In recent years, tremendous advances have been made in understanding the biochemical basis of eating disorders. The discovery of three hormones in particular - leptin, ghrelin, and most recently peptide YY (PYY) - has triggered a huge interest in the endocrine control of the appetite center in the hypothalamus. However, most of the research has focused on interfering with the hormonal pathway, either by blocking or stimulating hormone receptors. This strategy, says Bloom, is misguided.

"The current pharmaceutical approach of knocking out receptors across the brain does not seem a sensible approach, but focusing on the hormones might be useful," said Bloom. "Right at the moment, even on the future list [of drugs], there isn't anything that looks terrific," he said.

In 2000, more than 20% of the US population was estimated to be clinically obese, according to the Behavioral Risk Factor Surveillance System. "It's nice to know the US leads as always," quipped Bloom. However, other developed nations are not far behind. In the UK, the deaths of more than 2000 people every week can be attributed to obesity, which the Department of Health estimates shortens lifespan by an average of nine years. "Obesity is increasing, and it's increasing at an increasing rate," Bloom warned.

The standard advice to obese individuals is to eat less and exercise more, but this has done nothing to stem the obesity epidemic. "One of the reasons it doesn't work is we're actually designed to get fat when there's a harvest, to survive the ... famine to follow," he said. Consequently, many people are prepared to pay big bucks for a successful anti-obesity drug free of side-effects.

Currently, there are only two drugs on the market aimed specifically at fighting obesity, and a whole host of others that are undergoing trials. Orlistat (Xenical) interferes with lipase action, preventing the digestion of fatty acids and allowing about 30% of the fat eaten in a meal to pass through the gut. But because of its crude mode of action and side effects, Bloom is not persuaded: "Your laundry bills go up and your friends disappear," he summarized.

The other licensed drug, sibutramine (Meridia), suppresses appetite primarily by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin. However, this also increases libido and, in men, causes a persistent erection.

In his Dale Medal Lecture at the 22nd joint meeting of the British Endocrine Societies in Glasgow last week, Bloom reviewed the intertwined hormonal mechanisms that underlie appetite. The central dogma, he explained, is that the arcuate nucleus in the hypothalamus senses, integrates, and relays endocrine cues to the paraventricular nucleus, which then brings about coordinated changes in energy expenditure.

One of the most exciting of these endocrine cues comes from PYY, the newest member of a growing band of peptide hormones that are now known to influence satiety and appetite. PYY is synthesized in the gut, and released following a meal, causing circulating concentrations to rise. "When we mimic that rise, people eat a third less and lose their appetite," Bloom told BioMedNet News.

By contrast to current pharmaceuticals, PYY injection does not have any significant side-effects, probably because it is simply mimicking a natural hormonal fluctuation that the body is used to. "Surely this is going to be a more useful way of going forward," said Bloom. The drugs in development may be patentable and saleable, but have the disadvantage of huge potential side effects, he says, because they are acting on receptors throughout the body.

And there could well be new appetite-regulatory hormones waiting for discovery. "There are going to be more and more and more ... and then it's going to be really complicated," said Stephen Shalet, a clinical endocrinologist at Christie Hospital in Manchester, UK. "Only one or two people in the world will be able to understand it," he said.

In addition to looking at levels of hormones in the circulation of obese individuals, Bloom's group has recently detected increased levels of a neuroendocrine peptide in women suffering from anorexia nervosa (AN), which could be the first step towards understanding the biochemical basis of the disorder.

Overexpression of a peptide hormone, the poorly understood cocaine- and amphetamine-regulated transcript (CART), could change the way that this disorder is perceived, and suggests a target for future therapy.

AN, which is diagnosed through an assessment of psychological and physical factors, is estimated to affect between 1% and 5% of women in the UK. "CART is upregulated by about 50% in women with AN," said Sarah Stanley, a member of Bloom's team at Imperial College. "It's present in the circulatory system, crosses the blood-brain barrier and inhibits appetite," she said, adding that it is too early to speculate about possible drug therapy. "Whether this is a response to weight loss, or is causing it, we don't know," she said. "It's still very early."

"We need to find out more about CART in order to fully understand its functions," said Stanley, who also presented her findings in Glasgow. In particular, she emphasized that the action of this peptide in the periphery is entirely unknown. "Future work measuring levels in obese subjects and those that have lost appetite due to illness will help us to identify possible therapeutic uses for this molecule," she said.

The molecular mechanisms that lead to diminished food intake in AN are not clear, says Stephen O'Rahilly, a clinical biochemist at the University of Cambridge, UK. "This is something that needs a lot of new research and is intriguing," he said. "The main limitation is what the plasma levels tell us about what's going on in the brain."

Nevertheless, O'Rahilly is positive about the overall progress in the field of appetite research. "We're now getting to a stage where we're getting to a real understanding of what the molecules that influence human eating behavior are," he said.