LONDON - The network of molecules known to be involved in the control of appetite and obesity now has a new member, with the discovery in Denmark of a peptide that makes rats stop eating. Researchers hope, if they can identify the peptide's receptor in the brain, it may be possible to find a drug that will block the receptor and thus control obesity.
The peptide is known as CART, which stands for cocaine- and amphetamine-regulated transcript. Peter Kristensen, head of histology at Novo Nordisk A/S, of Bagsvaerd, Denmark, and his colleagues report their findings in a paper in the May 7 edition of Nature, titled “Hypothalamic CART is a new anorectic peptide regulated by leptin.“
Kristensen told BioWorld International the experiments “will help to unravel some of the mechanisms for starting and stopping eating and how these are regulated.“ The work by Kristensen and his group links the effects of CART to those of leptin and neuropeptide Y, which already are known to be involved in regulating food intake.
Leptin is a hormone synthesized by fat cells. It is involved in passing information on the animal's current feeding state from the periphery to the brain. One of the effector molecules influenced by leptin is neuropeptide Y, which normally initiates feeding behavior. For example, levels of neuropeptide Y are very high in the brains of ob/ob mice, which have defective leptin that cannot function as a signaling molecule. As a result, these mice feed constantly and become very obese.
The experiments reported by Kristensen and colleagues suggest CART acts as the counterpoise to neuropeptide Y. Like neuropeptide Y, CART is also lacking in ob/ob mice. The researchers hypothesize that it is never produced, because the mice, which eat constantly, never become satiated.
When ob/ob mice are given recombinant leptin, these animals eat much less than control ob/ob mice. The Danish group showed that, in the brains of the experimental group, production of mRNA encoding CART was restored. The team went on to investigate what effect CART had on feeding, both in normal rats and in rats in which feeding had been stimulated by injections of neuropeptide Y into the ventricles of the brain. They found that injections of CART inhibited feeding in both groups.
Rats that had been fasted for 24 hours also were given CART into the ventricles, and their food intake measured. One microgram of CART inhibited feeding by 59 percent, and 2 micrograms of CART inhibited feeding by 68 percent.
The next experiment looked at whether an antibody directed at CART could affect normal nighttime feeding behavior in rats. The team first took some serum from a rabbit before immunizing this animal with CART so that it produced anti-CART antibodies. The researchers then injected rats on alternate nights with either the pre-immune serum or the anti-CART antiserum.
“We found that both groups ate normally for the first two hours after the onset of darkness, but that the rats which had received the control serum then ate less for the remaining 10 hours,“ Kristensen said. “However, those in which CART was knocked out by the antibody ate more and ate for longer.“ This demonstrates, he added, that CART plays a role in the normal feeding cycle.
The group's next goal is to isolate the receptor on which CART acts. CART itself could not be used therapeutically because it must be delivered directly into the brain. It is a large protein, so it does not cross the blood-brain barrier. Kristensen said: “What we would like to find is a small molecule - a genuine pharmaceutical - which acts in exactly the same way as CART. That will be the only way to obtain this effect inside the brain.“ *
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