You may never get a second chance to make a first impression - but in medicine, from leeches to monoclonal antibodies onward, hardly anything works the first time. Which is why the leptin pathway remains an interesting anti-obesity target, with two recent papers reporting basic research that yet could help unlock its pharmaceutical potential.

The hormone leptin acts on the brain to inhibit food intake and increase energy expenditure. So after its discovery in 1994, the initial clinical strategy to exploit it was straightforward: administer leptin to obese patients.

That strategy bombed in clinical trials, as further basic research showed the reason why - obese people make plenty of leptin but are insensitive to its appetite-suppressant and energy expenditure effects, a phenomenon known as leptin resistance.

Undaunted, researchers next tried to find downstream targets in the leptin signaling pathway that might allow them to overcome leptin resistance.

One such potential site is PTP1b, a protein phosphatase. In cells, phosphatases remove phosphate groups from proteins to affect their activity. Kinases, which add phosphate groups to proteins, have been the subject of much pharmaceutical attention - which has resulted in the tyrosine kinase inhibitor Gleevec (imatinib, Novartis AG). But phosphatases have received less attention to date.

In 2002, Barbara Kahn and Ben Neel, both professors of medicine at Harvard Medical School, and their colleagues showed that global PTP1b knockout mice are hypersensitive to leptin and resistant to weight gain induced by a high-fat diet.

"One of the open questions in the field is where the site of leptin resistance is," Kahn told BioWorld Today. "But our results clearly showed that if you bypass proximal events, you can overcome leptin resistance." PTP1b works by dephosphorylating the Janus kinase 2, which is activated when leptin binds to its receptor.

However, because PTP1b is expressed in multiple tissues, the results, while basically promising in terms of targeting PTP1b to fight obesity, did not show which tissue type would make the most promising target for such efforts.

A paper to be published in Nature Medicine and available now online shows that "PTP1b inhibitors would have the maximum beneficial effect if they could be targeted to the brain," first author Kendra Bence, assistant professor at the University of Pennsylvania's School of Veterinary Medicine, told BioWorld Today.

The researchers created tissue-specific knockouts that lacked PTP1b expression in brain, liver, muscle or fat tissues. Mice lacking PTP1b in the brain showed the lean, weight-gain-resistant phenotype that the scientists had observed with the global knockouts, while liver and muscle knockouts showed no effect on body weight. Fat cell knockouts, surprising the scientists, had increased body weights.

Intriguingly, male and female knockouts had subtly different phenotypes. "Females have a slightly milder phenotype, and it takes a little bit longer for the resistance to weight gain to develop," Bence said. But "basically, the effects are the same" for males and females.

A paper published in the July 5, 2006, issue of Cell Metabolism by scientists from the Albert Einstein College of Medicine in New York and the University of Michigan at Ann Arbor show that preventing leptin from affecting a specific downstream protein, Stat3, prevented its effects on feeding and glucose metabolism.

Bence called the results in Cell Metabolism "consistent" with the results she and her colleagues reported in Nature Medicine, and added that the results "present the intriguing possibility that the improvements in glucose homeostasis seen in neuronal [PTP1b knockouts] may be a direct result of increased STAT3 signaling in central pathways."

Among the companies trying to exploit PTP1b commercially is Bothell, Washington-based Ceptyr Inc., where both senior author Kahn and co-author Benjamin Neel are on the scientific advisory board. Kahn said that Ceptyr, which is focused on developing drugs to inhibit protein tyrosine phosphatases, has licensed the global PTP1b knockout mouse, but was "not directly involved" in the research reported in Nature Medicine. The tissue-specific knockouts are as yet unlicensed.