A catalytic subunit of the DNA-dependent protein kinase complex (DNA-PKcs) has been shown to be important in DNA repair and VDJ recombination in lymphocytes. The inventors have discovered that DNAPKcs also plays novel, important roles in energy regulation and neurological function. The inventors observed that mature DNA-PKcs-deficient mice (also known as SCID mice) have a lower proportion of fat, resist obesity, and have significantly greater physical endurance than wildtype control mice, particularly with increasing age. The inventors also observed that DNA-PKcs-deficient mice have better memory and less anxiety.
One potential explanation for this is that they express higher levels of brain-derived neurotrophic factor (BDNF), which is associated with neurogenesis, memory formation and suppression of anxiety and depression. Moreover, DNA-PKcs-deficient cells produce less oxidative stress. Thus, inhibition of DNA-PKcs may have unexpected utility in the treatment of a wide range of diseases and conditions.
The invention discloses methods of inhibiting DNAPKcs activity to decrease adiposity, improve physical endurance, and increase insulin sensitivity and the number of mitochondria.
More info: Jay Chung, chungj@nhlbi.nih.gov
