A Metabolomics Approach to Investigate Kukoamine B—A Potent Natural Product With Anti-diabetic Properties

Abstract

Due to the surge in type 2 diabetes mellitus (T2DM), treatments for chronic metabolic dysregulations with fewer side-effects are sought. Lycii Cortex (LyC), a traditional Chinese Medicine (TCM) herb has a long history of being widely prescribed to treat T2DM as alternative medicine; however, the bioactive molecules and working mechanism remained unknown. Previous studies revealed kukoamine B (KB) as a major and featured compound for LyC with bioactivities for anti-oxidation and acute inflammation, which may be related to anti-diabetes properties. This study aims to understand the efficacy and the mode of action of KB in the diabetic (db/db) mouse model using a metabolomics approach. Parallel comparison was conducted using the first-line anti-diabetic drugs, metformin and rosligtazone, as positive controls. The db/db mice were treated with KB (50 mg kg−1 day−1) for 9 weeks. Bodyweight and fasting blood glucose were monitored every 5 and 7 days, respectively. Metabolomics and high-throughput molecular approaches, including lipidomics, targeted metabolomics (Biocrates p180), and cytokine profiling were applied to measure the alteration of serum metabolites and inflammatory biomarkers between different treatments vs. control (db/db mice treated with vehicle). After 9 weeks of treatment, KB lowered blood glucose, without the adverse effects of bodyweight gain and hepatomegaly shown after rosiglitazone treatment. Lipidomics analysis revealed that KB reduced levels of circulating triglycerides, cholesterol, phosphatidylethanolamine, and increased levels of phosphatidylcholines. KB also increased acylcarnitines, and reduced systemic inflammation (cytokine array). Pathway analysis suggested that KB may regulate nuclear transcription factors (e.g., NF-κB and/or PPAR) to reduce inflammation and facilitate a shift toward metabolic and inflammatory homeostasis. Comparison of KB with first-line drugs suggests that rosiglitazone may over-regulate lipid metabolism and anti-inflammatory responses, which may be associated with adverse side effects, while metformin had less impact on lipid and anti-inflammation profiles. Our research from holistic and systemic views supports the conclusion that KB is the bioactive compound of LyC for managing T2DM, and suggests KB as a nutraceutical or a pharmaceutical candidate for T2D treatment. In addition, our research provides insights related to metformin and rosiglitazone action, beyond lowering blood glucose.

Withaferin A promotes white adipose browning and prevents obesity through sympathetic nerve-activated Prdm16-FATP1 axis

“…Mounting evidence indicates that the external stimuli that promote WAT browning may also lead to an alteration in fatty acid composition in adipose tissues (Srivastava and Veech, 2019). Importantly, the modification of the fatty acid composition in WATs contributes to the promotion of WAT browning, which has been considered a novel strategy for obesity treatment (Chaurasia et al, 2016;Shen et al, 2013); (Li et al, 2018). The unsaturated fatty acids, such as oleic acid and arachidonic acid, facilitate the mitochondrial uncoupling and oxidative phosphorylation in adipocytes, contributing to the prevention of obesity, fatty liver disease and cardiovascular disease (Croset et al, 2000;Kantae et al, 2017;Matsuda et al, 2020;Vögler et al, 2008).…”

<p>Kukoamine B Ameliorate Insulin Resistance, Oxidative Stress, Inflammation and Other Metabolic Abnormalities in High-Fat/High-Fructose-Fed Rats</p>

“…The dose of Kuk B used was according to previous studies. 17 After 10 weeks of treatment, the rats were fasted overnight and blood glucose levels were determined with the aid of a glucometer (Accu-Check Performa, Roche, Mannheim, Germany). The experimental procedure was conducted in line with the National Institute of Health guide for the care and use of laboratory animals (NIH Publication No.…”

“…15,16 One of the bioactive constituents isolated from L. chinense is kukoamine B (Figure 1), a spermine alkaloid known for its wide range of therapeutic actions including antioxidant, antiinflammatory and antidiabetic effects. 17 Although kukoamine B has many pharmacological effects associated with it, there is no report on its effect on obesity and insulin resistance. Thus, this study investigated the anti-obesity effect of kukoamine B in high-fat diet/fructose-fed obese rats.…”

Identification of α-Glucosidase Inhibitors from Leaf Extract of Pepper (Capsicum spp.) through Metabolomic Analysis

“…Putrescine conjugates such as N-p-coumaroyl-N′-feruloyl putrescine and N,N′-diferuloyl putrescine were reported as potent α-glucosidase inhibitors [79]. Similarly, kukoamines A and kukoamines B exhibited antidiabetic effects in the mice model [78,80]. However, this is the first report on in vitro α-glucosidase inhibition using caffeoyl putrescine.…”