Norwegian Study Finds Obesity Mechanisms with Potential to Treat Early in Life

By Carol Morton

2 June 2022. The early weight gain that puts chubby cheeks on plump infants has little in common with adult obesity, report Norwegian researchers who investigated the changing genetic landscape of early childhood growth.

But a stronger genetic signature of early obesity risk gradually emerges as infants transform into children, the team recently reported in Nature Metabolism.

The findings come from a detailed study of 30,000 children and their parents in the Norwegian Mother, Father and Child Cohort Study (MoBa). The results highlight normal phases of growth, as well as several biological pathways related to appetite and energy metabolism.

Genetic variants may skew these pathways to put some children at early risk of obesity. Genetic risk scores may help identify groups of children who can benefit from early tailored intervention.

"Kids grow extremely dynamically," said senior author Stefan Johansson, professor at the Center for Diabetes Research, University of Bergen (UiB). By about 9 months, infants quickly double in weight to their maximum body mass index (BMI), known as the adiposity peak. Then their limbs lengthen, and their BMI dips to a minimum at ages 5 or 6 years.

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        Stefan Johansson and Pål Njølstad​

Johansson and his colleagues wondered if the same genes that govern the spurts of childhood growth are related to adult health, especially obesity and its health complications. "The overarching questions are: How do genes shape weight development in early childhood, and can we identify patterns that predict future obesity?" said Johansson, who also is a subject in the MoBa cohort, with his wife and two of his three children.

To answer these questions, first authors Øyvind Helgeland and Marc Vaudel at UiB performed genome-wide association studies (GWAS) of 12 points in time from birth to 8 years (birth; 6 weeks; 3, 6, and 8 months; and 1, 1.5, 2, 3, 5, 7, and 8 years).

      Øyvind Helgeland and Marc Vaudel

They found 46 common variants influencing BMI across early life, including 29 novel ones that have not been found in adult obesity studies. They sorted these into four distinct times of influence on body mass, which loosely line up with phases of early growth—newborn (birth cluster), infant (transient cluster), toddler (early rise cluster), and childhood (late rise cluster) growth.

The identified variants clustered near known monogenic obesity genes, and genes involved in appetite and energy regulation. The team also found "multi-signal association near genes coding important proteins/drug targets like LEPR and GLP1R," Vaudel tweeted when the preprint was first posted at medRxiv.

The researchers showed that adult-based polygenic risk scores (PRS) may identify children at higher risk of obesity from age 5. The authors also developed age-specific risk scores to help estimate obesity risk in younger children.

"We compared how PRSs trained at different ages fare during early growth, showing how birth weight effects wane while adult BMI take off," said Vaudel. "But only home-grown age-resolved scores could explain the variance around adiposity peak."

In further analysis, the team looked at parental effects, especially how quickly maternal effects disappear after birth. Two loci stood out, displaying a transient association with the maternal transmitted allele only. The maternal variants were associated with body mass early in life and type 2 diabetes later in life.

Pål R. Njølstad, a co-senior author who heads the UiB Center for Diabetes Research, summed up the findings in a news release: "It turned out that genes linked to extreme obesity, appetite, and the body's energy consumption are responsible for the growth regulation," he said.

"This is dynamic in that specific genes have an effect only on some of the different phases of growth," Njølstad said. "We believe that this is probably one of the reasons why parents have always noted that some children are born with a naturally higher appetite than others and have significantly more fat mass in infancy. It seems that these dynamic effects are especially important in the first years of life, and that they do not increase the risk of later obesity."

Rates of childhood obesity are rising, note the authors of an accompanying commentary. Most children classified as obese by age 3 continue to be obese as adolescents, which in turn increases the risk of severe obesity in adulthood.

"Thus, prevention of obesity during early childhood may be crucial for preventing health complications of obesity later in life, including type 2 diabetes, hypertension, and other cardiovascular diseases, and several cancers," write Carolina Downie and Kari North of the University of North Carolina, USA.

The polygenic risk scores (PRS) are a promising tool for early identification of disease risk, Downie and North write. "With the adult BMI-PRS identifying children at higher risk of obesity as early as 5 years old, these findings have important implications for precision medicine and may be used to target prevention and treatment options."