Obesity increases the risk of various diseases, such as type 2 diabetes, hypertension, coronary heart disease, and cancer. Obesity results from increase of proliferation and differentiation of adipocytes as a result of overnutrition or reduced energy expenditure. Adipocytes are the cells that primarily compose the adipose tissue which is specialized in storing energy as fat. Adipose tissue is located beneath the skin (subcutaneous fat), around internal organs (visceral fat), in bone marrow (yellow bone marrow), intermuscular (Muscular system) and in the breast tissue.
Adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and the cytokine TNFα. Moreover, adipose tissue can affect other organ systems of the body and may lead to disease. Therefore, the possibility of controlling the development of adipose tissue may be an opportunity for pharmacological intervention and treatment of obesity.
That led a team of researchers from the Sungkyunkwan University School of Medicine and the Sejong University in Korea (as described in this publication) to turn their interest towards fisetin because they noted it has been reported to reduce the prevalence of diabetic complications. Fisetin does this by decreasing methylglyoxal-dependent protein glycation in blood, kidney, and brain of diabetic mice, and by decreasing the levels of blood glucose, glycosylated hemoglobin, serum uric acid, and serum creatinine. While this already done research revealed for example that fisetin acts through suppressing of mTORC1 activity and regulates Sirt1 expression during early adipogenesis it remained unclear if there are additional benefits of fisetin’s transcriptional and epigenetic effects and whether it can inhibit early adipogenesis. Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. It is a critical process for controlling lipid homeostasis, energy balance and endocrine functions. Deregulated adipocyte differentiation is known to be closely linked to development of obesity.
The researchers tested and studied the validity of this hypothesis in-vitro on the 3T3-L1 cell line which is derived from mice 3T3 cells and is used in biological research on adipose tissue.
They found that fisetin inhibits lipid accumulation and suppresses the expression of PPARg in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARg and FoxO1, and enhanced the association of Sirt1 with the PPARg promoter, leading to suppression of PPARg transcriptional activity, thereby repressing adipogenesis.
This also supports existing research that severe obesity is associated with significant reductions in Sirt1 expression. Hence overall this reveals a potential therapeutic strategy of fisetin use for suppressing fat accumulation in obesity.