Developmental lineages and functions of macrophages in white adipose tissue

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ABSTRACT: Adipose tissue-associated disorders including obesity, lipodystrophy, and cancer-associated fat wasting collectively account for 1 in 4 deaths in the United States (1-3). Despite the devastatingly high number of deaths, therapeutic options remain limited and unsatisfactory. Landmark studies since the 1990’s have established that accumulation and activation of macrophages in adipose tissues are linked to inflammation, insulin resistance, and type 2 diabetes (4-20). However, the roles of adipose tissue macrophages outside tissue inflammation remain poorly understood. This is particularly important, as studies suggest that adipose tissue macrophages may be involved in fat development (21-23), fat storage (24), and protection against fat wasting (25). Our preliminary data published in Science (26) demonstrate that embryo-derived adipose tissue resident macrophages promote lipid storage in adipocytes via production of PDGFcc. This process is independent from inflammation and insulin resistance promoted by bone-marrow-derived macrophages. Our preliminary data in (Aim 1) suggest that macrophages are required for fat loss. Therefore, in Aim 1 I will delineate the responsible macrophage lineages (K99) and identify macrophage-dependent mechanisms (R00) that control fat mobilization/loss. In (Aim 2), I will determine the transcriptional basis for control of lipid storage by adipose tissue resident macrophages using single nucleus RNA-sequencing (K99). I expect to deduce changes in cellular circuitries and downstream signaling pathways that control fat storage. The candidate molecules identified here will be explored in the R00 phase of this research using human fat organoids and in vivo mouse models. In (Aim 3), I will use human fat organoids that contain human resident-like macrophages to confirm the role of PDGFcc in fat storage in humans (K99). I have found that human fat organoids that contain Pdgfc+ resident-like macrophages accumulate more lipids as compared to macrophage-less fat organoids. I will (R00) use these fat organoids to determine how macrophages affect lipid metabolism and identify whether macrophages act directly on adipocytes. Additionally, human organoids will be used to screen for macrophage- dependent mediators of energy storage identified in Aims 1 and 2. I will continue to be mentored by Dr Frederic Geissmann, a leader in the field of macrophage biology. The Geissmann lab is among the first to characterize the developmental lineages and functions of macrophages. I will also benefit from the expertise of my advisory committee that includes Anthony Ferrante, Chris Glass, and Olivier Elemento. Drs. Chris Glass and Olivier Elemento are highly respected scientists with expertise in analysis of macrophages and white adipose tissues by single cell methodologies. Whereas, Drs Anthony Ferrante is an expert in the areas of myeloid cell biology, metabolism, and adipose tissue function. My expectations are that this proposal combined with my expertise in drug development will not only provide a comprehensive functional view of adipose tissue macrophages but also aid in development of therapies that may control adiposity in obese, lipodystrophic, or cachectic patients.