Cardiovascular disease (CVD) is the leading cause of death in the United States and is a primary consequence of metabolic syndrome (MetS)[1–5]. MetS is progressive and diagnosed by the presentation of at least 3 of 6 cluster conditions, including obesity, dyslipidemia and elevated arterial pressure, which can contribute to the development of CVD[2,3]. Therefore, identification of treatments that beneficially target multiple cluster factor conditions of MetS are of great interest. Chronic Cannabis consumption has been associated with reduced MetS risk factors[6–12]. The most abundant constituent, cannabidiol (CBD), is of particular interest for pharmacological investigation due to recognized antioxidative properties and non-intoxicating, wide dose range. Clinical and pre-clinical studies using CBD are sparse but CBD has been shown to attenuate isolated conditions associated with MetS (e.g. hypertension, obesity). However, it is unclear if these effects would be observed in a translational model of cluster factor conditions (e.g., diabetes with insulin resistance, dyslipidemia, etc.). The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an obese, hypertensive, translational model of MetS that closely mimics the human condition. With this model, we probed the effects of CBD on clustered conditions of MetS. In the second chapter, we demonstrate that a chronic, high dose of oral CBD reduces hypertension in the presence of MetS comorbidities but does not appear to do so via modulation of the renin-angiotensin-aldosterone system (RAAS). In the third chapter, we demonstrate that CBD reduces adiposity and dyslipidemia. Metabolomic analyses suggested a shift in the metabolome and revealed the most significantly increased metabolite to be β-aminoisobutyric acid (BAIBA), which is a novel myokine implicated in the browning of white adipose tissue (WAT) and enhancement of lipolysis. Importantly, we note that CBD compounds do not correct the diabetic phenotype, despite reductions in adiposity, even in more severely impaired metabolism, as demonstrated in Chapter 4 and 5. Our findings contribute to the expanding pharmacology of CBD compounds and reveal novel implications for the use of CBD compounds in conditions of metabolic dysfunction.

Parasitic disease is a global health burden. Current and historical efforts to eradicate parasitic disease rely heavily on vector control and mass drug administration campaigns rather than vaccine induced immunity due in large part to effective parasite immune evasion. Toxoplasma gondii is an intracellular protozoal parasite estimated to infect up to a third of the world’s population, is the second leading cause of food-borne disease in the United States and demonstrates evasion of vaccine induced immunity (CDC, 2017). Previous work done by our lab suggest a crucial role for B-1 cells for the control and clearance of highly virulent T. gondii strains. A genetic link between Nfkbid and the resistant murine phenotype prompted our endeavor to analyze antibody reactivity to T. gondii. We used serum antibody to probe T. gondii protein via western blot and found 1) A/J and C57BL/6J serum IgM and total IgG antibody target the same proteins below 50kDa which are likely known GPI anchored proteins, 2) B-1 cell deficient Nfkbid null C57BL/6J mice lose 87% serum IgM reactivity and 91% total IgG reactivity when compared to wild type C57BL/6J mice, 3) A/J and C57BL/6J antibody reactivity to T. gondii protein relies heavily on the presence of the lipid moiety of the GPI anchor and 4) A/J mice to produce more antibody overall than C57BL/6J mice. These findings contribute to our growing body of work which correlates resistance to T. gondii infection with enhanced antibody production to antigens likely targeted by B-1 cells. Resolution of the contribution of this protective antibody response may provide novel insight for the development of a completely protective and long-lasting vaccine against parasite.