Uncovering the ancestral function of UCP1 using novel techniques, combining metabolic phenotyping, stable isotope tracing and respiratory flux

Brown adipose tissue of placental mammals produces heat due to the unique mitochondrial uncoupling protein 1 (UCP1), allowing the defense of high body temperatures in the cold.

UCP1 burns fat, releasing energy as heat via mitochondrial inefficiency, and is thus a target for the urgently needed treatment of human obesity and its comorbidities.

Most research on UCP1 has centered around model organisms, namely mice, ignoring potential insights from broader comparative analyses.

In this 3-year project, I will investigate marsupials to provide key insights into the origin, evolution, and conservation of thermogenic adipose tissue.

The commonalities and differences of thermogenic adipose tissue between marsupial and placental mammals have yet to be teased apart. By metabolically phenotyping a novel CRISPR-Cas9 UCP1-knockout opossum in the laboratory of Dr.

Frank van Breukelen at the University of Nevada, I will characterize adipose tissue among cold-challenged marsupials and establish the role of UCP1 at the whole animal level. I will utilize transcriptomics to uncover the genetic networks fueling thermogenesis. Finally, I will determine the ancestral function of marsupial UCP1 in the laboratory of Dr.

Ajit Divakaruni, University of California Los Angeles using state-of-the-art stable isotope tracing.

This study will open a window into the evolutionary past, uncovering how UCP1 and adipose tissue became refined to burn fat, providing a basis for future therapeutic developments.