A new role for IGF1 signalling in driving fat tissue formation in heart disease

Breakthrough research uncovers biological understanding of how fat tissue is formed in the heart following a myocardial infarction

For this first time, scientists at AstraZeneca’s Innovative Medicines and Early Development (IMED) Biotech Unit, in collaboration with colleagues at Boston Children’s Hospital/Harvard Medical School, Icahn School of Medicine at Mount Sinai and the AstraZeneca Integrated Cardio Metabolic Centre (AZ-ICMC) at the Karolinska Institutet have discovered a new role for insulin-like growth factor 1 (IGF1) in driving the formation of epicardial fat tissue in the heart, post-myocardial infarction.

It has recently been uncovered there is a strong association between epicardial fat formation and heart disease. An excess of cardiac fat can contribute to greater left ventricular mass and work, diastolic dysfunction and attenuated septal wall thickening. Following a myocardial infarction the injured heart tissue reactivates a subset of epicardial-derived stem cells to cause them to differentiate into several different cell lineages including fat (adipose) tissue and increase epicardial thickening. However, the controlling mechanisms of how this happens have not been understood.

The results published in the recent issue of Circulation reveal that IGF1 signalling controls the formation of fat tissue in the heart during ischaemic heart disease, following a myocardial infarction.

 “It is the first time that a modified-RNA library screen has been used to study how paracrine factors can re-direct progenitor cell fate in vivo. Here we applied this concept to study the mechanism of how epicardial fat tissue is formed during heart disease,” says Dr William Pu, Harvard Stem Cell Institute, Harvard Medical School, and Boston Children’s Hospital. “By doing so we have shown IGF1 signalling is responsible for directing epicardial progenitor cells to form adipocytes following a myocardial infarction.”

This finding confounds previous understanding that IGF1 is cardioprotective. It was therefore important the team could confirm this was not just a finding seen in mouse models but also relevant in the human setting.  

“AZ has access to primary human EPDCs from patients undergoing operation for heart disease thanks to Drs. Marie Jose Goumans and Adriana Gittenberger-de Groot at Leiden University Medical Center. It was exciting to see the results from human cells correlated with the mouse data. Together the data highlights the importance of the IGF1 pathway in controlling heart fat tissue formation during heart disease,” says Kenneth Chien, Distinguished Professor of the Swedish Research Council, AZ-ICMC, and the Department of Cell and Molecular Biology at the Karolinska Institutet.

“Cardiovascular disease, and heart failure in particular, is one of our priority science areas within AstraZeneca. Drawing on these new findings opens up the potential of targeting the IGF1 signaling pathway to treat the burgeoning problems of ischaemic heart disease and obesity,” says Dr Qing-Dong Wang, Principal Scientist, Cardiovascular and Metabolic Diseases, IMED Biotech Unit, AstraZeneca.