Discovery and characterization of a novel natural product for the treatment of both diabetes and obesity - Project Summary Despite the wide application of commonly used drugs for type 2 diabetes (T2D) treatment, the prevalence of T2D continues to rise in the US. Insulin resistance and progressive decline in functional β-cell mass are two key driving forces for T2D. Obesity is a leading pathogenic factor for developing T2D, which is a significant obstacle for effective glycemic control in many patients with T2D. Thus, identifying novel agents that can simultaneously ameliorate obesity and promote insulin sensitivity and β-cell function would be a more effective strategy for preventing and treating T2D. In searching for agents with both anti-obesity and anti-hyperglycemic activities, we found for the first time that elenolic acid (EA), a small molecule generated from hydrolyzing olive leaf-derived oleuropein, is such a highly promising compound. Excitingly, oral administration of EA reversed hyperglycemia while also promoting weight loss and suppressing food intake in obese diabetic mice, Notably, EA was more effective in managing hyperglycemia and obesity than that of metformin. Interestingly, EA induced peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion from intestinal L-cells. In this grant, we propose to test hypothesis that EA is a dual acting agent for simultaneous treatment of obesity and diabetes via triggering PYY and GLP-1 secretion. Aim 1 will characterize the anti-diabetic and anti-obesity effects of EA. In that regard, diet- induced obese mice and obese diabetic db/db mice will receive EA treatment once daily via oral gavage. The effects of EA on metabolic profiles of obese diabetic mice will be examined for determining its anti-obesity and anti-diabetic efficacy. In addition, euglycemic-hyperinsulinemic clamps in combination with ex vivo analyses of peripheral tissues will be performed to examine the effects of EA on insulin action, fat metabolism, and gluconeogenic programs. Immunohistochemistry will be carried out to analyze Islet β-cell mass and function. Further, oral bioavailability, metabolism, and potential toxicity of EA will be studied. Lastly, mouse models with T2D will be used to investigate the synergistic metabolic effects of EA plus metformin combination therapy. Aim 2 will identify the mechanisms by which EA suppresses food intake and protects against obesity. First, the effects of EA on feeding responses and stomach emptying in mice will be evaluated, followed by ex vivo analyses of hypothalamic pathway controlling food intake. Next, pair-feeding in combination with energy expenditure analyses will be performed to examine the extent to which the anti-obesity efficacy of EA is driven by reduced energy intake. Additionally, intracerebroventricular administration of pharmacological inhibitors targeting GLP-1 receptor (GLP-1R) or PYY receptor (Y2R) as well as the receptor null mice will be used to investigate whether EA inhibition of food intake requires the central PYY/Y2R and/or GLP-1/GLP-1R signaling systems. The results of this project are expected to defining the efficacy of a novel compound for treating both diabetes and obesity as well as uncovering the mechanism underpinning these effects, which will potentially lead to developing new, safe, and effective therapy for battling both diabetes and obesity.
