Date of Award

2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Christoph Thaiss

Abstract

Animals must protect themselves from environmental challenges to survive and reproduce. However, the mechanisms that underlie adaptive tissue responses to (1) environmental cold temperatures and (2) ingested toxin exposure remain poorly understood. In the first section of this thesis, I find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which are critical for an improved thermogenic response to secondary cold encounter. A primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis program even after cessation of the original stimulus, which protects from subsequent exposures. By combining single-nucleus RNA sequencing, spatial transcriptomics, and immunofluorescence imaging, I discover that this lipogenic response is carried out by a distinct subpopulation of brown adipocytes that is localized along the perimeter of classical Ucp1high brown adipocytes. The protective effect of the lipogenic program is associated with the production of acyl carnitines, and supplementation of acyl carnitines recapitulates improved secondary cold responses even in the absence of lipogenesis. Overall, these findings highlight the importance of heterogenous brown adipocyte populations for “thermogenic memory” in the setting of repeated cold exposure, which may have implications for therapeutic efforts leveraging short-term thermogenesis to counteract the hypercaloric state of obesity. In the second section of this thesis, I hypothesized that the small intestine has intrinsic responsiveness to the protein GDF15 which plays a role in the response to ingested toxins. GFRAL forms the receptor for GDF15, and currently it is thought that GFRAL is exclusively expressed by neurons in the hindbrain. By combining single-nucleus RNA sequencing of the enteric nervous system with whole mount immunofluorescence I discover that a subpopulation of enteric neurons in the small intestine express the Gfral receptor and characterize their anatomical location in the myenteric plexus. Further, I discover that Gfral-expressing enteric neurons share a similar transcriptional signature to Gfral-expressing neurons in the hindbrain. Given that GFRAL is a promising therapeutic target for the treatment of human diseases ranging from cancer cachexia to obesity, the discovery of Gfral-expressing enteric neurons may inform the development of GFRAL-targeting therapeutic approaches.

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