LONDON _ The discovery of a brain peptide that regulates foodintake in rats could lead to a new generation of drugs to treat obesityin humans within a decade. Agriculture could benefit, too, as thework may make it possible to rear heavier calves and pigs per poundof feed.
The peptide is called glucagon-like peptide, or GLP-1. Steve Bloom,professor of endocrinology at the Royal Postgraduate Medical Schoolat Hammersmith Hospital in London, together with colleagues fromthe department of anatomy at the University of Cambridge, report inthe January Nature that GLP-1 can powerfully inhibit feeding in ratsthat have been fasted.
The existence and sequence of GLP-1 has been known for about 10years. The sequence is highly conserved _ it is the same in allmammalian species studied _ suggesting that GLP-1 plays a crucialphysiological role. But its function remained a mystery until 1988,when Bloom and colleagues discovered that, infused into thebloodstream in humans, it triggered release of insulin from the beta-cells of the pancreas. The researchers showed that GLP-1 is releasedfrom the gut after a meal and stimulates insulin release. Their findingprovided an explanation for why people being fed intravenously _for example, following surgery _ often become temporarily diabetic.Without the stimulus of food passing through the gut, little or noGLP-1, and hence no insulin, is released.
Bloom and his co-workers went on to discover that, in rats, GLP-1also is present in the hypothalamus of the brain. Using techniquesthat allowed them to deliver the peptide directly into the ventricles ofthe rats' brains, they observed that rats given GLP-1 did not appear tofeel hungry.
"Their pattern of behavior was identical to that seen after a meal _they groomed, licked and lay down and fell asleep," Bloom said."They did not seem disturbed but contented _ so far as you can tellwith a rat."
GLP-1 Triggered Insulin Release
The researchers postulated but could not prove that the GLP-1present in the hypothalamus probably had a role in limiting foodintake. "The breakthrough came," said Bloom, "when in 1993 anantagonist to GLP-1, called exendin 9-39, became available." Givento rats intravenously, this GLP-1 blocker caused them to becomediabetic after meals. "This proved the hypothesis that the animals'own gut GLP-1 was important in triggering insulin release after ameal."
The team then turned their attention to what effect the GLP-1antagonist would have on the GLP-1 produced in the animals' brains.Rats provided with plentiful food normally eat during the night (ordark phase) and sleep all day (the light phase). At the end of the darkphase, they fill up with food, ready for the long fast during the lightphase. Thus, at the beginning of the light phase, they have eaten asmuch as they want.
Rats in this state, given exendin directly into the ventricles of thebrain, suddenly wake up and eat more. Bloom says: "This suggeststhat by giving exendin, we are blocking some factor that stops themeating when they are full. But exendin had no effect on appetite at thebeginning of the dark phase, when the animals are ravenous,presumably because they are not themselves releasing GLP-1 at thispoint. We postulate that GLP-1 is only released in the animals' brainswhen they are full."
In their paper, the researchers report that the food intake of rats givenintracerebroventricular exendin at the start of the light phase morethan doubled. They also present data showing that giving ratsintracerebroventricular GLP-1 caused activation of neurons in tworegions of the brain already known to have a role in the regulation offeeding, but not in other regions.
Because the structure of GLP-1 was already public knowledge, noone can patent it. Bloom predicted that several biotechnology andpharmaceutical companies are likely to search for compounds thateither activate the GLP-1 receptor or block it. "It seems likely thatthere will be a number of rival products coming out in seven or eightyears' time," he said.
The Search For Orally Effective Compounds
Mike Stock, professor of physiology at St. George's HospitalMedical School, warned that finding analogues that can survivedigestion and then cross the blood-brain barrier will not be easy."This work is very interesting and well worth following up, but thereare still a lot of problems to be overcome," he said. "If GLP-1 isproduced in the brain, and has its actions there, we need to find outwhat are the mechanisms that switch on its production at the end of ameal _ this could lead to the development of orally effectivecompounds that stimulate endogenous brain GLP-1."
The quest for drugs to control obesity will, no doubt, be driven by thepotentially enormous market. Bloom said that three out of five mendie of ischemic heart disease and stroke caused by build-up ofatheroma in the arteries, which in turn is caused by overeating.
"Given that overeating has such a deleterious effect on us, preventingit would be a major therapeutic goal but in the first instance suchdrugs might be more likely to be used to treat people with diabetescaused by severe obesity where weight reduction would giveimmediate pay- back in terms of quality and length of life," he said.
Conversely, an antagonist to GLP-1 might be helpful in people withanorexia, those with cancer who are losing weight and those who findit difficult to put on the pounds following surgery.
The researchers' other plan is to use their recent findings to unravelhow leptin, the other major inhibitor of food intake, operates. Oddly,there appear to be few receptors for leptin, the protein produced bythe Ob gene, in the hypothalamus. Bloom said, "This suggests thatleptin may act indirectly _ possibly by increasing the release ofGLP-1. If so, giving exendin, the antagonist of GLP-1, ought to blockthe effect of leptin, and we are planning to find this out." n
-- Sharon Kingman BioWorld International Correspondent
(c) 1997 American Health Consultants. All rights reserved.