Researchers using genetic engineering developed a mouse model that resisted weight gain and arterial disease, even when fed a high-fat diet. The study demonstrated that deficiency in a specific transcription factor, USF1, appears to protect against obesity, insulin resistance, and cardiovascular disease.
USF1, or upstream stimulatory factor 1, is a transcription factor known to affect triglycerides and cholesterol levels, having previously been linked to familial combined hyperlipidemia, a disease that increases blood fats and can cause early heart attacks and coronary artery disease in humans. The factor’s influence on cardiovascular and metabolic health, however, has not been studied.
Researchers investigated whether the gene and its deletion had a beneficial or detrimental effect on cardiometabolic health. Using mice as animal models, the researchers eliminated the USF1 gene and observed that these mice showed a blood lipid profile favorable to their overall heart health, with low levels of triglycerides, and high levels of high-density lipoprotein (HDL) cholesterol (“good cholesterol”).
The study, “USF1 deficiency activates brown adipose tissue and improves cardiometabolic health,” was published in the journal Science Translational Medicine.
Importantly, the scientists observed that, even on a high-fat diet, mice with USF1 gene deletion remained lean, while normal mice on the same diet nearly doubled their weight. After ruling out possible explanations, such as decreased food consumption, differences in nutrient absorption or increased physical activity, the researchers discovered that the mice had increased metabolic rates due to brown fat, whose activity was higher in mice lacking the gene.
Brown adipose tissue burns fat to generate heat and maintain the body’s normal temperature. In the study, even at normal temperatures, the brown fat of mice lacking USF1 was active, burning fat and sugar, and causing the mice to not gain weight even at high caloric intake. It also cleared fat and sugar from circulation, protecting arteries from vascular disease. Moreover, researchers observed that these mice had one-fourth fewer artery plaques compared to normal mice.
Interestingly, the researchers also analyzed population samples in Finland and found that individuals carrying gene variants that reduced the expression of USF1 demonstrated better cardiac and metabolic profiles, improved insulin sensitivity, and reduced atherosclerosis. Researchers believe that USF1 is a promising potential therapeutic target for metabolic and cardiovascular disease.