Enhancing FGF21 in Fat Tissue Extends Lifespan in Obese Mice by 26%

Researchers at the University of Texas Southwestern Medical Center have discovered that increasing the production of fibroblast growth factor 21 (FGF21) specifically in the fat tissue of adult male mice can significantly prolong their lifespan, even under a sustained high-fat diet. This achievement was notable because it extended lifespan without associated negative effects such as slowed growth or decreased bone density.

Obesity, affecting approximately 35% of Americans over 65, combined with aging, increases the risk of conditions like insulin resistance, fatty liver disease, and other chronic ailments. FGF21, a hormone primarily produced by the liver, has garnered attention due to its role in regulating metabolism across various tissues. Previous studies indicated that FGF21 could improve insulin sensitivity, reduce lipid accumulation in the liver, and promote longevity pathways. However, earlier models that expressed FGF21 continuously from birth faced developmental issues like dwarfism.

In this new study, published in Cell Metabolism, scientists engineered mice with a doxycycline-inducible system that overexpressed FGF21 exclusively in fat tissue during adulthood. The mice, initiated at 10-12 weeks old, were fed a high-fat diet supplemented with doxycycline to activate FGF21 expression in adipocytes, including epididymal and subcutaneous white fat, as well as brown adipose tissue. The research involved comprehensive assessments including body weight, calorimetry, glucose and insulin tolerance, serum lipid levels, liver histology, bone density, immune profiling, and lipidomics.

The results showed an average increase in median lifespan of approximately 26%, with transgenic mice living up to 3.3 years compared to 1.77 years in controls. These mice exhibited higher energy expenditure, increased locomotor activity when young, and maintained better insulin sensitivity, lower fasting glucose, and reduced triglycerides and cholesterol levels as they aged. Notably, body weight remained significantly lower, with a higher proportion of lean mass relative to fat, yet no evidence of bone loss.

Histological analysis revealed reductions in liver fat accumulation and smaller, less inflamed fat cells. Flow cytometry indicated a shift toward anti-inflammatory macrophages in the fat, and lipidomic profiling found lower levels of ceramides—lipids associated with insulin resistance and cell apoptosis—in visceral fat and serum. These effects persisted even in mice lacking adiponectin, suggesting a direct role of FGF21 that does not depend on this hormone.

The findings support the potential of fat-specific FGF21 elevation as a strategy to enhance metabolic health and longevity in obesity-related conditions, highlighting its ability to combat inflammation and harmful lipid accumulation without impairing growth. While promising, translation of these results to humans remains uncertain, and further studies are necessary to evaluate potential therapeutic applications.