Dissecting the cellular interplays of adipose tissue remodeling in the regulation of insulin sensitivity

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PROJECT SUMMARY/ABSTRACT This proposed career development award will provide Dr. Diana Alba MD with targeted mentored training to ensure she develops into an independent researcher utilizing both experimental approaches and models, and “omics” coupled with bioinformatic tools, to probe the mechanisms linking obesity to adipose tissue dysfunction and diabetes. In certain individuals, adipose tissue is dysregulated in obesity, and this is an early mediator of diabetes pathogenesis. However, precisely what underlies this dysfunction is not well-defined. Subcutaneous white adipose tissue (sWAT) fibrosis is associated with insulin resistance, whereas the abundance of heat- generating brown-like adipocytes in sWAT (“beiging”) is linked to metabolic health. The proposed research plan aims to close key knowledge gaps regarding the reciprocal influences of sWAT fibrosis and beiging on insulin sensitivity. To do so, the PI will take advantage of an innovative human cohort containing individuals with widely divergent levels of both sWAT fibrosis and insulin sensitivity and use this resource to comprehensively probe key cellular constituents and molecular pathways that shift sWAT away from being influenced by beige adipocytes to developing fibrosis and insulin resistance. The PI aims to 1) identify transcriptional signatures across cell types in the sWAT that coordinately modulate WAT fibrosis, body fat distribution, and glucose homeostasis, 2) probe reciprocal influences of sWAT beige activity and fibrosis on insulin sensitivity via transcriptional regulation, 3 ) use the BXD panel of recombinant inbred mice as an orthogonal genetic reference to model divergent patterns of fat distribution and validate the mechanistic relevance of pathways and cell types identified in the humans studies. The proposed 5-year career development and training plan incorporates strategically designed didactic learning, mentored practical training, and career advising to complement the PI’s expertise in ways that are critical to completion of her research and career goals. The specific career development goals outlined in this application include developing mechanistic expertise in 1) adipose tissue biology through hands-on molecular and computational biology training; 2) metabolic assessment of mouse models; 3) the human translation of adipose tissue biology including multi-omics and metabolic phenotyping. She will be training at UCSF, a world- class center for basic and translational research and an excellent environment for physician-scientist training with experts in all aspects of the proposed training. She will be closely mentored by Dr. Suneil Koliwad, an expert in inflammation, nutrition, and glucose/energy metabolism, and Dr. Shingo Kajimura, an expert in adipogenesis and beige fat. The long-term goal is to provide Dr. Alba with the skills required to become an independent, R01- funded faculty member working to identify adipose tissue disease-relevant mechanisms and risk markers for diabetes, particularly in high-risk populations, and elucidate targets to specifically mitigate insulin resistance.