Similar to neoplastic tissues, growth and development of adipose tissue are thought to be angiogenesis-dependent. Since visceral adipose tissue (VAT) is associated with development and progression of nonalcoholic fatty liver disease (NAFLD), we hypothesized that angiogenesis inhibition would attenuate obesity-induced NAFLD. We fed C57BL/6J mice a low-fat diet (LFD, chow 10% kcal fat), a high-fat diet (HFD, 45% kcal fat) or HFD supplemented with the lemon-balm extract ALS-L1023 (HFD-ALS) for 15 weeks. ALS-L1023 reduced endothelial cell-tube formation in vitro. HFD increased VAT angiogenesis and induced weight gains including body weight, VAT mass and visceral adipocyte size compared with LFD. However, HFD-ALS led to weight reductions without affecting calorie intake compared with HFD. HFD-ALS also reduced serum ALT and AST levels and improved lipid metabolism. HFD-ALS suppressed steatosis, infiltration of inflammatory cells, and accumulation of collagen in livers. HFD-ALS modulated hepatic expression of genes involved in lipid metabolism, inflammation, fibrosis, antioxidation, and apoptosis. Concomitantly, analysis of VAT function revealed that HFD-ALS led to fewer CD68-positive macrophage numbers and lower expression of inflammatory cytokines compared with HFD. Our findings show that the anti-angiogenic herbal extract ALS-L1023 attenuates NAFLD by targeting VAT during obesity, suggesting that angiogenesis inhibitors could aid in the treatment and prevention of obesity-induced human NAFLD.
The growth and development of adipose tissue are believed to require adipogenesis, angiogenesis, and extracellular matrix remodeling. As our previous study revealed that ginseng reduces adipose tissue mass in part by decreasing matrix metalloproteinase (MMP) activity in obese mice, we hypothesized that adipogenesis can be inhibited by ginseng and its active components ginsenosides (GSs). Treatment of 3T3-L1 adipocytes with Korean red ginseng extract (GE) inhibited lipid accumulation and the expression of adipocyte-specific genes (PPARγ, C/EBPα, aP2, and leptin). GE decreased both the mRNA levels and activity of MMP-2 and MMP-9 in 3T3-L1 cells. These effects were further inhibited by total GSs (TGSs) and individual GSs. TGSs and individual GSs also significantly decreased MMP-2 and MMP-9 reporter gene activities in the presence of phorbol 12-myristate 13-acetate (PMA), the MMP inducer. Among the GSs, Rb1 most effectively inhibited MMP activity. In addition, PMA treatment attenuated the inhibitory actions of GE and GSs on adipogenesis. Moreover, GE and GSs reduced the expression of NF-κB and AP-1, the transcription factors of MMP-2 and MMP-9. These results demonstrate that ginseng, in particular GSs, effectively inhibits adipogenesis and that this process may be mediated in part through the suppression of MMP-2 and MMP-9. Thus, ginseng and GSs likely have therapeutic potential for controlling adipogenesis.
It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.
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