Title of project

Investigation of the transcriptional regulation of leptin in human adipocytes

Abstract

Leptin, a pivotal adipocyte-derived hormone discovered in the 1990s, plays a key role in the
regulation of energy homeostasis by suppressing appetite and increasing energy expenditure in
response to increased adiposity. However, despite the important role of leptin in human physiology,
surprisingly little is known about the regulation of leptin gene expression.

The aim of this project is to obtain unprecedented insight into the transcriptional regulation of human
leptin expression. I will do this by mapping the 3D architecture of the leptin locus in human
adipocytes and integrate this with unpublished multi-omics analyses from the Mandrup Group as well
as publicly available datasets. The function of the predicted key regulatory enhancers in modulating
leptin expression will be investigated by 1) CRISPR-based approaches combined with drug/hormone
treatment in SGBS adipocytes, one of the few cell culture systems that express near physiological
levels of leptin; 2) linking enhancer activities to transcriptional effects and extrinsic and intrinsic
signals in isolated mature adipocytes from different subcutaneous human adipose depots and sex. The
insights into the regulation of leptin expression generated in this project may enable therapeutic
modulation of leptin expression, which could reduce obesity comorbidities.