CLEVELAND -- Two enduring biological mysteries have remained unsolved for decades: why almost everyone who loses weight gains it back, no matter how they lost it, and why obesity passes from mother to child at rates that diet and environment cannot explain. Now, scientists from Harrington Discovery Institute at University Hospitals and Case Western Reserve University have identified why.
In a recent study published in Cell Reports , researchers found that obesity creates a lasting biological change in fat cells that keeps the hunger hormone asprosin elevated (“obesity memory”) even after weight loss. The findings may help explain why many people regain weight after dieting or discontinuing GLP-1 medications and why obesity risk can persist across generations.
“Imagine having an appetite-stimulating signal stuck in the ‘on’ position day after day, despite losing weight,” explained Atul Chopra, MD, PhD , senior author of the study, investigator and associate director of the Harrington Rare Disease Program at Harrington Discovery Institute at UH, and associate professor of medicine, genetics and genomics at Case Western Reserve University School of Medicine. “Our findings suggest one reason weight regain can be so difficult to prevent after treatment ends. This same signal can also cross the placenta from mother to baby. The result is a child born with a programmed susceptibility to obesity. This may also explain why obesity became such an epidemic, and why the cycle has continued for generations.”
The researchers also found that blocking the asprosin pathway in mice, from the gene that produces it to the receptor in the brain that responds to it, prevented both weight regain after dieting and inherited obesity risk. The finding points to new therapeutic strategies that could address the relapse problem drug companies are actively trying to solve.
“These patterns have been observed for decades, but nobody knew the exact molecular mechanism that makes obesity so persistent or how it transmits across generations,” added Dr. Chopra. “We wanted to find the biological basis for that persistence.”
The researchers initiated the study in search of what turns up the hunger hormone asprosin in obesity. They found that an inflammatory signal, called TGF-β1, does this. The biggest surprise was that a brief exposure to this signal created a lasting change that persisted for weeks after the signal was gone.
“It was like flipping a light switch that stays on even after you remove your finger,” said Dr. Chopra. “Even after mice lost all the excess weight and TGF-β1 returned to normal, this switch in their fat cells remained flipped, keeping asprosin and appetite elevated. This gives us a molecular explanation for why GLP-1 drugs, which suppress appetite while you take them, cannot fix the underlying biological memory that drives hunger back up once treatment ends. This same signal crosses the placenta and programs a baby's fat cells before birth.”
Dr. Chopra said the key message for clinicians is that obesity relapse is not a failure of willpower or discipline. It is driven by a durable biological memory written into fat tissue that sustains hunger long after the pounds come off.
“We need to treat obesity as a condition that leaves lasting biological scars, not just a temporary state of excess weight,” he said.
This explains why patients on GLP-1 medications regain weight when they discontinue the drugs. The medication suppresses appetite temporarily but does not erase the epigenetic memory in fat cells.
Pharmaceutical companies are actively seeking ways to help people maintain weight loss after treatment. The new findings identify a potential complementary target: a pathway that may sustain the biological drive toward regain after weight reduction.
The study was designed to test its central observation beyond a single laboratory. A separate laboratory led by Seth J. Field, MD, PhD, reproduced the key persistence finding. Field is director of physician-scientist programs and chief scientific officer at the Harrington Discovery Institute at UH and a professor at Case Western Reserve School of Medicine. Analyses of publicly available mouse and human datasets also yielded supporting evidence. While further human research is needed, the convergence across laboratories and datasets strengthens the case that the mechanism warrants serious investigation.
The critical next step in this research is translating the findings into humans. The researchers plan to confirm that the same epigenetic memory operates in human fat tissue after weight loss, and test whether therapies that block asprosin or reset these epigenetic marks can prevent weight regain in people.
“Given the need for durable obesity treatments, we are interested in whether asprosin-blocking therapies could be used alongside or after GLP-1 treatment to prevent rebound,” concluded Dr. Chopra.
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Kim, Brian C., Field, Seth J., Chopra, Atul R., et al. , Adipose TGFβ-asprosin memory promotes obesity relapse and offspring obesity susceptibility. Cell Reports. Volume 45, Issue 8117809, August 25, 2026. DOI: 10.1016/j.celrep.2026.117809
About Harrington Discovery Institute
Harrington Discovery Institute at University Hospitals in Cleveland, Ohio aims to advance academic discoveries into medicines to address unmet need. It was created in 2012 with a $50 million founding gift
from the Harrington family and has supported more than 200 scientists throughout the US, UK, and Canada. Harrington Discovery Institute uses an innovation model that surrounds scientists with drug development and business expertise and employs both philanthropic funding and catalytic investment capital to advance projects into the clinic and through commercialization. For more information, visit: HarringtonDiscovery.org | LinkedIn | X
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 200 locations, including hospitals, outpatient facilities and physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, NEOMED, Oxford University, Technion Israel Institute of Technology, and National Taiwan University College of Medicine. The main campus also includes UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the nation’s most distinguished clinical and translational research programs, with more than 3,500 active clinical research studies underway — the most of any health system in Ohio. Research funding has grown from $160 million in 2020 to $237 million in 2025, supporting discoveries that improve patient care and population health. UH’s academic, research, educational and clinical excellence has earned recognition among the world’s leading academic medical centers, ranking #15 globally and #7 in the United States by UK Brand Finance. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn , Facebook and Twitter . For more information, visit UHhospitals.org .
About Case Western Reserve University
As one of the fastest-growing research universities in the United States, Case Western Reserve University is a force in career-defining education and life-changing research. Across our campus, more than 12,000 students from around the world converge to seek knowledge, find solutions and accelerate their impact. They learn from and collaborate with faculty members renowned for expertise in medicine, engineering, science, law, management, dental medicine, nursing, social work, and the arts. And with our location in Cleveland, Ohio—a hub of cultural, business and healthcare activity—our students gain unparalleled access to academic, research, clinical and entrepreneurial opportunities that prepare them to join our network of more than 125,000 alumni worldwide. Visit case.edu to see why Case Western Reserve University is built for those driven to be a force in the world.
Cell Reports
Adipose TGFβ-asprosin memory promotes obesity relapse and offspring obesity susceptibility.
25-Aug-2026