By David N. Leff
Try this multiple-choice quiz:
In the average human body, muscle mass amounts to: (a) 5 percent; (b) 25 percent; or (c) 45 percent of body weight.
If you picked 'b,' you won.
Body fat, of course, varies from person to person - from the very slim to the grossly obese. "An estimated 150 million people worldwide are affected by obesity and its complications," points out a press statement released Monday by Genset Corp, the La Jolla, Calif., branch of the French company Genset SA. It added that in the U.S., some estimates of obesity range from one-fourth to one-third of the population.
"Obesity-related diseases," the communiqui continues, "including diabetes, cardiovascular diseases and certain cancers, lead to several hundred thousand deaths per year in the U.S."
Genset's media announcement referred to preclinical results of its anti-obesity recombinant drug, Famoxin, by the company's scientific adviser, biologist Harvey Lodish, at the Whitehead Institute for Biomedical Research in Cambridge, Mass. Lodish is senior author of the research paper describing this experiment, in the Proceedings of the National Academy of Sciences (PNAS), dated Feb. 13, 2001, but made public on Tuesday. Its title: "Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice."
The article identifies that protein as Acrp30 (adipocyte complement-related protein), licensed by Whitehead to Genset, which has named it Famoxin.
By either name, Lodish and his co-authors (among them, Bernard Bihain, Genset's vice president of functional genomics) report discovery of a fragment of the human protein that controls body weight in mice without affecting their food intake.
"We identified this protein we called Acrp30 five years ago in mice," Lodish told BioWorld Today. "It's made only by fat cells, and secreted into the blood. At the time we cloned and published it, we didn't know much about Acrp30, except that insulin enhanced its secretion. Reports from others soon after found that certain obese mice and humans made less of it. Its gene sits on the long arm of human chromosome 3.
"That was it," Lodish went on, "until we started this collaboration with Genset. What we determined was that the full-length molecule is inactive pharmacologically. But there is a fragment of Acrp30, which contains what we called the C-terminal globular domain - the protein's active site."
Protein's Recombinant Nose-Cone Burns Fat
He continued: "We synthesized a very similar fragment of the human protein, which presumably represents the natural substance. Our experiments," he recounted, "showed that this recombinant sequence has three properties: First of all, in culture systems it enhanced fatty acid oxidation by muscle.
"The second set of experiments tells what happened when we injected this fragment of Acrp30 into living mice. When we fed them a high-fat meal, there was a very rapid increase in fatty acids in their blood. But that went down much quicker when we injected them with Acrp30, because it was taken up by muscle and burned - oxidized.
"Then in our third experiment," Lodish continued, "we took massively obese mice, which had been fed a cafeteria diet - ad lib ingestion of sugar and coconut oil treats. When we injected this compound into those fat, chubby mice, they continued to gorge on this horrible high-fat diet, but they lost weight - as much as 8 percent of their body mass in two weeks. That's huge."
Lodish digressed to point out that the letters "cr" in Acrp, standing for "complement-related," are inaccurate. "It's in the title because when we identified the protein, its closest homologue was C1q, a prominent protein of the immune system's complement cascade. But as far as we now know it's not complement-related. In fact, as we later showed, the globular domain of Acrp's amino-acid sequence resembles in its structure tumor necrosis factor - TNF-alpha - a more interesting protein. That was what got us onto the notion that we might have a new hormone here."
Leptin, of course, is also a hormone, with reputed weight-losing properties.
"Like Acrp30," Lodish observed, "leptin is made in fat cells. A point that emerges from this whole picture is that fat cells can now be considered as endocrine cells. They are probably secreting a number of proteins that regulate fat metabolism - leptin and Acrp30 being two such proteins that are really understood now. But they have fundamentally different modes of action," he added. "Leptin acts in the brain to inhibit appetite, in some ways that are not well understood, whereas Acrp30 appears to act mainly in muscle. The net effect is weight reduction in these mice, but the mechanisms are entirely different."
Lodish noted, "Leptin has not been working in humans, and of course it's anyone's guess as to whether Acrp will. I think everyone agrees," he observed, "that there are more of these proteins out there, which are potentially interesting.
"The bottom line from the basic-science point of view," he summed up, "is that we've got a hormone that affects fat metabolism. Whether it can be converted into a human drug is for the drug companies to figure out. We've been working with Genset on this."
Clinical Phase I Trials Likely In Europe
In fact, the firm's press release stated, "The discovery of a new hormone like Acrp30 allows Genset to envisage increasing the energy expenditure of obese subjects. Based on the recently reported and other preclinical results, the company anticipates initiating clinical trials of Famoxin toward the end of this year."
Genset's world headquarters is in Paris. Bihain told BioWorld Today, "We will probably start Phase I human studies in Europe. We will select severely obese people with Type II diabetes, and determine in these people their blood plasma level of full-length Acrp30 and the fragment. Our clinical trials will start by giving this to the participants who are missing it in their plasma. We have already identified those people.
"Coming from mice to humans is always a very big challenge," Bihain concluded. "But here we have something that is missing - and we're really going to give it." n