New bull's-eye for obesity fighting drugs

The culprit of this fat-causing mechanism is an enzymatic collection of 1441 amino acids called Tripeptidyl peptidase II (TPPII). It has already stood accused of making people feel hungry, but this latest research from Jonathan Graff and his colleagues at UT Southwestern Medical Center, Texas, US, suggests it may be much more deeply involved in causing obesity. Although genetic mutations that could contribute to obesity are reported relatively frequently, it is much less common for a new, viable drug target to be discovered. Given that obesity is one of the developed world's greatest health challenges - estimates of the number of obese Americans top 100 million - the need for new ways to tackle it is obvious. The work was first conducted in Caenorhabditis elegans​ (C. elegans​) worms, where the team found that TPPII regulates the equilibrium the worm maintains through metabolism. RNA interference (RNAi) of the target decreased worm fat stores independently of feeding behaviour. This occurred in the worm's intestines - the site of fat storage. The process by which this happens was then investigated in mammalian cell cultures. TPPII was found to stimulate the development of fat cells from preadipocytes (adipogenesis). As TPPII is a protease enzyme and so breaks down other proteins to release energy, the team also modified the protein so that it was catalytically inactive and found that it could still increase adipogenesis. Mice that with dysfunctional versions of the Tpp2 gene in both chromosomes didn't survive, but those with only one insertion in the DNA sequence survived and were thinner than normal mice, despite eating the same. The authors hope that TPPII could be exploited as a drug target to help fight increasing levels of obesity; that's to its dual role in metabolism, inhibiting the enzyme could both increase feelings of fullness after eating and decrease build up of fat cells. Even if a drug company was to develop a good treatment for obesity, many would argue that we already have a 'cure' for the majority of cases: a better diet and more exercise. But while there are those that ignore such sound advice, the pharma industry will continue to search for fat-busting drugs.