In vivo imaging of adipose growth dynamics in zebrafish

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Fat tissue is highly dynamic and can expand and contract throughout life. Fat tissue can expand via two distinct mechanisms: (i) by the addition of new fat cells (hyperplastic growth) and (ii) by the growth in size of existing fat cells (hypertrophic growth). The mechanism by which fat tissue expands exerts a strong influence on cardiometabolic disease risk. For example, excessive hypertrophic growth which results in adipose characterised by few, but very large fat cells (so called 'hypertrophic morphology') is associated with insulin resistance, diabetes and cardiovascular disease. Whereas, hyperplastic growth characterised by many, small fat cells (so called 'hyperplastic morphology') is associated with improved metabolic parameters. Therefore, understanding how hyperplastic and hypertrophic growth are regulated and coordinated to pattern adipose morphology is of central biomedical importance. Surprisingly, owing to current methodological constraints, real-time in vivo imaging of adipose growth and remodelling has not been extensively attempted at a cellular-level resolution. For such a dynamic tissue, this lack of in vivo imaging has resulted in large knowledge gaps pertaining to dynamic cellular processes that underpin adipose growth. To fill these knowledge gaps, we have developed a new in vivo imaging model in zebrafish that allows us to visualise fat cells and their precursors non-invasively in living animals and in real-time. These new transgenic tools and methodologies allow us an unprecedented view of the dynamic nature of fat tissue growth. The overall goal of this proposal is to leverage our new zebrafish in vivo imaging model to understand how hyperplastic and hypertrophic growth mechanisms are coordinated, and how they contribute to cardiometabolic disease risk. Our preliminary studies have identified that zebrafish fat tissue undergoes phasic growth characterised by 'waves' of hyperplastic growth, coupled with transient fat cell shrinkage and expansive hypertrophic growth. In Aim 1 of this project, we will conduct studies to understand the molecular and genetic regulation of phasic hyperplastic adipose growth in zebrafish. In Aim 2, we will conduct experiments to understand how fluctuations in fat cell size are regulated and help pattern adipose. Finally, in Aim 3, we will combine human and zebrafish data to identify new candidate genes which we think regulate hyperplastic/hypertrophic growth. Then, we will perform large-scale mutagenesis in zebrafish to functionally evaluate these candidate growth genes. Altogether, this proposal will leverage new and exciting imaging methodologies to provide foundational new insights into the dynamic cellular processes that pattern adipose tissue.