Scientists have discovered two distinct types of obesity with physiological and molecular differences that may have lifelong implications for health, disease, and drug response. The study, published in Nature Metabolism, offers a more nuanced understanding of obesity than current definitions and may provide more accurate ways to diagnose and treat obesity and related metabolic disorders. The results also reveal new details about the role of epigenetics and provide insight into the link between insulin and obesity.
About two billion people worldwide are considered overweight and there are over 600 million people with obesity. Currently, obesity is diagnosed using body mass index (BMI), an index correlated to body fat generated by comparing weight and height. However, it does not consider factors such as muscle mass, bone density, age, sex, or ethnicity, which can lead to misrepresentation of a person’s health status.
Using a combination of laboratory studies on mouse models and data analysis from TwinsUK, a study cohort developed in the UK, the researchers discovered four metabolic subtypes that affect individual body types: two prone to leanness and two prone to obesity.
One obesity subtype is characterized by greater fat mass while the other was characterized by both greater fat mass and lean muscle mass. Unexpectedly, the team found that the second type of obesity was also associated with increased inflammation, which may increase the risk of certain cancers and other diseases. Both subtypes have been observed in several study cohorts, including children. These findings are an important step in understanding how these different types affect disease risk and treatment response.
Obesity subtypes in a mouse model
After identifying the subtypes in the human data, the team verified the results in mouse models. This approach allowed the scientists to compare genetically identical individual mice raised in the same environment and fed the same amounts of food. The study found that the inflammatory subtype appears to result from epigenetic changes that were triggered purely randomly. They also found that there did not seem to be any middle ground, meaning genetically identical sibling mice grew or stayed smaller, with no gradient between them. A similar pattern was seen in data from more than 150 pairs of human twins, each of which was genetically virtually the same.
The laboratory results were consistent with data from human twins. They again saw two distinct subtypes of obesity, one of which appeared to be epigenetically “triggered” and characterized by higher lean mass and fat, strong inflammatory signals, high insulin levels, and a strong signature epigenetics.
Unexplained phenotypic variation and epigenetics
Depending on the calculation and traits in question, only 30-50% of human trait results can be linked to genetic or environmental factors. This means that half of who we are is governed by something else. This phenomenon is called unexplained phenotypic variation (UPV) and offers both a challenge and untapped potential.
The study indicates that the roots of UPV likely lie in epigenetics, the processes that determine when and to what extent instructions in DNA are used. Epigenetic mechanisms are the reason that individuals with the same genetic blueprint, like twins, can develop different traits such as eye color and hair color. Epigenetics also offers tantalizing targets for precision treatment. Epigenetics can act as a light switch that turns genes on or off, which can promote health or disease.
Yang CH et al. Independent phenotypic plasticity axes define distinct obesity sub-types. Nat Metab. 2022 Sep 12. doi: 10.1038/s42255-022-00629-2. Epub ahead of print. PMID: 36097183. https://www.nature.com/articles/s42255-022-00629-2