Examination Date
Spring 5-1-2025
Degree
Dissertation
Degree Program
Physiology
Examination Committee
Flavia Souza-Smith, PhD; Patricia Molina MD, PhD; Robert Siggins, PhD; Liz Simon, PhD; Lisa Harrison-Bernard, PhD; Alison Quayle, PhD
Abstract
Alcohol is the most abused substance in the United States with about one-quarter of the adult population partaking in heavy drinking. Heavy alcohol use impairs insulin-dependent responses in AT and induces insulin resistance. However, mechanisms driving alcohol-induced AT dysfunction and its contribution to systemic metabolic dysregulation are not well understood. Our previous studies suggest that alcohol-induced mesenteric lymphatic leakage and subsequent perilymphatic AT inflammation may be a primary event in the development of systemic immunometabolic dysregulation seen with chronic alcohol administration. Our laboratory has previously demonstrated that chronic alcohol-induced lymphatic leakage is coupled with local perilymphatic AT (PLAT) proinflammatory changes and perturbances in insulin-stimulated glucose utilization. Interestingly, we have found that chronic alcohol increases PLAT fat regulatory T cells (fTregs), which are the drivers of age-associated insulin resistance. We speculate that cells or molecules leaking from lymphatic vessels into PLAT stimulate fTreg expansion and lead to PLAT metabolic dysregulation. The studies in this dissertation aimed to further characterize the consequences of alcohol-induced lymphatic leakage on PLAT-specific immunometabolic changes and systemic glucose homeostasis, explore lymph constituents potentially responsible for these alterations, and investigate latent mechanisms and functional implications of fTreg expansion in PLAT. The results showed that chronic alcohol feeding in rodents produced PLAT-specific alterations in adipokine expression, and naïve PLAT explants stimulated with lymph from alcohol-fed animals exhibited a proinflammatory milieu. Furthermore, immunometabolic changes in PLAT coincided with alterations in systemic glucose clearance after chronic alcohol feeding. Chronic alcohol feeding increased fTregs in PLAT, specifically, ST2⁺ fTregs were significantly increased in the PLAT of alcohol-fed rats. Upon further exploration of IL-33/ST2 signaling cascade as a mechanism of PLAT fTreg expansion, we found that stimulation of naïve adipose-derived stem cells (ADSCs), the biologically relevant source of IL-33, with lymph from alcohol-fed animals increased IL-33 release. Additionally, naïve ADSCs stimulated with lymph from alcohol treated animals presented significantly increased necrosis compared with control lymph. Finally, naïve PLAT glucose uptake was significantly increased when co-cultured with fTregs isolated from PLAT of control animals and unchanged when co-cultured with fTregs isolated from PLAT of alcohol-fed animals. Collectively, these findings support that chronic alcohol-induced lymph leakage is a mechanism that contributes to alcohol-induced PLAT dyshomeostasis. Our studies suggest that alterations in PLAT immune milieu, specifically increased fTregs, may contribute to deficiencies in PLAT metabolic function after chronic alcohol exposure. Further studies are required to determine specific lymph components leading to PLAT immunometabolic dysregulation.
Recommended Citation
Autin, Kourtney, "Lymph-Adipose Crosstalk: A Novel Mechanism of Alcohol-Induced Adipose Tissue Dysfunction" (2025). School of Graduate Studies. 18.
https://digitalscholar.lsuhsc.edu/etd_sgs/18
Dissertation Report Form