In the pediatrician’s office, the same scene often plays out: An 8- or 10-year-old child comes in with the family because of being overweight or obese. Conversations typically focus on diet, sedentary behavior, school schedules, and family environment. However, research suggests that it may be necessary to look back further. Obesity does not always develop when excess body weight is present. In some cases, risk may begin before birth, during pregnancy, through interactions among fetal metabolism, epigenetics, the microbiome, and the prenatal environment.

This shift in perspective is changing how researchers understand one of the major public health challenges of the 21st century. For years, obesity has been largely attributed to lifestyle habits. Current research suggests that some of the risks for childhood obesity may begin during pregnancy and the earliest years of life.

This approach is part of the developmental origins of health and disease framework, which examines how environmental conditions during pregnancy and early life, including nutrition, stress, and exposure to toxins, can influence the risk for chronic diseases later in life, including obesity, diabetes, and cardiovascular disease. During critical periods of development, the body responds to environmental signals that can shape metabolic functions and increase or reduce vulnerability to conditions, such as obesity.

Umbilical Proteins and Early Gut Bacteria

The possibility that obesity risk could be traced back to birth was once difficult to establish. However, a recent study has provided some of the strongest longitudinal evidence to date. The study was published in mSystems and followed up with 16,600 participants over 26 years. Researchers found that certain biological signatures present at birth, together with the composition of the early gut microbiota, were associated with a higher risk of developing obesity decades later.

After birth, another process begins in the gut, which may influence the risk for obesity. Colonization of the gut microbiota begins at birth and is influenced by factors such as the mode of delivery, breastfeeding, antibiotic exposure, and the surrounding environment. During this period, interactions among the developing microbiota, metabolism, and immature immune system may help shape metabolic health.

The study also found that the gut microbiota composition during the first year of life was associated with obesity risk decades later. Researchers identified microbial patterns associated with changes in bile acid signaling, a metabolic pathway involved in fat storage, glucose regulation, and insulin sensitivity.

The findings do not suggest that there is a single “obesity microbiota.” Rather, certain bacterial communities may form part of a broader biological system involved in metabolic regulation from the earliest stages of development.

Speaking with El Médico Interactivo, part of the Medscape Professional Network, Angelica Ahrens, PhD, from the Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, College of Agricultural and Life Sciences, University of Florida, in Gainesville, said, “The finding does not mean that obesity is predetermined or inevitable. What we see is measurable biological vulnerability from the earliest stages of life. The findings cannot predict with certainty who will develop obesity, she added, but they reveal biological differences that can be detected from birth.”

One of the key findings of this study was that umbilical cord blood contains proteomic signatures associated with future metabolic risk. One of the biomarkers was angiopoietin-like 4 (ANGPTL4). Higher ANGPTL4 levels in cord blood were associated with later obesity, and this association persisted after adjusting for maternal BMI. This suggests that the finding was not explained solely by maternal adiposity and may reflect the biological characteristics present in the newborn.

Parental BMI remains an important predictor of future obesity. However, adding these early biological signatures improved the ability to identify long-term risk trajectories, suggesting that information from umbilical cord blood may provide additional predictive value beyond established family factors.

These findings challenge the idea that obesity is simply a matter of individual willpower. “When a person has obesity, we think it is their fault, and that is not the case,” said María del Mar Malagón Poyato, PhD, deputy scientific director of the Maimonides Biomedical Research Institute of Córdoba and former president of the Spanish Society for the Study of Obesity (SEEDO). “Metabolism makes it easier to maintain obesity.”

Pregnancy Effects

If obesity risk can be traced back to birth, pregnancy may play an important role in shaping metabolic health. Pregnancy is a dynamic metabolic environment in which the fetus receives and responds to signals from the maternal environment that can influence future development.

A study by researchers from the Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center, University of Oviedo, Oviedo, and the INCLIVA Health Research Institute, a biomedical research institute in Valencia, both in Spain, identified persistent molecular changes in newborns of mothers with obesity and gestational diabetes. The study showed that the intrauterine environment can leave lasting epigenetic marks that may alter the regulation of genes involved in energy metabolism and mitochondrial bioenergetics.

The lead researcher, Juan José Alba‑Linares, said, “Epigenetic marks persisted after birth supports the possibility that metabolic risk can be programmed very early in life. It is not a destiny written in stone but a biological biography with more than one page already written when the child comes into the world,” he said.

Epigenetics does not alter the DNA sequences. Instead, they change the manner in which certain genes are activated or silenced in response to environmental conditions.

