Intrinsic and Extrinsic Factors Controlling Brown Fat Development Ethan C Fein

Format:

Book

Thesis/Dissertation

Author/Creator:

Fein, Ethan C., author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0306.

0379.

0573.

0719.

0758.

Local Subjects:

0306.

0379.

0573.

0719.

0758.

Physical Description:

1 electronic resource (205 pages)

Contained In:

Dissertations Abstracts International 87-07B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Obesity and its comorbidities pose an ever-increasing challenge to public health, highlighting the need for effective and multifaceted therapeutic approaches. Brown adipose tissue (BAT) is specialized to burn calories and generate heat (thermogenesis). In addition to guarding against hypothermia, BAT activity prevents obesity and its metabolic consequences in rodent models and is highly correlated with metabolic health in humans. Unfortunately, the prevalence of BAT in humans is low and declines steeply with age and obesity. Increasing the amount of metabolically active BAT in humans will require a greater understanding of how BAT develops. In the work presented in this thesis, we sought to fill critical gaps in the understanding of BAT development. We focused on two sequential, temporally distinct phases in BAT development: adipogenesis, during which progenitor cells gradually commit to the adipocyte lineage, and thermogenic differentiation, during which nascent brown adipocytes gain the capacity for heat production. To investigate adipogenesis, we performed single-cell and spatial transcriptomic analyses of mouse embryos to reconstruct the lineage trajectory of brown adipocytes. We identified CDH4+/EBF2+ mesenchymal cells as candidate progenitors and found that GATA6 is selectively expressed in brown preadipocytes. Genetic ablation of GATA6 in dermomyotome-derived cells resulted in a near-complete absence of preadipocytes and brown adipocytes, establishing GATA6 as an essential regulator of adipogenic commitment in the BAT lineage. Turning next to thermogenic differentiation, we tested whether the dominant regulator of BAT's response to cold, the sympathetic nervous system, plays any role in the development of the tissue. Using genetic models that ablate sympathetic innervation or block downstream signaling in adipocytes, we found that tissue size, adipocyte morphology, and thermogenic gene expression developed normally in the absence of sympathetic input. Functional assays confirmed that BAT from mice with genetically ablated sympathetic nerves retained normal thermogenic capacity. Taken together, this work provides insights into the commitment of progenitor cells to the brown adipocyte lineage and demonstrates that the subsequent thermogenic differentiation of nascent brown adipocytes proceeds independently of sympathetic signaling. These insights have direct relevance to efforts aimed at engineering functional brown adipocytes for the treatment of metabolic disease

Notes:

Advisors: Seale, Patrick Committee members: Zepp, Jarod A.; Raj, Bushra; Luo, Wenqin; Kahn, Mark L.

Source: Dissertations Abstracts International, Volume: 87-07, Section: B.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276001548

Access Restriction:

Restricted for use by site license