A team of scientists has uncovered a critical mechanism that could pave the way for safer and more effective obesity treatments. The findings, published today in Nature Communications, shed light on how leptin, a hormone that regulates appetite and energy balance, works in the brain.
Produced by fat tissue, leptin normally signals the brain to suppress hunger and increase energy expenditure. In obesity, this signaling breaks down, despite high levels of circulating leptin. This leptin resistance prevents the brain from recognizing satiety signals, which can lead to persistent overeating and weight gain.
“Leptin resistance is a major barrier to treating obesity,” said senior author Işın Çakır, Ph.D., assistant professor of endocrinology and metabolism at the University of Pittsburgh School of Medicine. “By understanding this phenomenon, we can explore how it may be safely reversed.”
The research builds on earlier findings that drugs called HDAC6 inhibitors can restore leptin sensitivity and reduce body weight in obese mice. Until now, the central mechanism behind this effect was unclear.
The new study demonstrates that HDAC6 inhibitors act through two enzymes – FAK and PYK2 – in the hypothalamus, the brain region that controls eating behavior. When researchers blocked or genetically removed these enzymes, the weight-reducing effect of HDAC6 inhibitors disappeared and leptin signaling was severely impaired.
Current obesity medications, such as GLP-1 agonists, have transformed treatment but come with limitations, including gastrointestinal side effects and loss of lean muscle mass. Patients tend to mostly regain fat after discontinuation of these medications, but not lean muscle mass, which could leave them in worse health than before they started the medications.
“HDAC6 inhibitors offer a promising alternative,” said Çakır. “In animal studies, these compounds primarily reduce fat mass while preserving lean tissue, a critical advantage for long-term metabolic health.”
The study suggests that HDAC6 inhibitors act indirectly by triggering a signal from adipose tissue to the hypothalamus. Researchers hope to identify this molecule, which could become a novel therapeutic target.