This distinction shifts the focus from genetic inheritance alone to the interaction between biology and the environment during a particularly sensitive developmental period.

Multiple Causes

A multi-omics analysis of more than 800 European children further supports the view that childhood obesity does not follow a single biological pathway. The analysis incorporated DNA methylation, microRNA, messenger RNA, proteins, metabolites, and environmental exposure during early childhood.

Published in Nature Communications, the study linked maternal obesity and gestational diabetes with changes in the regulation of genes involved in energy metabolism and inflammation in children. Researchers also identified different biological profiles associated with varying risks for obesity and metabolic complications.

During fetal development, the body responds to signals from the maternal environment and accordingly adjusts its metabolic development. The analysis found that some risk profiles were associated with industrial compounds, others with heavy metals such as mercury, and others with combinations of metabolic and inflammatory markers.

This perspective moves beyond the traditional view of obesity as a condition that is primarily influenced by diet and physical activity. Risk may also be shaped by environmental exposure, socioeconomic conditions, and the biological environment during pregnancy. Pregnancy transmits genes but also exposes the developing fetus to a broader biological and environmental context.

Brain Development

Gut and metabolism function together. Growing evidence suggests that metabolic programming also involves neural circuits that regulate hunger and satiety.

A review in Endocrine Reviews described how the metabolic environment during fetal development influences the maturation of the hypothalamus, the brain region responsible for regulating appetite and energy expenditure. Conditions such as maternal obesity and gestational diabetes can alter hormonal and metabolic signals that reach the fetus. Leptin and insulin are among the signals involved in the maturation of hypothalamic circuits.

Changes during this period may have affected later responses to hunger and satiety. These neural circuits can respond to food-related cues before nutrients reach the stomach. 

Before Eating

Recent studies have shown that the brain can anticipate food intake and prepare the body before eating begins.

One study identified a mechanism in animal models in which certain hypothalamic neurons use glycogen stored in glial cells to activate when food is detected. Simply seeing or smelling food is sufficient to trigger an anticipatory metabolic response that prepares the body for feeding.

When researchers blocked this mechanism, animals lost the ability to anticipate food intake. When subsequently exposed to a high-fat diet, they were more likely to develop obesity and insulin resistance.

Another study published in Nature Metabolism showed that neural circuits involved in satiety can be activated by sensory stimuli before nutrients reach the intestine. The findings suggest that the brain can anticipate the energy it is about to receive and adjust appetite-related signals in advance.

Both studies were conducted in animal models; therefore, the findings cannot be directly extrapolated to humans. However, they provide a possible mechanistic explanation for how the brain anticipates food intake and prepares the body to maintain energy balance.

This view is consistent with the gut-brain axis, a bidirectional communication system through which gut microbes, metabolic byproducts, and immune signals influence brain function, while the brain simultaneously affects gut motility and environment. This axis is an important area of research on how obesity develops from the earliest stages of life.

Early Prevention

Obesity risk may be shaped during pregnancy and early childhood; however, this does not mean that obesity is determined before birth. The evidence instead points to varying levels of biological vulnerability that interact with factors throughout life, including diet, physical activity, family environment, socioeconomic conditions, and access to healthcare.

Early biological programming did not replace lifestyle factors or indicate that obesity was inherited. Rather, it suggests that prevention may need to begin before excess weight develops, with attention to maternal health, pediatric follow-up, and early identification of risk factors.

The SEEDO calls for a continuous, multidisciplinary, and stigma‑free approach to obesity care. The Spanish GIRO Guidelines promote person‑centered management that moves away from simplistic messages focused only on willpower or weight loss.

Albert Lecube, MD, PhD, head of the Section of the Endocrinology and Nutritional Department at Vall d’Hebron University Hospital in Barcelona, Spain, and former vice president of SEEDO, described obesity as a “chronic, complex, relapsing disease” driven by multiple biological and environmental factors and requiring a comprehensive approach.

When Does the Risk for Obesity Begin?

Research on metabolic programming aims to understand how biology and the environment interact and identify opportunities for earlier, more personalized prevention rather than labeling newborns.

Perhaps, in a few years, a pediatric visit will include a broader discussion of obesity risk. Instead of focusing only on a child’s diet and physical activity, clinicians may also consider pregnancy, early life, and family metabolic health. The aim is to understand when obesity risk begins and identify opportunities for prevention before excess weight develops, rather than to assign blame. If obesity risk can begin long before a child develops eating habits, prevention may also need to begin long before the first diagnosis.

This article was translated from El Médico Interactivo.