Fat tissue in obesity results from adipocyte hyperplasia or the formation of new adipocytes from progenitors, and from hypertrophy (enlargement) of pre-existing adipocytes. It is a form of adipocyte, white adipocytes, that are primarily responsible for fat retention and storage. A new approach for reducing their production is needed to reduce the presence of fat storing white adipose tissue, thereby reducing obesity.
Beige adipocytes utilize fat to create thermal energy and do not store large quantities of fat like white adipocytes. Beige adipocytes may have the potential to prevent diet-induced obesity. Our inventors have identified Clk1 (cdc2-like kinase1) inhibition as a mediator of beige adipocyte induction. By inhibiting Clk1 in terminal differentiation of adipocytes, the body can be induced to produce more beige adipocytes that contain more mitochondria and burn, rather than store energy via increased UCP1 expression and increased fatty acid oxidation. These compounds will be an effective treatment of obesity by preventing the proliferation of fat storing white adipocytes in favor of beige adipocytes.
Oil Red O staining indicates a substantial decrease in total lipid content in adipose cells treated with TG003 and DC677, as compared to the control.