Obesity is an increasingly prevalent metabolic disease that affects 38% of adults and 16% of children and costs the United States healthcare system nearly $200 billion annually. Consequently, there is an urgent need to better understand the factors that regulate the development of obesity. Emerging studies indicate that white adipose tissue (WAT)-resident immune cell populations critically regulate the development of obesity by producing cytokines that modulate glucose utilization, lipid storage, and energy expenditure. However, despite our growing understanding of the influence of immune cells on obesity, how metabolic cells such as adipocytes control immune cell responses remains poorly defined. In preliminary studies, I have identified that adipocytes transfer their mitochondria to a subset of macrophages in WAT in vivo, potentially defining a new macrophage population. Strikingly, this process is impaired in high fat diet (HFD)-induced obesity. Further, mitochondria transplantation to mice results in tissue-specific accumulation of macrophages in WAT and release of free fatty acids into circulation. These observations suggest that intercellular mitochondria transfer is a dynamically regulated physiologic process that has important functional effects on lipid metabolism. To dissect the mechanisms of intercellular mitochondria transfer, I performed a genome-wide CRISPR-knockout screen. The top-scoring gene, Exostosis 1 (Ext1), is required for heparan sulfate synthesis and is essential for normal lipid metabolism in mice and humans. Critically, my data indicate that Ext1 is necessary for mitochondria transfer in vitro without affecting uptake of other foreign bodies. Collectively, these data provoke the central hypothesis that intercellular transfer of mitochondria from adipocytes to macrophages is a previously unrecognized mechanism that controls macrophage function and systemic metabolic homeostasis. This hypothesis forms the basis of my two aims.
In Aim 1, I will determine the identity and function of macrophages that have acquired mitochondria from adipocytes and investigate the immunologic and metabolic potential of these cells.
In Aim 2, I will investigate whether EXT1 is required for intercellular mitochondrial transfer and regulation of metabolic homeostasis in vivo. These will be addressed employing the intellectual and scientific resources available in the Brestoff lab, novel strains of mitochondria reporter mice, new genetic models of disrupted mitochondria transfer, and a suite of metabolism and immunology core facilities at Washington University School of Medicine. Importantly, these findings may impact how we approach the treatment of metabolic disorders beyond existing therapeutic paradigms.
Obesity is one of the most significant public health problems in the United States and is linked to the development of many illnesses such as type 2 diabetes, heart disease, and cancer. Immune cells in fat tissue have been linked to the development of obesity. The proposed studies will investigate the role of a recently discovered process called intercellular mitochondria transfer in the regulation of immune cells and obesity to aid in the identification of new pathways that could potentially be targeted to prevent or treat obesity.
