Could NAADP/cholecystokinin-combo attack fat from inside and out?

One traditional approach to pharmaceutical design uses so-called “first messengers” – hormones, other natural facilitators or synthetic products – to initiate various cellular cascades for the desired physiological effect. To date, despite concerted efforts at all levels of research, this approach has failed to develop a truly successful obesity drug to address this major global health problem.

Enter a recently discovered and already controversial natural molecule called nicotinic acid adenine dinucleotide phosphate (NAADP), which is active in cells from plants to humans. NAADP is thought to be a so-called “second messenger,” because it works from inside cells, rather than externally. However its mode operation remains unknown – and controversial in several aspects.

Results of a new study “establishes NAADP as a new second messenger, and the study of this novel molecule has potential to extend its clinical significance, possibly as a candidate for treating obesity,” according to the lead author, Michiko Yamasaki at the Department of Pharmacology, University of Oxford, United Kingdom.

Yamasaki is presenting the research at the 35th Congress of the International Union of Physiological Sciences in San Diego, March 31 - April 5, 2005.

The team working on the study was comprised of Michiko Yamasaki, Grant Churchill and Antony Galione at the Department of Pharmacology, University of Oxford; Sandip Patel at University College London; and Jose M. Cancela at CNRS, Laboratoire de Neurobiologie Cellulaire et Moleculaire, Gif-sur-Yvette, France.

Viagra is the best-known “second messenger” targeting agent

One of the problems with many drugs is their side-effects, which range from annoying to lethal. “The most fundamental answer to solve safety and other issues,” Yamasaki said, “is increasing the specificity of a drug, and NAADP could provide a key in the area of obesity.”

In another therapeutic arena, she notes, Viagra is the world’s most successful and recognized secondary messenger targeting drug to reach the market.

Cholecystokinin, a first messenger, activates NAADP; so which is ‘therapeutic?’

Several earlier drugs designed for obesity treatment were chosen because they released a chemical – the hormone serotonin -- in the brain that controls satiation, as well as mood and body temperature. “More recently, another hormone, cholecystokinin, has been considered to be a potential drug target,” Yamasaki noted. Cholecystokinin is a naturally-occurring chemical synthesized both in the small intestine and in the brain when eating.

Cholecystokinin is a first messenger that tells cells to release digestive enzymes in the pancreas and to cause satiety in the brain. “The more cholecystokinin that’s produced, the more digestive enzymes are released and the more quickly your brain tells you that you’re full – or at least satisfied. Indeed, it also could be a potential drug for the treatment of obesity, Yamasaki noted.

“We have shown that cholecystokinin activates NAADP production through a specific protein on the cell surface, the cholecystokinin-A receptor. The existence of the cholecystokinin-A receptor in the brain strongly implies a possible role of NAADP in cholecystokinin-induced satiety,” Yamasaki said.

Methods, results and conclusions

The team worked on the theory that NAAPD mobilizes Ca2+ from lysome-related organelles and plays a crucial role in cholecystokinin-induced Ca2+ mobilization in pancreatic acinar cells. Despite the intensive study into the physiological role of NAADP in Ca2+ signaling in pancreatic anicar cells, direct demonstration of changes in NAADP levels in response to agonist-stimulations has been lacking, Yamasaki said.

“We found that application of cholecystokinin to isolated populations of pancreatic acinar cells caused NAAPD level to increase as much as 6-fold in only 5 to 10 seconds,” Yamasaki said. The cholecystokinin-A receptor, expressed predominantly in pancreatic acinar cells, has two binding sites, one of high and one of low affinity.

“Unequivocal evidence that NAADP is a crucial messenger”

“Intriguingly, the plot of NAADP level versus cholecystokinin concentration was best fit with a two-site model, suggesting that both the high- and low-affinity sites were linked to NAADP production,” Yamasaki said. In contrast to the hormone cholecystokinin, the neurotransmitter acetylcholine failed to affect NAADP level, even when applied at supramaximal concentrations in terms of physiological relevance and which saturate the calcium amplitude and spiking frequency.

In conclusion, Yamasaki said, “Our data in this experiment provides the first direct evidence that cholecystokinin elicits a rapid, dose-dependent and selective increase in NAADP, and thus unequivocal evidence that NAADP is a crucial messenger employed by cholecystokinin.”

Yamasaki noted that NAADP has “a short history compared to other traditional intracellular messengers and many aspects of this molecule remain under investigation. However the potential of this new messenger as a therapeutic target should not be underestimated,” she added.