Doctoral Dissertations
Date of Award
8-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Major
Nutritional Sciences
Major Professor
Ling Zhao
Committee Members
Jiangang Chen, Guoxun Chen, Jun Lin
Abstract
Impaired thermogenesis and decreased energy expenditure as a result are hallmarks of obesity and obesity-associated metabolic dysfunction, such as type 2 diabetes mellitus (T2DM). By increasing the number of thermogenic adipocytes, the browning of white adipocytes has emerged as a promising target for increasing energy expenditure and treating obesity and its associated metabolic dysfunctions. However, the thermogenic and browning capacity of insulin-resistant models in response to dietary browning agents, such as resveratrol (RES), and the underlying mechanisms linking browning to improved insulin sensitivity remain incompletely understood. In this dissertation, the thermogenic capacities of diabetic db/db mice (characterized with a loss-of-function mutation in the leptin receptor) and the browning potential of their adipose tissue-derived stromal cells (ADSCs) in response to RES were investigated and compared to those of wild-type mice with a focus on sex differences. Also, as a proof-of-concept, the contribution of UCP1-mediated browning to insulin sensitization in response to rosiglitazone (ROSI), a well-studied anti-diabetic drug, was examined using 3T3-L1 adipocytes with UCP1 gene knockout (KO).
It was found that db/db mice exhibited markedly reduced energy expenditure and impaired cold tolerance, along with lower expression of thermogenic genes in brown and white adipose tissue, indicating diminished thermogenic capacities in these diabetic mice, regardless of sex. Despite systemic insulin resistance, the ADSCs from db/db mice retained the ability to undergo browning in response to RES and ROSI, as evidenced by increased Ucp1, Pgc1α mRNA expression, and mitochondrial uncoupling. This browning effect is accompanied by insulin-sensitizing improvement. Sex differences were also observed in response to treatments. Finally, it was found that ROSI enhanced insulin signaling in scrambled control cells but not Ucp1 KO 3T3-L1 adipocytes, demonstrating a significant contribution of Ucp1-mediated thermogenesis to ROSI-induced insulin sensitization.
In summary, this dissertation provides new insights into the thermogenic defects in db/db mice and demonstrates that db/db mice’s ADSCs retain browning capacities and can be browned by RES. Moreover, UCP1 is shown to play a significant role in mediating the insulin-sensitizing effects of ROSI. Overall, these results highlight the therapeutic potential of targeting adipose browning and thermogenesis with dietary or pharmacological agents for the treatment of obesity and obesity-associated T2DM.
Recommended Citation
Xu, Xinyun, "Exploring the Browning and Anti-Diabetic Effects of Resveratrol: Impact of Sex and Diabetic Status. " PhD diss., University of Tennessee, 2025.
https://trace.tennessee.edu/utk_graddiss/12789