Ramulus Mori (Sangzhi) Alkaloids Ameliorate Obesity-Linked Adipose Tissue Metabolism and Inflammation in Mice

Abstract

Obesity has become a global epidemic disease as it is closely associated with a chronic low-grade inflammatory state that results in metabolic dysfunction. Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from Morus alba L. were licensed to treat type 2 diabetes (T2DM) in 2020. In this study, we explored the effect of SZ-A on adipose tissue metabolism and inflammation using an obesity model induced by a high-fat diet (HFD). C57BL/6J mice were fed high fat for 14 weeks and followed by SZ-A 400 mg/kg treatment via gavage for another six weeks, during which they were still given the high-fat diet. The results showed that SZ-A notably reduced body weight and serum levels of lipid metabolism-related factors, such as triglycerides (TG) and total cholesterol (TC); and inflammation-related factors, namely tumor necrosis factor alpha (TNFα), interleukin 6 (IL6), fibrinogen activator inhibitor-1 (PAI-1), angiopoietin-2 (Ang-2), and leptin (LEP), in the HFD-induced mice. SZ-A increased the protein and mRNA expression of lipid metabolism-related factors, including phosphorylated acetyl coenzyme A carboxylase (p-ACC), phosphorylated hormone-sensitive triglyceride lipase (p-HSL), adipose triglyceride lipase (ATGL), and peroxisome proliferator-activated receptor-alpha (PPARα), in adipose tissue. Immunohistochemistry results demonstrated that SZ-A significantly reduced the infiltration of pro-inflammatory M1-type macrophages in epididymal fat. The data also suggested that SZ-A down-regulates the transcriptional levels of inflammatory factors Il6, Tnfα, monocyte chemoattractant protein-1 (Mcp1), and F4/80, and up-regulates interleukin 4 (Il4), interleukin 10 (Il10), and interleukin 13 (Il13) in adipose tissue. Overall, the results indicate that SZ-A exhibits potential in regulating lipid metabolism and ameliorating obesity-linked adipose inflammation.

Pharmacokinetics and tissue distribution of Ramulus Mori (Sangzhi) alkaloids in rats and its effects on liver enzyme activity

“…Our previous study showed that SZ-A could improve lipid metabolism and inhibit weight gain in HFD-induced obese mice by inhibiting fatty acid synthase and increasing lipolytic enzyme expression to inhibit fat accumulation. Additionally, SZ-A has been found to have a beneficial effect on obesity-induced chronic inflammation in adipose tissue (Sun et al, 2022). All the current studies have shown that SZ-A plays a role in adipose tissue, and our discovery of the distribution of the main components of SZ-A in adipose tissue provides a foundation for further research on its mechanism in regulating adipose tissue.…”

“…In a previous study, we found that SZ-A could exert multiple pharmacological effects on T2DM-related target tissues, including adipose tissue and the liver, by oral or intraperitoneal administration (Chen et al, 2022). For example, SZ-A ameliorated HFD-induced weight gain and significantly stimulated adiponectin expression and secretion in adipose tissue (Sun et al, 2022). Additionally, SZ-A alleviates hepatic steatosis and regulates lipid metabolism and oxidative stress in the liver (Chen et al, 2022).…”

“…This pharmacological feature is conducive to faster and better control of postprandial blood glucose, while greatly reducing adverse reactions such as flatulence and exhaust in East Asian patients consuming carbohydrates as their staple food (Nojima et al, 1998;Liu et al, 2021). In addition to selectively inhibiting intestinal a-glucosidase, an in-depth study of the mechanism underlying the effects of SZ-A found that exerts multiple in vitro and in vivo pharmacological effects on the regulation of pancreatic islet ß-cell function, insulin resistance, lipid metabolism, intestinal flora, and inflammation (Cao et al, 2021;Liu et al, 2021;Chen et al, 2022;Lei et al, 2022;Sun et al, 2022). In a previous study, the therapeutic effects and mechanism of action of SZ-A on lipid metabolism were explored in high-fat diet (HFD)-induced obesity and non-alcoholic fatty liver disease (NAFLD) mice.…”

Microbe-Derived Antioxidants Alleviate Liver and Adipose Tissue Lipid Disorders and Metabolic Inflammation Induced by High Fat Diet in Mice

“…It could also significantly increase the gene expressions of anti-inflammatory factors IL-4 and IL-13. Sun et al (2022) found that Ramulus Mori (Sangzhi) alkaloids achieved the amelioration adipose tissue inflammation by reducing macrophage infiltration in adipose tissue, which, in turn, significantly inhibited the expression of pro-inflammatory factors TNF-α and MCP1 and up-regulated the gene transcription of anti-inflammatory factors IL-4, IL-10 and IL-13 [ 43 ]. We found that MA increased the expression of M2-type macrophage marker CD163 in liver tissue and EAT, and the average fluorescence intensity of (CD163 + CD68)/(CD86 + CD68) was significantly increased.…”

Ramulus mori (Sangzhi) alkaloids regulates gut microbiota disorder and its metabolism profiles in obese mice induced by a high-fat diet

“…Among these three major alkaloid components, DNJ has the highest proportion, accounting for more than 50% of the total alkaloid, and the sum of the three main components accounts for more than 80% of the total alkaloid. Besides its good hypoglycemic effect, previous studies have confirmed that SZ-A has multiple pharmacological effects, including alleviating high-fat diet-induced obesity and nonalcoholic fatty liver disease and ameliorating obesity-linked adipose tissue metabolism and inflammation, indicating the potential of SZ-A to regulate obesity and metabolic syndrome (Chen et al, 2022;Sun et al, 2022). Accumulated evidence confirmed that gut microbiota and their metabolic profiles played an important role in the occurrence and development of obesity and metabolic syndrome.…”