Student Theses and Dissertations

Jingyi Chi

Date of Award

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Cohen Paul Laboratory

Abstract

Obesity affects more than one in three adults in the United States and is a significant risk factor for a constellation of chronic diseases. The crucial role of adipose tissue in energy balance has driven great interest in investigating this tissue as a target for treatment of obesity and its sequelae. While white adipocytes store excess energy, thermogenic brown and beige adipocytes convert lipids and glucose into heat, thereby increasing energy expenditure. Unlike classical brown adipocytes which are thermogenic under basal conditions, inducible brown adipocytes, commonly known as beige adipocytes, reside in white adipose depots and need to be activated by external stimuli such as the sympathetic nervous system to drive thermogenesis. Recent studies have shown that active beige adipocytes can increase energy expenditure and are associated with anti-obesity and anti-diabetes effects in mice and humans. However, the origin of beige adipocytes and how they interact with other adipose cell types remains unclear, creating critical hurdles to manipulating these cells for therapeutic ends. To seek a comprehensive understanding of beige adipocyte formation, we developed a novel technique that enables whole-tissue immunostaining, clearing, and imaging in adipose tissue. Using this new method, we profiled various murine white adipose depots and observed pronounced depot to depot variability in tissue organization. Analysis of cold-induced beige adipocyte formation in whole adipose depots uncovered prominent regional variation in beige adipocyte distribution in subcutaneous fat. Through morphological characterization of the sympathetic nerve projections in subcutaneous fat, we found a dense network of sympathetic parenchymal neurites localizing to the same region where beige adipocytes readily arise. To understand how the dense sympathetic network is established, we used an adipocyte-specific Prdm16 knockout mouse model to ablate beige adipocyte function and demonstrated that the density of sympathetic parenchymal innervation depends on the presence of functional beige adipocytes. These results suggest that communication between beige adipocytes and the sympathetic neurites is important for the establishment of sympathetic innervation. To address whether the regulation by beige adipocytes occurs during early tissue morphogenesis, we applied whole-tissue imaging to examine the development of sympathetic innervation in subcutaneous fat. We found that parenchymal neurites actively grow between postnatal day 6 (P6) and P28, overlapping with early postnatal beige adipogenesis. Constitutive deletion of Prdm16 in adipocytes led to a significant reduction in early postnatal beige adipocytes and sympathetic density within this window. Using an inducible, adipocyte-specific Prdm16 knockout model, we ablated the function of early postnatal beige adipocytes and found strongly impaired sympathetic growth. These data suggest that sympathetic growth in subcutaneous fat depend on a PRDM16- mediated mechanism. However, deleting Prdm16 in adult animals, did not affect sympathetic structure. Together, these findings highlight that beige adipocyte-sympathetic neurite communication is crucial to establish sympathetic structure during the early postnatal period, but may be dispensable for its maintenance in mature animals. These studies unravel the complex interaction between beige adipocytes and the sympathetic nervous system, providing a framework for further investigation of the molecular mechanisms underlying this interaction. Lastly, investigation of the early postnatal beige adipocytes allowed us to appreciate an unprecedented link between early postnatal and adult beige adipocytes. By fate mapping beige adipocytes through development, we found that the majority of cold-induced beige adipocytes in adult subcutaneous fat arise from existing mature adipocytes that were once early postnatal beige adipocytes. These studies provide fundamental insights into beige adipocyte formation and will guide future investigation of the origin and fate of beige adipocytes.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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