UC Merced

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.