Adipose tissue retains an epigenetic memory of obesity after weight loss

Laura C. Hinte, Daniel Castellano-Castillo, Adhideb Ghosh, Kate Melrose, Emanuel Gasser, Falko Noé, Lucas Massier, Hua Dong, Wenfei Sun, Anne Hoffmann, Christian Wolfrum, Mikael Rydén, Niklas Mejhert, Matthias Blüher and Ferdinand von Meyenn ()
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Laura C. Hinte: ETH Zurich
Daniel Castellano-Castillo: ETH Zurich
Adhideb Ghosh: ETH Zurich
Kate Melrose: ETH Zurich
Emanuel Gasser: ETH Zurich
Falko Noé: ETH Zurich
Lucas Massier: Karolinska University Hospital Huddinge
Hua Dong: ETH Zurich
Wenfei Sun: ETH Zurich
Anne Hoffmann: University of Leipzig and University Hospital Leipzig
Christian Wolfrum: ETH Zurich
Mikael Rydén: Karolinska University Hospital Huddinge
Niklas Mejhert: Karolinska University Hospital Huddinge
Matthias Blüher: University of Leipzig and University Hospital Leipzig
Ferdinand von Meyenn: ETH Zurich

Nature, 2024, vol. 636, issue 8042, 457-465

Abstract: Abstract Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

Date: 2024
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DOI: 10.1038/s41586-024-08165-7

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