Obesity may leave lasting biological changes in adipose tissue that keep levels of the hunger hormone asprosin elevated, potentially contributing to weight regain and increased obesity susceptibility in offspring, new preclinical research suggested.

“We found that obesity leaves a lasting ‘memory’ in fat cells that keeps the hunger hormone asprosin turned on, even after weight is lost,” senior author Atul Chopra, MD, PhD, investigator and associate director of the Harrington Rare Disease Program at the Harrington Discovery Institute at University Hospitals and associate professor of genetics and genome sciences at the School of Medicine, Case Western Reserve University, both in Cleveland, told Medscape Medical News.

“It’s like flipping a light switch that stays on after you remove your finger,” he said. “Even after the original trigger is gone, fat cells keep producing extra asprosin, which drives hunger and pushes the body to regain lost weight.”

The researchers also found evidence in mice that maternal obesity may produce changes in offspring before birth that increase their susceptibility to obesity later in life, Chopra said.

The study was published online in Cell Reports.

Unexpected Link

The researchers sought to understand why people frequently regain weight after weight loss and why children of mothers with obesity have an increased susceptibility to obesity.

“We suspected that these two puzzles might have the same underlying answer,” Chopra said.

Relapse and inheritance could indicate that obesity leaves behind a molecular imprint that promotes its recurrence, the authors wrote.

Among adipose-derived endocrine factors, asprosin has emerged as a potent hormonal signal elevated in obesity. Asprosin, generated by C-terminal cleavage of fibrillin-1 (Fbn1), is secreted primarily from white adipose tissue and acts on Ptprd-expressing neurons in the hypothalamus to increase neuronal excitability and stimulate appetite.

Circulating asprosin has been found to correlate with body weight and insulin resistance, but the molecular mechanism by which obesity inc reases Fbn1 expression and circulating asprosin has remained unclear.

To investigate whether obesity leaves an enduring signal that promotes weight regain, the researchers studied cultured adipocytes and mouse models of diet-induced obesity, measuring Fbn1 expression, circulating asprosin, and changes in chromatin. They then tested the effects of blocking asprosin or its appetite-related receptor pathway.

Four days of exposure to transforming growth factor-beta-1 (TGF-beta-1), a cytokine elevated in obesity, increased Fbn1 expression and asprosin production in cultured fat cells. Both remained elevated 14 days after exposure ended.

In mice with prior obesity, asprosin remained elevated after weight loss, even when body weight returned to control levels. These mice regained more weight on a high-fat diet, whereas neutralizing asprosin prevented the excess gain in one weight-loss model.

The investigators also found evidence of a persistent effect in offspring. Offspring of mice with obesity and offspring of mice given TGF-beta-1 late in gestation had higher asprosin levels and gained more weight on a high-fat diet. In the latter group, adipose tissue showed 65% greater enrichment of a chromatin marker associated with Fbn1 activation.

Raising maternal asprosin alone did not reproduce the effect, leading the investigators to identify maternal TGF-beta-1 as the proposed signal to the fetus.

Overall, the findings identified an unexpected link between an obesity-associated cytokine and persistent chromatin remodeling at the Fbn1 locus, suggesting a potential shared mechanism underlying weight regain and transmission of obesity susceptibility to offspring.

Not a Willpower Problem

“The biggest message is that weight regain is not a willpower problem but a biological one,” Chopra said. “Our findings show that fat tissue can hold onto a ‘memory’ of obesity that keeps hunger signals elevated long after the weight itself is gone, which helps explain why so many patients regain weight even when they’re doing everything right.”

For clinicians, Chopra said the findings supported treating obesity as an ongoing condition rather than considering treatment complete once a patient loses weight. Patients may require continued support to maintain weight loss.

He also cautioned that many factors influence a child’s future weight, including genetics, diet, physical activity, and family environment. The findings suggest that maternal metabolic health during pregnancy could represent another factor by influencing fetal fat cells before birth.

However, the findings are not yet ready for clinical translation.

“This is animal research, and the next step is confirming that the same ‘switch’ exists in human fat tissue and that it behaves the same way during human pregnancy,” Chopra said.

Asprosin and the pathway maintaining its elevated production could eventually provide a therapeutic target. In the mouse models, blocking the pathway prevented excess weight regain and reduced obesity susceptibility in offspring.

If the findings are replicated in humans, they could “open the door to a treatment that could be paired with weight-loss drugs to help people keep weight off after they stop taking them, or potentially to protect children of mothers with obesity before they’re even born,” Chopra said.

Although this still is “years away, it’s a concrete target rather than a vague idea, which is what excites us most,” he said.

Novel Mechanism

Commenting for Medscape Medical News, Yu (Aaron) An, MD, PhD, assistant professor in the Department of Anesthesiology, Critical Care and Pain Medicine at the Institute of Perioperative Medicine, The University of Texas Health Science Center at Houston (UTHealth Houston), called the findings significant for the field.

“The authors discovered a convergent pathway, characterized by sustained elevation of an appetite-stimulating hormone driven by an epigenetic memory,” said An, who also serves as an adjunct assistant professor at the Center for Metabolic and Degenerative Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Disease at McGovern Medical School, UTHealth Houston.

An noted that the study makes a twofold contribution.

“It provides a novel mechanism of how this fat cell-produced appetite-stimulating hormone, asprosin, is induced in obesity and sustained at high production, and it also provides a potential solution to a critical challenge for current GLP-1 receptor agonist weight-loss drugs — weight rebound.”

An identified several steps needed to bring this research toward clinical application, including identifying a suitable therapeutic target within the pathway.

If asprosin is indeed “targetable, a humanized neutralizing antibody can be considered, but it needs to be tested in preclinical settings before moving to a clinical study.”

Chopra was supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the Harrington Investigatorship. The other authors were supported by grants from the National Institutes of Health, the Harrington Discovery Institute, and the Diabetes Action Research and Education Foundation. Chopra reported being awarded asprosin-related patents and being a co-founder, equity holder, and former officer of Aceragen; a co-inventor on related intellectual property; and a co-founder, equity holder, and officer of Recall Therapeutics and Pathway21. An declared no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).