The Aging-Induced Decline in Beige Adipose Tissue Development

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Doctor of Philosophy (PhD)
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Cell and Molecular Biology
Adipocyte precursor cell
Adipose tissue
Beige adipose tissue
Beige fat
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Holman, Corey, D.

Both aging and obesity are associated with dysfunctional adipose tissue leading to the pathogenesis of numerous comorbidities including heart disease, type 2 diabetes, and numerous cancers. Unlike energy-storing white adipose tissue, beige adipose tissue burns energy in the form of heat and thus has therapeutic potential to increase energy expenditure and combat obesity. Aging has been shown to decrease the amount and function of beige adipose tissue, but the mechanism is incompletely understood. Beige adipose tissue develops in two ways: either through the de novo differentiation of adipocyte stem and progenitor cells (ASPCs), or the activation of existing adipocytes. My thesis begins in Chapter 1 with summary of existing knowledge in the field of adipose tissue. In Chapter 2, we establish that there is a beiging defect with age and use lineage tracing to demonstrate that de novo beige adipogenesis from Pdgfra+ ASPCs is reduced. We see no impairment of ex vivo differentiation and observe remarkably similar ASPC populations by single cell RNA-sequencing between ages, leading to the conclusion that the defect in de novo beige adipogenesis is likely cell non-autonomous. Using single-nucleus RNA-sequencing to transcriptionally profile adipocytes, we identify four adipocyte populations that are altered by aging and cold exposure. We identify two adipocyte-specific systems that may contribute to the decline in beige fat response with age: the de novo lipogenesis (DNL) pathway and natriuretic peptides. In Chapter 3, we follow-up on hypotheses from Chapter 2 and assess the aged environment using transplantation experiments and examine two candidate genes, Pdgfrl and Npr3, to further elucidate their mechanisms. I conclude in the discussion of Chapter 4 that both ASPCs and adipocytes contribute to the beiging defect with age. There is a small contribution from Pdgfra+ ASPCs, likely due to cell non-autonomous effects, and a larger contribution from adipocytes, with high levels of Npr3 and low levels of DNL with age, that likely inhibits adipocyte conversion. With greater understanding of the decline in beige adipose tissue development with age, we hope to improve metabolic health and facilitate the discovery of beige fat-targeted therapeutics for the aging population.

Seale, Patrick
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