), compared with BMI-matched women before surgery. Further follow-up studies also documented improved insulin sensitivity, lipid profile, and inflammatory markers in offspring born after maternal surgery (8). Similar reductions in BMI were also observed in an independent cohort of 21- to 25-y-old offspring born after maternal surgery (9). Despite the concern that maternal weight loss might cause child undernutrition, particularly if pregnancy is initiated soon after bariatric surgery, no significant increases in low birth weight or other adverse outcomes were detected. In the article by Guénard et al., the authors report that offspring born after maternal surgery also had reduced waist and hip circumference, blood pressure, and fasting insulin levels, even after adjustment for age and pubertal status. These provocative data suggest that improving metabolism or limiting excessive gestational weight gain in obese women, even without completely normalizing maternal BMI, can reduce obesity risk in offspring.

What mechanisms are responsible for these improvements in offspring health as a result of maternal weight loss? Purely genetic factors should not differ, on average, in siblings conceived postsurgery vs. presurgery. Thus, both intrauterine and postnatal environmental influences must also have potent effects on child obesity. Net energy balance does not differ following biliopancreatic diversion (10), but the chronic lipid malabsorption, which develops postoperatively, may contribute to sustained weight loss, improved β-cell function, and reduced insulin resistance (10, 11). Because maternal insulin resistance, even in the absence of obesity or hyperglycemia, can alter lipid metabolism and increase early-life adiposity in mice (12, 13), normalization of maternal insulin resistance may be beneficial. Weight gain during pregnancy, which is linked to offspring obesity risk (14), is also reduced in postbariatric surgical pregnancies (15, 16). In addition, early childhood weight gain, another marker of obesity risk (17, 18), could be reduced if the postsurgical mother promotes healthier food choices and a more active lifestyle for the entire family.

If early-life exposures confer disease risk during adult life, the molecular mechanisms mediating these effects are likely to be durable. For example, a suboptimal metabolic environment during key windows of fetal development may alter size and structure of organs (19, 20) or reduce the number or function of stem cell populations (21). Similarly, environmentally induced epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNAs, may result in dysregulation of transcriptional responses to future environmental cues. For example, differences in DNA methylation at the insulin-like growth factor 2 locus has been observed in individuals exposed to prenatal famine (22), and methylation at the retinoid X receptor-α locus in umbilical cord samples has been linked to childhood obesity (23).

In their article, Guénard et al. (2) assess DNA methylation in genomic DNA isolated from circulating leukocytes in offspring born before or after maternal bariatric surgery. Using a microarray-based strategy, differential methylation was identified in 3% of CpG sites, after appropriate correction for multiple comparisons. Interestingly, pathway analysis of 5,698 genes adjacent to differentially methylated probes indicated that pathways linked to inflammation and metabolic disease were overrepresented. For genes within these pathways, there were modest correlations between whole-blood gene expression and methylation marks; very robust correlations were observed for a small number of selected loci.

Although these methylation data are interesting, multiple questions remain. Do differentially methylated loci truly result from early-life environmental exposures? Do such epigenetic marks alter transcriptional responses, particularly within inflammatory and metabolic pathways, and thus contribute to the primary pathogenesis of obesity? Or are they secondary to obesity, which was already present in presurgical offspring at the time of sample collection (24)? Does differential methylation in circulating leukocytes reflect patterns in specific tissues or the influence of age and pubertal stage, which differed between groups in this population (25)? To what extent do DNA sequence differences (26) and variability in leukocyte populations contribute to differences in methylation patterns in siblings born before and after maternal surgery? Is methylation the best marker of epigenetic dysregulation? The answers to these important questions will require detailed longitudinal studies in both animal models and in human children.

More broadly, these data provide optimism that efforts to reduce maternal obesity and improve metabolism will have long-lasting health benefits for both mother and child. Additional testing is needed to determine if the beneficial effects of BPD on offspring outcomes will also be observed after less-robust weight loss, as with the bariatric procedures more commonly used in clinical practice today or lifestyle modification strategies. We also need to be careful not to swing the pendulum too far in the opposite direction; maternal nutrient deprivation could also worsen fetal outcomes, a concern prompting current guidelines that pregnancy should be deferred for several years after bariatric surgery. Nevertheless, these data underscore the importance of public health efforts directed toward optimizing body weight and metabolism in women of reproductive age, preferably before conception. Even after conception, careful attention to optimizing maternal weight gain during pregnancy and early postnatal life may reduce the impact of maternal obesity on offspring obesity risk. More importantly, such interventions may help to interrupt the vicious intergenerational cycles of obesity likely contributing to the worldwide obesity epidemic (Fig. 1).