Obesity represents a major health risk and is strongly linked to metabolic diseases. While weight loss can improve metabolic health, sustained maintenance of reduced body weight over the long term remains difficult, often resulting in the so-called 'yoyo' effect. Our previous work suggests that this phenomenon may be partly driven by obesogenic memory, wherein adipose tissue retains abnormal transcriptional profiles even after weight loss. These persistent transcriptional changes are linked to epigenetic dysregulation and persist in human and mouse adipocytes following surgical or dietary interventions.
In recent years, anti-obesity medications emerged as potent alternatives to conventional weight loss strategies based on lifestyle changes. However, most patients experience weight regain after cessation of the drug treatment. Whether this relapse is also founded on persistent transcriptional and epigenetic changes, remains unclear.
We aim to assess whether weight-loss drugs such as semaglutide (GLP-1RA) affect the formation of an epigenetic memory in vivo. Specifically, we are investigating possible effects of semaglutide on the epigenetic memory of prior obesity using an inducible transgenic mouse model (AdipoERCre x NuTRAP), which allows for adipocyte-specific analysis of both the transcriptome and epigenome. Additionally, we are exploring whether semaglutide-induced weight loss can prevent or modulate the 'yoyo' effect and promote sustained metabolic health in previously obese wildtype mice.
Overall, we seek to advance our understanding of the epigenetic dynamics underlying obesity and weight cycling and how this can be modulated.