Polyphenols modulation of angiogenesis and obesity.
Mohsen Meydani, Asma Ejaz, Syeda Tahira Hasan, and Jean Marc Zingg.
Vascular Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on
Aging at Tufts University. 711 Washington Street, Boston, MA 02111.
Angiogenesis is necessary for the growth of tumors or any growing tissues such as
adipose tissue. There is a reciprocal regulation of angiogenesis and adipogenesis, which
suggests that inhibition of angiogenesis may inhibit adipose tissue formation. Several
natural polyphenols, including catechins, resveratrol and curcumin may, with their antiangiogenic activities, modulate adiposity, body weight gain and associated inflammation
by interfering with adipocyte development, macrophage activation, and production of
inflammatory mediators. In one study, we examined the effect of curcumin, a natural
polyphenol present in turmeric, on angiogenesis, pre-adipocyte growth, lipid
accumulation in adipocytes and macrophages, differentiation, apoptosis and gene
expression involved in lipid and energy metabolism in cell culture systems and on body
weight gain and adiposity in mice fed high fat diet supplemented with 500 mg
curcumin/kg diet for 12 wks. Curcumin in a dose-dependent manner suppressed
adipocyte differentiation and caused apoptosis. It also inhibited adipokine-induced
angiogenesis of human umbilical vein endothelial cells (HUVEC) and accumulation of
lipids in adipocytes and macrophages. Supplementing the high fat diet of mice with
curcumin did not affect food intake but reduced body weight gain, hepatosteatosis,
adiposity, and microvessel density in adipose tissue, which coincided with reduced
expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2.
Curcumin increased AMP activated kinase (AMPK) phosphorylation, reduced glycerol3-phosphate acyl transferase (GPAT-1), and increased carnitine palmitoyltransferase-1
(CPT-1) expression, which lead to increased oxidation and decreased fatty acid
esterification. The in vivo effect of curcumin on the expression of these enzymes was also
confirmed by RT-PCR. In addition, dietary curcumin significantly lowered blood
cholesterol levels and the expression of peroxisome proliferator-activated receptorgamma (PPAR-) and CCAAT/enhancer binding protein-alpha (C/EBP-), two key
transcription factors involved in adipogenesis and lipogenesis. To investigate whether
these effects of curcumin on lipid metabolism can reduce the risk of atherosclerosis, we
supplemented high fat-fed LDLr-/- mice with increasing doses of curcumin (500, 1000,
1500 mg/kg diet) in another study for 16 weeks and found a significant reduction in
atheroma lesions with 1000 mg curcumin/Kg diet. We also found that accumulation of
lipids in macrophages collected from the peritoneal cavity was reduced along with
reduction in the expression of scavenger receptor CD36 and fatty acid binding protein,
aP2. Our findings suggest that in addition to suppressing angiogenesis in adipose tissue
combined with its effect on lipid metabolism and its reduction of lipid accumulation in
adipocytes and macrophages, curcumin may contribute to a lower body fat and body
weight gain and may reduce obesity-associated inflammation of arteries and
atherosclerosis.
Supported by AFRI grant:10248826/2009-02916 & USDA Contract#-58-1950-7-707.