GSBS Dissertations and Theses

ORCID ID

0000-0002-7949-1396

Approval Date

12-16-2016

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Program in Molecular Medicine

First Thesis Advisor

Silvia Corvera

Keywords

Human adipocyte, White adipocyte, Brown adipocyte, Brite adipocyte, Beige adipocyte, Metabolism, Thermogenic adipose tissue, Insulin resistance, Glucose homeostasis, Adipocyte implantation

Abstract

During embryonic development, adipocytes emerge from microvasculature. Lineage-­‐tracing studies in mice have shown that adipocyte progenitors reside in the adipose tissue capillaries. However, the direct evidence of an association between adipocyte progenitors and vasculature in humans is lacking. A specific class of adipocytes (brown and beige/brite) expresses the uncoupling protein 1 (UCP1), which consumes glucose and fatty acids to generate heat. The abundance of UCP1- containing adipocytes correlates with a lean metabolically healthy phenotype in human. However, a causal relationship between the presence of these cells and metabolic benefits in human is not clear.

In this thesis, I report human adipocyte progenitors proliferate in response to pro-angiogenic factors in association with adipose capillary networks in-vitro. The capillary-derived adipocytes transform from being UCP1-negative to positive upon adenylate cyclase activation, a defining feature of the brite/beige phenotype. Activated cells have denser, round mitochondria with UCP1 protein, and display uncoupled respiration. When implanted into NOD-scid IL2rgnull (NSG) mice, the adipocytes can form a vascularized fat pad that induces vascularization and becomes integrated into mouse circulatory system. In normal or high fat diet-fed NSG mice, activated brite/beige adipocytes enhance systemic glucose tolerance and improved hepatic steatosis, thus providing evidence for their potential therapeutic use. The adipocytes also express neuroendocrine and secretory factors such as Interleukin-33, proprotein convertase PCSK1 and proenkephalin PENK, which are correlated with human obesity. Finally, analyses on single-cell clones of capillary-sprout cells reveal the existence of diverse adipogenic progenitor populations. Further characterization of the clones will define the identifying features of the diverse adipocyte progenitor types that exist in human adipose tissue.

DOI

10.13028/M20598

Rights and Permissions

Licensed under a Creative Commons license

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Friday, December 15, 2017

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