Obesity and the metabolic syndrome, characterized by metabolic anomalies including hypertension, central obesity, insulin resistance, and dyslipidemia, constitute major health problems worldwide. Chronic nutrient excess causes tissue damage and cell dysfunction, which can lead to type 2 diabetes (T2D), among other diseases. T2D itself, in turn, is a major risk factor for cardiovascular disease, which is one of the leading causes of death worldwide.
A detailed analysis of the effects of nutrient excess on immune cells and metabolically relevant tissue cells, as well as their interaction with each other, was not well understood and investigated before the start of the project. Thus, the aim of the present project was to uncover and understand relevant signaling pathways and interactions that contribute to tissue damage and T2D disease progression in order to identify potential targets for future T2D therapies.
For this purpose, a joint research group of Prof. Dr. Maike Sander (BIH Visiting Fellow) and Prof. Dr. Birgit Sawitzki (host) was established at the Berlin site of the Charité and the BIH with the help of the BIH Einstein Visiting Fellowship, combining the expertise of Prof. Maike Sander in the field of beta-cell biology, diabetes and metabolism and of Prof. Dr. Birgit Sawitzki in the field of immune cell biology. Extensive single cell RNA analyses and mass cytometric analyses were performed on pancreatic tissue sections of mice fed with normal chow diet or "western diet" resulting in obesity. Molecular and functional changes in immune cells and local signaling networks in the pancreas, triggered by nutrient excess, could be detected. In particular, specific subtypes of macrophages were shown to respond to nutrient excess by secreting proinflammatory cytokines and chemokines thereby recruiting and activating other immune cells, such as cytotoxic T cells, into the pancreatic tissue. Thus, nutrient excess triggers local inflammatory responses, which may further drive the chronic disease progression of T2D.