In a discovery that could reshape how metabolic diseases are understood and managed, researchers at the UF Health Cancer Center have found that silent genetic mutations in blood-forming stem cells — which naturally accumulate with age — may directly trigger obesity, type 2 diabetes, and fatty liver disease.
The study, published in the Journal of Clinical Investigation, challenges the prevailing notion that such metabolic conditions merely result in blood abnormalities.
Instead, it can play a causal role for blood stem cell mutations in the onset of chronic illnesses. The findings open avenues for early detection through routine blood tests, and potentially, preventive interventions based on an individual’s genetic risk profile.
“Most people don’t think about the blood as causing obesity and related diseases, but our surprising findings highlight that there’s a causal relationship between mutations in blood stem cells and metabolic diseases,” said Dr. Bowen Yan, lead author and Research Assistant Professor in the Department of Pharmacology and Therapeutics, UF College of Medicine.
As people age, hematopoietic stem cells in the bone marrow — responsible for producing blood cells — accumulate genetic mutations. While most of these changes are benign, some mutated cells begin to outcompete normal cells, a condition known as clonal hematopoiesis. This phenomenon, present in roughly 10% of older adults, has previously been linked to increased risk of blood cancers such as leukemia.
Earlier studies had suggested that obesity and metabolic disorders might contribute to the development of clonal hematopoiesis. However, the current research reverses that understanding.
“We found that blood cell mutations don’t just show up because of poor health — they can cause it,” said Dr. Yan.
To test this theory, the researchers introduced a clonal hematopoiesis-associated mutation into the blood system of otherwise healthy mice. The results were striking: mice with the mutation consumed more food, gained weight faster, developed elevated blood sugar levels, and showed signs of hepatic dysfunction.
When these mice were fed a Western-style diet, rich in fat and sugar, their condition worsened significantly — mirroring the trajectory of human metabolic diseases in real-world settings.
“Mutations in the blood system are driving these conditions,” said Dr. Olga Guryanova, senior author and Associate Professor in the Department of Pharmacology and Therapeutics.
“Clonal hematopoiesis is usually a silent condition, but if you know you have it, you’re better aware of the risks it’s associated with.”
She added that identifying such genetic risks early could enable personalised interventions — whether through dietary changes, lifestyle modifications, or targeted drug therapy.
The findings are especially significant as obesity has now surpassed smoking as the leading preventable risk factor for cancer globally. Researchers believe that by better managing obesity and metabolic disorders, it may be possible to mitigate downstream cancer risks as well.
“With the ability to predict the risk of obesity and metabolic disease and better manage it, we could also eventually mitigate the risk of developing cancer,” Dr. Guryanova noted.
The study was supported by funding from the National Institutes of Health, American Cancer Society, and several other institutions, with contributions from researchers at Queen’s University, Canada.
