A hormone known for regulating energy balance also helps the body cope with influenza by triggering protective responses in the brain, a study led by UT Southwestern Medical Center researchers shows.

The findings, published in the Proceedings of the National Academy of Sciences, suggest that targeting this pathway could offer a new pharmacological approach for treating the flu.

“Our work demonstrates that FGF21, a stress-induced hormone that regulates whole-body metabolism, acts on the brain to protect against the hypothermia and weight loss caused by influenza infection,” said senior author Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology at UT Southwestern.

The study found that levels of fibroblast growth factor 21 (FGF21) rose in both humans and mice during flu infection. In mice, the hormone activated a brain region that regulates the noradrenergic nervous system, prompting heat production from tissues that help regulate body temperature in mice.

How FGF21 helps fight infection

This thermogenic response helped stabilize body temperature and improved the response to flu infection. Mice lacking FGF21 or its receptor in these neurons recovered more slowly, while treatment with pharmacologic FGF21 improved recovery.

The hormone did not change viral levels, indicating that it protects the body by mitigating the physiological stress of infection rather than directly targeting the virus. Collectively, these results suggest FGF21 could help the body respond more effectively to a range of infections, not just influenza.

“For serious cases of influenza infection, the care is mostly supportive,” Dr. Kliewer said. “Our findings suggest a new pharmacological approach for treating the flu. Further studies are required to determine if these findings are applicable to other infections.”

Building on decades of research

The research builds on decades of work from the Mangelsdorf/Kliewer Lab at UTSW, which previously identified FGF21 as a hormone produced by the liver in response to metabolic stresses such as fasting and alcohol exposure.

The new study extends that work to infection, showing that FGF21 uses the same liver-to-brain signaling pathway to help the body maintain metabolic balance during illness.

“These findings demonstrate that the immune system is not the only critical part of the response to infection,” said corresponding author Kartik Rajagopalan, M.D., Ph.D., Assistant Professor of Internal Medicine in the Division of Pulmonary and Critical Care Medicine and in Children’s Medical Center Research Institute at UT Southwestern.

“There are signals that are sent to the brain that reprogram metabolism for an optimal response.”

Collaboration and clinical implications

The work was a collaboration among UT Southwestern’s Departments of Pharmacology, Molecular Biology, and Internal Medicine, bringing together expertise in infection, endocrinology, and neuroscience. It also engaged trainees at multiple levels, including postdoctoral and clinical fellows, and incorporated human data showing that FGF21 levels rise during influenza infection.

“This project highlights the power of integrating basic and clinical research, which is a defining strength of UT Southwestern,” Dr. Kliewer said. “There are very few places where a project like this could have blossomed. We’re fortunate that UT Southwestern is one of them.”