Why do some people with obesity remain relatively healthy, while others develop serious complications such as diabetes, hypertension, or heart disease? The answer may lie in genetic differences, according to a major new study published in Nature Medicine.
An international team led by researchers at the Icahn School of Medicine at Mount Sinai in New York and the University of Copenhagen in Denmark analysed genetic data from over 452,000 people. They discovered genetic variants in 205 regions of the genome that are linked to higher body fat but surprisingly better metabolic health.
The researchers built a genetic risk score based on these variants. People with higher scores were more likely to develop obesity but were also less likely to face obesity-related complications such as high blood pressure, diabetes, or high cholesterol. This protective effect stems partly from differences in how fat cells behave in different individuals.
Importantly, these genetic benefits were observed even in children. Kids carrying protective variants tended to gain weight but did not display early warning signs of metabolic disease.
“Obesity is not a single condition , it is made up of different subtypes, each with its own risks,” explained Nathalie Chami, Instructor of Environmental Medicine and Artificial Intelligence and Human Health at Mount Sinai. “By uncovering these genetic differences, we can start to understand why obesity leads to different health outcomes in different individuals. This could eventually change how we predict, prevent, and treat obesity and its complications.”
The study went further to identify eight distinct obesity subtypes, each associated with unique health outcomes. This classification may help doctors identify patients most at risk of complications and even inspire treatments that mimic the protective effects of these genes.
However, the team cautioned that the findings do not mean obesity is harmless. “Most people with obesity still face health challenges, and lifestyle factors such as diet and exercise remain critical for overall health,” noted Zhe Wang, Assistant Professor at the University of Alabama at Birmingham.
The study drew on data from the UK Biobank, which includes individuals of European ancestry, and used a comprehensive genome-wide screening approach. The researchers analysed three adiposity-related traits and eight cardiometabolic traits covering blood pressure, glucose, and lipid levels.
Future research aims to extend these findings to more diverse populations. By doing so, scientists hope to better understand biological pathways that separate obesity from its related diseases and translate those insights into more personalised healthcare strategies.
According to Ruth Loos, Professor at the University of Copenhagen, these findings could transform obesity management. “By revealing new biological pathways that separate obesity from related diseases, the findings may pave the way for more personalised care, better-targeted therapies, and earlier prevention strategies, even from childhood,” she said.
The research underscores that obesity is not a uniform condition but a spectrum influenced by genetics, environment, and lifestyle. While some genetic variants offer protection, researchers stress that maintaining healthy habits remains vital to reduce long-term risks.
