The role of lysosomes in determining adipose tissue dysfunction in obesity

• Applicant: Katharina Sieckmann, Ph.D.
• Subject Area: Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578074967

Obesity is associated with adipose tissue dysfunction and a markedly increased risk of cardiovascular disease (CVD), largely driven by high blood cholesterol. White adipose tissue (WAT) is the major site for lipid storage and can constitute up to 50 % of body weight in obesity, thereby strongly impacting systemic lipid dynamics. However, the contribution of cholesterol uptake to the WAT remains poorly understood. Adipocytes acquire cholesterol mainly via low-density lipoprotein receptor (LDLR)-mediated endocytosis. Expression of LDLR increases in WAT during obesity, suggesting that adipose tissue may act as a sink for cholesterol sink under these conditions. The size of adipocytes increases during obesity (hypertrophy) and the capacity of adipocytes to continue storing triglycerides without “spilling over” excess lipids into the circulation is a key determinant of tissue function. Importantly, cell growth also increases the demand for cholesterol. Therefore, a central hypothesis of this project is that larger adipocytes are uniquely equipped to manage increased lipid availability in obesity. Lysosomes may be central to this adaptation, as the organelles serve as signaling hubs, where cholesterol can activate the growth-promoting mechanistic target of rapamycin (mTOR) pathway. In the proposed project, I aim to reveal how lysosomal signaling via mTOR regulates cholesterol homeostasis in adipocytes during obesity. By combining mouse models, human WAT biopsies, and 3D culture systems, I will systematically assess cholesterol handling, lysosomal abundance, and mTOR activity across different depots and species. The results will provide an in-depth map of lysosome-dependent regulation of cholesterol metabolism in obesity. This will significantly advance our molecular understanding of how weight gain results in hypercholesteremia and vascular dysfunction, opening novel therapeutic strategies to prevent metabolic and cardiovascular complications in obesity.

• DFG Programme: Fellowship
• International Connection: Sweden
• Host: Professorin Carolina Hagberg, Ph.D.