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Novel apoptotic mechanism of bioactive flavonoids in obesity

Modulating apoptosis is emerging as a promising strategy for prevention and treatment of obesity. Effects of flavonoids on the cell‐death fate are mediated via multiple signaling pathways converging on cellular Ca2+ (Sergeev, 2009). Ca2+ signaling has been implicated in regulation of apoptosis, however, the flavonoid‐activated Ca2+‐dependent apoptotic molecular targets have not been identified. We investigated mechanism of flavonoid‐induced apoptosis in obesity using a model of mature mouse 3T3‐L1 adipocytes. The results obtained demonstrated that soy isoflavones (genistein) and polymethoxyflavones from orange peel induce the apoptotic Ca2+ signal, sustained increase in concentration of intracellular Ca2+, in adipocytes in a concentration‐ and time‐dependent fashion. The flavonoid‐induced Ca2+ increase was associated with activation of Ca2+‐dependent μ‐calpain and Ca2+/calpain‐dependent caspase‐12. The activation of these proteases appears to be sufficient for executing morphological and biochemical consequences attributed to apoptosis. These findings indicate that flavonoids can trigger the apoptosis‐initiating Ca2+ signal and recruit Ca2+‐dependent apoptosis‐executing effectors. Targeting of Ca2+ signaling in mature adipocytes via dietary supplementation with flavonoids capable of inducing apoptotic cell death can represent an effective, safe and affordable preventive and therapeutic approach to obesity. Supported by USDA 2009‐35200‐05008, SD00H325, and WellGen.