Date of Award

Summer 8-2024

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Lucy Liaw

Second Committee Member

Robert Koza

Third Committee Member

Karen Houseknecht

Additional Committee Members

Aaron Brown

Dorothy Klimis-Zacas

Abstract

The leading cause of death worldwide is cardiovascular disease (CVD), and the risk of developing CVD increases with metabolic dysfunction. Metabolic dysfunction of adipose tissue can lead to obesity, and this can affect the adipose depot that surrounds blood vessels and contributes directly to vascular health. This unique adipose depot is called perivascular adipose tissue (PVAT) and like other adipose depots, PVAT is susceptible to both age- and diet-related metabolic dysfunction. Developing therapies that counteract age- and diet-related adipose dysfunction is crucial to effectively treat metabolic dysfunction and associated excess adiposity that contribute to increased risk of CVD. Methionine restriction (MR) has been found to counteract age-related pathologies, extend lifespan, and increase health span primarily. Many of these benefits are associated with changes in liver and adipose function, such as hepatokine and adipokine secretion. However, it is not known what durations of MR are necessary to obtain metabolic benefits or if the benefits of MR extend to PVAT and associated vasculature. Furthermore, there are several pathways reported to mediate the effects of MR that are important for the ability of PVAT to modulate vascular response. Therefore, we hypothesize that MR will induce beneficial effects that can modulate age- and diet- related alterations in metabolism and these benefits will extend to the vasculature and associated PVAT. To test this hypothesis, we employ morphometric and molecular techniques to assess if an 80% MR influences overall metabolic health in male mice in vivo, as well as morphological, molecular, and proteomic techniques to measure changes in the thoracic aorta, associated PVAT, and additional adipose depots. This approach was applied to study the effects of long-term MR in age- related metabolic decline in three different aged cohorts, young, middle-age and old mice. This was also applied to study the effects of short-term MR in diet-related metabolic dysfunction in obese mice for 3-10 days. Additionally, an in vitro model was developed to study cellular effects of MR on PVAT-derived pre-adipocytes and adipocytes, as well as test proteomic targets of MR in PVAT. The data discussed provides evidence that MR counteracts age-related and diet-related metabolic dysfunction, and for the first time that MR induces lean phenotype in thoracic PVAT. This lean phenotype was simulated in our novel in vitro model of MR in PVAT-derived adipocytes. Proteomic analysis of PVAT reveals a transient metabolic signature, hallmarked by reductions in lipogenic pathways and increase in understudied lysosomal protease. Proteomic analysis of thoracic aorta reveals vascular remodeling signature; however, no morphological changes were observed. With these studies, we provide evidence that MR has even greater potential to reduce risk of cardiovascular and metabolic disease by impacting thoracic PVAT and aorta. These findings have potential to increase the utility of MR to improve cardiometabolic health in three adult life phases as well as for short durations.

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