Pitt Researchers Identify Key Enzymes That Help Promote Fat Loss While Preserving Muscle

Study shows HDAC6 inhibitors act through FAK and PYK2 enzymes in the brain to restore leptin sensitivity and reduce obesity.

Feb. 4, 2026 at 7:23pm

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A team of scientists at the University of Pittsburgh School of Medicine has uncovered a critical mechanism that could pave the way for safer and more effective obesity treatments. The researchers found that HDAC6 inhibitors, a class of drugs, act through two enzymes - FAK and PYK2 - in the hypothalamus, the brain region that controls eating behavior, to restore leptin sensitivity and reduce body weight in obese mice without causing loss of lean muscle mass, a common side effect of current obesity medications.

Why it matters

Leptin resistance is a major barrier to treating obesity, as it prevents the brain from recognizing satiety signals, leading to persistent overeating and weight gain. Current obesity medications have limitations, including gastrointestinal side effects and loss of lean muscle mass. This discovery of HDAC6 inhibitors' mechanism of action offers a promising alternative approach that primarily reduces fat mass while preserving lean tissue, a critical advantage for long-term metabolic health.

The details

The research builds on earlier findings that HDAC6 inhibitors can restore leptin sensitivity and reduce body weight in obese mice. The new study demonstrates that these drugs act through the FAK and PYK2 enzymes in the hypothalamus. When researchers blocked or genetically removed these enzymes, the weight-reducing effect of HDAC6 inhibitors disappeared and leptin signaling was severely impaired. The study suggests that HDAC6 inhibitors act indirectly by triggering a signal from adipose tissue to the hypothalamus, and researchers hope to identify this molecule as a potential therapeutic target.

  • The findings were published on February 5, 2026 in Nature Communications.

The players

Işın Çakır

An assistant professor of endocrinology and metabolism at the University of Pittsburgh School of Medicine and the senior author of the study.

Luca Galgano

A co-author of the study, also from the University of Pittsburgh.

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What they’re saying

“Leptin resistance is a major barrier to treating obesity. By understanding this phenomenon, we can explore how it may be safely reversed.”

— Işın Çakır, Assistant Professor of Endocrinology and Metabolism (upmc.com)

“HDAC6 inhibitors offer a promising alternative. In animal studies, these compounds primarily reduce fat mass while preserving lean tissue, a critical advantage for long-term metabolic health.”

— Işın Çakır, Assistant Professor of Endocrinology and Metabolism (upmc.com)

What’s next

Pharmaceutical companies are actively exploring HDAC6 inhibitors for conditions ranging from neurodegenerative diseases to cardiovascular disorders. Additionally, more work is needed to optimize these compounds for metabolic disorders while minimizing toxicity.

The takeaway

This discovery exemplifies Pitt Health Sciences' commitment to bridging fundamental biology with translational impact, as it moves beyond molecular insight to inform future strategies for treating obesity and related metabolic disorders by identifying a promising new approach that can promote fat loss while preserving muscle mass.