ADIMMUNE · Decoding interactions between adipose tissue immune cells, metabolic function, and the intestinal microbiome in obesity

Obesity and its metabolic co-morbidities have given rise to a rapidly expanding ‘metabolic syndrome’ pandemic affectinghundreds of millions of individuals worldwide. The integrative genetic and environmental causes of the obesity pandemicremain elusive. White adipose tissue (WAT)-resident immune cells have recently been highlighted as important factorscontributing to metabolic complications. However, a comprehensive understanding of the regulatory circuits governing theirfunction and the cell type-specific mechanisms by which they contribute to the development of metabolic syndrome islacking. Likewise, the gut microbiome has been suggested as a critical regulator of obesity, but the bacterial species andmetabolites that influence WAT inflammation are entirely unknown.We propose to use our recently developed high-throughput genomic and gnotobiotic tools, integrated with CRISPR-mediated interrogation of gene function, microbial culturomics, and in-vivo metabolic analysis in newly generated mouse models, in order to achieve a new level of molecular understanding of how WAT immune cells integrate environmental cues into their crosstalk with organismal metabolism, and to explore the microbial contributions to the molecular etiology of WAT inflammation in the pathogenesis of diet-induced obesity. Specifically, we aim to (a) decipher the global regulatory landscape and interaction networks of WAT hematopoietic cells at the single-cell level, (b) identify new mediators of WAT immune cell contributions to metabolic homeostasis, and (c) decode how host-microbiome communication shapes the development of WAT inflammation and obesity.Unraveling the principles of WAT immune cell regulation and their amenability to change by host-microbiota interactionsmay lead to a conceptual leap forward in our understanding of metabolic physiology and disease. Concomitantly, it maygenerate a platform for microbiome-based personalized therapy against obesity and its complications.