Adipose tissue retains an epigenetic memory of obesity after weight loss

Hinte LC; Castellano-Castillo D; Ghosh A; Melrose K; Gasser E; Noe F; Massier L; Dong H; Sun W; Hoffmann A; Wolfrum C; Ryden M; Mejhert N; Bluher M; von Meyenn F

doi:10.1530/ey.22.11.4

11.4

Prev Next

Section Contents Cite

ESPE Yearbook of Paediatric Endocrinology (2025) 22 11.4 | DOI: 10.1530/ey.22.11.4

ESPEYB25 11. Obesity and Weight Regulation Adipocytes at the Centre of Action (3 abstracts)

11.4. Adipose tissue retains an epigenetic memory of obesity after weight loss

Hinte LC , Castellano-Castillo D , Ghosh A , Melrose K , Gasser E , Noé F , Massier L , Dong H , Sun W , Hoffmann A , Wolfrum C , Rydén M , Mejhert N , Blüher M & von Meyenn F

Author affiliations

Laboratory of Nutrition and Metabolic Epigenetics, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland. [email protected]

Nature 2024 Nov 18;636:457-465 doi: 10.1038/s41586-024-08165-7 https://pubmed.ncbi.nlm.nih.gov/39558077

Brief Summary: The study reveals that adipose tissue retains a persistent "epigenetic memory" of obesity, even after significant weight loss (WL), which primes adipocytes for dysfunctional responses to future obesogenic stimuli. Using multi-omics in both humans and mice, the researchers demonstrate that transcriptional and epigenetic changes in adipocytes—particularly histone modifications and enhancer activation—remain long after weight normalization, contributing to the common rebound weight gain seen after dieting.

While previous studies have documented improved metabolic function after WL, clinical data consistently show high rates of weight regain [1,2]. Hinte et al. demonstrate that adipocytes, APCs, and endothelial cells maintain transcriptional profiles indicative of prior obesity despite weight normalization. This confirms and extends the concept of metabolic memory [3], into the context of adipose tissue. The retention of histone marks such as H3K4me3, H3K27ac, and H3K27me3 at specific adipocyte promoters/enhancers (e.g., IGF1, Gpam, PDE3A) supports the existence of a durable epigenetic scar. A key insight is that weight-reduced adipocytes exhibit heightened glucose and palmitate uptake, aberrant lipid handling, and accelerated transcriptional responses to high fat diet, indicating a “primed state” even after normalization of body weight.

In the broader perspective, the authors uncover that adipocytes retain epigenetic scars from obesity that predispose individuals to relapse. This insight, built upon rigorous multi-omics and human–mouse comparative analyses, offers a robust molecular explanation for the clinical failure of many WL strategies and opens up new therapeutic avenues targeting the epigenome itself.

References: 1. Nordmo, M., Danielsen, Y. S. & Nordmo, M. The challenge of keeping it off, a descriptive systematic review of high-quality, follow-up studies of obesity treatments. Obes. Rev. 21, e12949 (2020). 2. Wilding, J. P. H. et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes Obes. Metab. 24, 1553–1564 (2022).3. Reddy, M. A., Zhang, E. & Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58, 443–455 (2015).