Understand the contribution of yolk sac-derived macrophage progenitors to the generation of adipose tissue macrophages and the development of insulin resistance

• Applicant: Privatdozent Dr. Tamás Röszer, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277878931

Insulin resistance (IR) is a non-curable metabolic disease, which is reaching pandemic proportions and it is predicted to emerge a leading worldwide morbidity by 2030. Immune cells, the so-called adipose tissue macrophages (ATMs) have key roles in the development of IR. Modulation of ATM development is considered as a straightforward approach to abrogate IR. This project was initiated to understand the origin and replenishment mechanism of ATMs, which should provide new opportunities to prevent or combat IR. The project has already delivered key concepts on ATM development. We have found that (a) ATM progenitors develop before birth from yolk sac (YS) hematopoietic stem cells, (b) and are maintained by self-renewal in adulthood, with minor contribution from blood monocytes. We have found that increasing self-renewal of ATMs improves AT health and reduces IR. Moreover, we have found that (c) AT-specific cues determine the replenishment of ATMs. Our yet unpublished data show that YS-derived ATMs (YS-ATMs) have an unexpected, active metabolic role: they convert breast milk-derived lipid signals into ether lipids which maintain a thermogenic, “fat burning”, beige AT phenotype in the neonate. Moreover, our preliminary data show that this mechanism can be used to reduce IR in adulthood. Our project has developed to a crucial point, which strongly suggests that AT health is critically dependent on YS-ATMs, and physiological AT function can be restored by YS-ATMs in IR. This mechanism can provide alternative of the life-long medication of patients with IR, and has the potential to change the therapeutic concept of IR.

• DFG Programme: Research Grants