Theses Doctoral

Characterizing the secretome of adipose tissue in metabolic stress

Goodman, Joshua

Adipose tissue is a crucial organ that sits at the nexus of organismal metabolism. Evolutionary systems seemingly developed to regulate weight such that the risk of starvation accompanying low weight was balanced against the risk of predation accompanying high weight, but the molecular underpinnings of these systems have not been fully elucidated.

The modern obesogenic diet has led these processes to become dysregulated, resulting in increased rates of obesity and associated metabolic disorders, making a full understanding of the mechanisms underlying weight regulation even more important. Parabiosis experiments support the existence of an uncharacterized anorectic factor that opposes weight gain. A previously established system of murine overfeeding recapitulates the defense of body weight against rapid weight gain and uncovers a non-inflammatory adipose tissue environment in the setting of obesity.

Building on this past work, this thesis sets out to characterize the protein secretome of adipose tissue from overfed mice in order to provide insight into possible candidate anorectic factors and better understand the physiology of adipose tissue in this experimental form of obesity.In doing so, we uncover a previously unappreciated phenomenon of mitochondrial secretion from adipose tissue depending on metabolic state. We find that mitochondria are secreted in greater number from overfed adipose tissue and that these mitochondria are enriched for enzymes related to de novo lipogenesis.

We also demonstrate that mitochondria are released intact. We find that some of these phenotypes are shared in genetically obese db/db mice, pointing toward potential physiological roots. We also characterize the plasma proteomes of overfed mice, finding that in overfed mice, inflammatory pathways are increased in the absence of induction of canonical inflammatory cytokines and in the absence of inflammation in the adipose tissue.

Collectively, this work demonstrates the utility and importance of using experimental models in order to better disentangle phenomena of feeding, obesity, and inflammation. It offers direction for future studies that can positively identify an adipocyte-secreted anorectic factor peptide and work to define the manner in which local and systemic inflammation can be uncoupled from adipose tissue hypertrophy.


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More About This Work

Academic Units
Cellular, Molecular and Biomedical Studies
Thesis Advisors
Ferrante, Anthony W.
Ph.D., Columbia University
Published Here
January 31, 2024