Asprosin Transcription Underlies Obesity Relapse and Inheritance [ATAC-seq]

Obesity is a unique disease, marked by its near-certain relapse after weight loss and its transmission to offspring of obese mothers. The biological mechanisms behind these phenomena remain elusive. We have found that the obesity-associated cytokine Tgf-β1 activates Fbn1 transcription in adipocytes, driving overproduction of the appetite-stimulating hormone asprosin. Remarkably, a single exposure to elevated Tgf-β1 reshapes chromatin at the Fbn1 locus, cementing its overexpression in a manner that is unrelenting, even after weight loss and normalization of Tgf-β1 levels. This results in an enduring plasma asprosin elevation despite weight loss, sustaining heightened appetite and a ceaseless pull toward regaining the lost weight. Strikingly, maternal Tgf-β1 passes through the placenta leading to fetal adipose reprogramming and plasma asprosin elevation that persists in childhood, transmitting obesity across generations. Our findings reveal a powerful chromatin remodeling and transcriptional event that results from a single exposure to obesity, causing a profoundly enduring elevation of an appetite-stimulating hormone, fueling both relentless recurrence and hereditary transmission.