DOI
https://doi.org/10.25772/6SH8-0D43
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
L. Ashley Cowart
Second Advisor
Sarah Spiegel
Third Advisor
Brian Watternberg
Fourth Advisor
Lisa Shock
Fifth Advisor
Francesco Celi
Abstract
The prevalence of obesity in the United States has reached staggering numbers, affecting approximately 100.1 million adults and 14.7 million children as of 2023, according to the estimates of the Center for Disease Control and Prevention. Many comorbidities develop because of obesity impairing quality of life and burdens the health care system. Consequently, there is an urgent need for interventions and treatments to reverse obesity and restore health. Studying the sphingolipid pathway has provided new insights into the relationship between obesity and metabolic syndrome. Among the sphingolipids, Sphingosine-1-phosphate (S1P) has emerged as a highly active player in obesity, both in mice and humans, with significantly elevated levels found in the plasma of obese individuals. Our laboratory has previously demonstrated that adipocyte-specific deletion of SphK1 abolishes this protective effect against obesity. The literature shows that S1PR signaling in adipose tissue promotes adiposity and impedes UCP1. While there are several works on the numerous S1P receptors (R1-3) in adipose tissue and their effects on UCP1 mRNA expression, there is a gap in studying SphK1, the enzyme that produces the S1P ligand for these receptors. This study presents data to close this gap. We show that there is a relationship between SphK1 deletion in adipose tissue and regulation of core body temperature, and enhanced UCP1 protein expression in iWAT and gWAT depots. Paradoxically, this enhanced UCP1 expression is a compensatory response for reduced proton availability due to impaired mitochondria complex IV activity in the absence of SphK1 in iWAT and ssWAT. Despite excessive UCP1 expression in white adipose of our mutant mice, body temperature is solely regulated by SphK1 effect on UCP1 in the BAT. This study presents a novel function for SphK1 in adipose thermogenesis.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-31-2023