Cell autonomous role of lymphatic VEGFR2 signaling in diet induced obesity

• Applicant: Dr. Martin Lange
• Subject Area: Cell Biology ; Developmental Biology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431473248

Diet induced obesity is a major health problem in the western world. Developing new approaches to prevent lipid uptake into the body is desired for prevention of diet induced obesity and its associated diseases such as type 2 diabetes, cardiovascular diseases and increased risk of cancer. Dietary fats are absorbed into intestinal enterocytes and assembled into triglyceride-enriched particles called chylomicrons. Thereafter, chylomicrons are taken up by terminal intestinal lymphatics called lacteals and transported into the lymphatic circulation and further into the blood circulation for subsequent metabolism.Conditional deletion of Vegf-c or Dll4 in mice blocks lacteal growth and prevents high fat diet (HFD)-induced obesity, providing genetic evidence that lacteals could be targets to prevent obesity.Lymphatic endothelial cells (LECs) in lacteals are connected by VE-cadherin-positive discontinues button-like junctions. The openings between button-like structures render lacteals highly permeable, thereby allowing uptake of intestinal fluids and chylomicrons into the circulatory system. Thus, lacteal junctions appear as ideal targets to prevent chylomicron uptake. How lacteal junctions are regulated is largely unknown.A recent publication in Science from the laboratory of Prof. Eichmann, shows that enhancing VEGFR2 signaling in intestinal villi induces a change in junctional properties of lacteals from button-like (open, high permeability) to zipper-like (closed, low permeability). This results in decreased uptake of chylomicrons by lacteals. The goal of this project is to obtain precise understanding of the underlying mechanisms regulating lacteal junctions. Specifically, the cell autonomous role of VEGFR2 in lymphatic endothelial cells (LEC) and its downstream targets will be investigated. In addition, new molecular targets that can be used to prevent diet-induced obesity will identified by screening for LEC specific protein thyrosine phosphatases. This will help to prevent diet induced obesity and its complications in the future.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Anne Eichmann, Ph.D.