JNCASR’s novel molecule prevents obesity in mice

• The developed world suffers from numerous cases of obesity due to a more sedentary mode of life.
• Developing world - obesity due to irregular food habits and economic stress
• Leads to accumulation of visceral fat in the stomach area & liver.

Obesity

• More of a lifestyle-related health disorder
• Can lead to several other diseases such as non-alcoholic fatty liver disease, diabetes and osteoarthritis.
• No reliable drugs available for obesity and its associated disorders.

Epigenetics

• A branch of molecular biology working on how the modifications of the gene rather than the gene sequence itself can regulate gene function.
• Epigenetic changes are reversible and directly correlated with habits as well as social and environmental cues.
• Histones - Protein balls around which the genetic material DNA is wrapped.
• Different chemical modifications of both DNA and histones dictates the fate of genes in terms of them being switched on or remaining switched off.
• This balance of gene expression is critical for health and disease.

LTK-14A

• A chemical modification of histone — lysine butyrylation — is critical for fat cell development that underlies obesity manifestation.
• Helps to search for a small molecule that could specifically inhibit this modification and thereby arrest or ameliorate obesity.
• A semi-synthetic derivative of garcinol (molecule naturally found in Garcinia indica (kokum) fruit rind) is found to selectively reduce the levels of this modification by inhibiting the catalytic activity of the master epigenetic enzyme p300 responsible for it.
• Molecule LTK-14A is very specific for only one enzymatic activity of the multi-functional enzyme p300.
• So, minimal toxicity from this compound.

Effectiveness of LTK-14A

• Protective effect of LTK-14A
• Kokum (Garcinia indica) extracts are known to have a protective effect against obesity.
  • But, its major chemical constituent garcinol was found to be toxic as it targets many enzymes non-specifically.
• LTK-14A is more efficient for targeted inhibition of the less abundant butyrylation modification.
• Not only inhibits fat synthesis in mice cell lines but also prevents obesity in mice feeding on high fat-diet.
• Could reduce the weight of genetically obese and highly diabetic mice as well.
• Could reduce fat accumulation in the liver also.
• Almost non-toxic.