Advancing Leptin Research to Combat Obesity - Understanding the Brain’s Role in Weight Regulation
March 13, 2025
Isin Cakir, PhD, is an assistant professor in the Division of Endocrinology and Metabolism at the University of Pittsburgh. Before joining the faculty in January 2024, he was a research investigator at the University of Michigan’s Life Sciences Institute. He earned his PhD from Brown University in 2010 and has since dedicated his research to understanding how the brain regulates body weight and food intake, with a focus on energy metabolism and leptin function.
Leptin is a hormone secreted by fat cells that communicates with the brain — primarily the hypothalamus — to regulate hunger and energy expenditure. In individuals with obesity, leptin signaling is often disrupted leading to a state of leptin resistance. This resistance prevents the brain from recognizing satiety signals, which can lead to persistent overeating and weight gain.
“Our work centers on understanding why leptin resistance occurs and how we can reverse it to restore the body's natural ability to regulate weight,” says Dr. Cakir.
Investigating Leptin Sensitization Mechanisms and Potential Therapeutic Targets
Dr. Cakir’s research focuses on leptin sensitizers, which are small molecules that enhance the body’s response to leptin. His lab is working on two promising classes of compounds.
The first are histone deacetylase 6 HDAC6 Inhibitors, which are compounds that block histone deacetylase 6 (HDAC6), an enzyme linked to leptin resistance. In preclinical models, HDAC6 inhibitors restore leptin’s effects, leading to reduced food intake and weight loss.
Another area of study involves activating nuclear factor erythroid 2-related factor 2 (NRF2), a protein that regulates cellular defense mechanisms. One NRF2 activator, sulforaphane — a natural compound found in cruciferous vegetables like broccoli and Brussels sprouts — has been shown to reverse leptin resistance in animal models.
“Both of these approaches target different pathways but ultimately lead to the same outcome —reduced food intake and weight loss in obese mice,” says Dr. Cakir.
His research also explores how metabolic signals from peripheral tissues influence leptin sensitivity. The lab is investigating systemic factors secreted by muscle and fat tissue to determine whether they can be harnessed for therapeutic intervention.
Findings on HDAC6 Inhibition and Leptin Sensitivity
One of Dr. Cakir’s recent publications titled, “Histone Deacetylase 6 Inhibition Restores Leptin Sensitivity and Reduces Obesity,” demonstrated that inhibiting HDAC6 significantly improves leptin sensitivity in diet-induced obese mice. The study found that HDAC6 inhibitors, such as tubastatin A, reduced food intake, fat mass, and liver fat accumulation while improving glucose metabolism. These effects were observed specifically in obese mice, suggesting that HDAC6 inhibition selectively restores leptin signaling under conditions of hyperleptinemia.
The research also identified that HDAC6 inhibition did not affect lean mice, further reinforcing its potential as a targeted therapeutic strategy for obesity. Additionally, tubastatin A was ineffective in mice with defective leptin-melanocortin signaling, such as db/db and MC4R-KO mice, indicating that the compound’s effects depend on intact leptin receptor function.
“Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent,” says Dr. Cakir. “This finding supports the idea that leptin sensitizers may work by modulating peripheral metabolic signals rather than directly altering brain function.”
Findings on Sulforaphane as a Leptin Sensitizer
Another study led by Dr. Cakir, “Sulforaphane Reduces Obesity by Reversing Leptin Resistance,” examined how NRF2 activation influences obesity and metabolism. His team found that sulforaphane, a potent NRF2 activator, enhances leptin sensitivity and promotes weight loss in diet-induced obese mice. Sulforaphane did not affect weight or food intake in lean mice but significantly reduced body weight in obese mice by increasing fat oxidation and suppressing fatty acid synthesis.
The study showed that sulforaphane’s effects were largely dependent on functional leptin receptor signaling, as its anti-obesity properties were absent in leptin-deficient (ob/ob) and leptin receptor mutant (db/db) mice. Additionally, transcriptomic analysis of metabolically active tissues showed that sulforaphane reduces oxidative stress, suppresses inflammation, and alters lipid metabolism —mechanisms that can contribute to improved metabolic function.
“Skeletal muscle appears to be a key site of action for sulforaphane, which enhances metabolic flexibility and reduces inflammation,” says Dr. Cakir. “These findings suggest that NRF2 activation could be a viable approach for addressing metabolic dysfunction in obesity.”
Beyond Weight Loss: Exercise and Metabolic Health
Dr. Cakir’s research has also examined how certain compounds influence metabolic performance and endurance. While much of this work remains preliminary, early studies suggest that specific molecules may enhance exercise efficiency and metabolic function.
“We see increased endurance and improved metabolic flexibility in these animals, which could have implications for conditions beyond obesity, such as metabolic disorders and muscle aging,” says Dr. Cakir.
Future Research Directions
Dr. Cakir’s lab is now focused on refining these discoveries and moving them closer to clinical applications. His team is investigating whether these compounds can be optimized for human use and whether additional molecular pathways contribute to leptin signaling defects.
One priority of the lab is understanding the long-term effects of these interventions. His lab is also examining whether these small molecules could be combined with existing obesity treatments (e.g. GLP-1 agonists) to enhance their effectiveness while preventing the muscle loss often associated with current weight-loss drugs.
“We are working to determine how sustainable these interventions are and whether they could be integrated into broader obesity treatment plans,” says Dr. Cakir. “We’re still in the preclinical stages with all of this research but it’s promising and exciting work and I look forward to sharing more of what we learn in the future.”
By integrating neurobiology, metabolism, and pharmacology, Dr. Cakir’s research may help to develop new, more effective obesity treatments that go beyond simple calorie restriction, offering new possibilities for sustainable weight management.
