Is obesity a disease, or merely an unsightly bodily condition?
"Obesity isn't really a disease - or is it?" observed pathologist Francis Kuhajda at Johns Hopkins University in Baltimore. "I think it is," he added, "but maybe not everybody does."
William McIntosh, chief business officer of FASgen Inc., thinks it is. His company was co-founded in August 1999 by Kuhajda and other faculty members at Hopkins. "The incidence of obesity and Type II diabetes is increasing at an alarming rate," McIntosh told BioWorld Today, "especially in countries of the Western world. In the U.S., one-third of adults and children are obese, and 16 million people have diabetes Type II. Hypertension, heart and kidney disease, cancer and arthritis will inevitably follow - creating major public health problems.
"An estimated $30 billion to $50 billion is spent annually in the U.S.," McIntosh continued, "on weight-loss therapies that produce very little in the way of lasting benefits. An effective long-term appetite suppressant, with no untoward side effects would meet an urgent need."
Research physician Jules Hirsch, at the Rockefeller University, points out that "treatments with many different diets, behavior modification, nutrition counseling, over-the-counter drugs and dietary supplements are the basis for a lucrative weight-loss industry that hardly makes a dent in the problem."
Kuhajda is trying to make that dent. He is senior author of a paper in Tuesday's Proceedings of the National Academy of Sciences (PNAS), released June 11, 2002. Its title: "C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity."
Fatty acid oxidation is the oil-burning internal-combustion engine that powers many cells, tissues and organs in the human body with energy. "If you're starving, for example," Kuhajda explained, "you have to burn fat because you're no longer eating anything."
Hirsch explained that "the brain's hypothalamus has long been known as a major locus for food intake regulation. One of the neuropeptides it secretes, orexigens, promotes food intake; another, anorexigens, curtails the appetite."
A Mechanism Wrapped In A Paradox
"We've been using a compound called C75," Kuhajda recounted. "We designed it to inhibit fatty acid synthase [FAS], which shuts off neuropeptide Y expression in the hypothalamus. It stops appetite - and mice on a high-fat diet lost more weight than their pair-fed controls.
"We found that this C75 compound, in addition to inhibiting fatty acid synthase, stimulates an enzyme, CPT-1, which is the gatekeeper for fatty acid oxidation on the mitochondrial surface," he continued. "Mitochondria supply the body with energy. That allows for fatty acid oxidation to freely take place. Even when we block fatty acid synthase, which C75 does, the substrate for FAS, called malonyl-CoA, goes up. When it does, it should inhibit CPT-1. But in the presence of C75, it no longer can. So fatty oxidation takes place. Malonyl-CoA is the switch; when you're making fat, it goes up and blocks CPT-1 so you don't burn up the fat you just made. When we block FAS, it goes up even higher. So you'd say, No fat is going to get oxidized at all!' But that's not true, and we're surprised that C75 prevents the effect of malonyl-CoA on CPT-1. That's the paradox.
"Now I think we understand that C75 stimulates fatty acid oxidation. It has two effects: One in the central nervous system, the hypothalamus, and, second, a peripheral effect in the liver, which produces fat, where it will allow increased fatty acid oxidation and energy production to take place," Kuhajda said.
He described his in vivo experiments with rodents binging on a fattening diet. "These were obese mice, which had been kept on a defined saturated-fat diet from post-weaning to 12 weeks old, when we started to do the experiments," he said. "Then we treated them with C75, and found that they produced more heat than their pair-fed control littermates. And they lost more weight. We noted this was an energy sink - producing more heat with C75.
"One can look at an obesity diabetes therapy based on these results," Kuhajda suggested, "and maybe electively work at appetite and fatty acid oxidation. So our goal is to separate these effects, and we're having some success with that. The ultimate goal is the therapy part. It's a long way off. C75 is a test compound, and we're learning a lot about its physiology. Because, whether obesity is or isn't a disease, the drug treatment will have to be incredibly safe. It has to go through a lot of testing before entering a Phase I trial in humans, then Phase II and III down the road. For an obesity compound such as C75, approval could take five, six, seven years, because we just can't move the biology any faster."
FASgen Takes It From There
FASgen's McIntosh described his company's reach beyond obesity and diabetes toward cancer and tuberculosis. "It turns out that fatty acid biosynthesis is a ubiquitous process," he told BioWorld Today. "It's essential for all living forms of life that have a biosynthetic pathway to deal with fatty acids. There are a number of drug-discovery targets along that pathway. The principal one is fatty acid synthase, which we're inhibiting.
"Cancer cells - preferentially and substantially - up-regulate FAS. It's believed necessary for rapid proliferation of tumor cells. So a significant portion of cancers are FAS-positive. If you interfere - down-regulate the FAS or otherwise shut off fatty acid synthase production - you induce an apoptotic state, essentially killing the cell. It can't survive without up-regulating FAS. Normal cells have the ability to up-regulate FAS, but don't do so because most of their fatty acid requirements are met by their normal diet. A FAS inhibitor can selectively poison or kill tumor cells without affecting normal cells."
McIntosh went on: "We know the TB bacillus - Myobactirium tuberculosis - has a waxy, fatty outer coat, which makes it pretty impenetrable to normal antibiotics, so TB is difficult to treat. It appears that fatty acid inhibitors interfere with the metabolic pathway that builds that wall, punching holes in its outer coat, leaving the organism susceptible to antibiotics, and they die.
"To date," McIntosh said, "FASgen has raised $3 million, generated by venture capitalists. [Johns Hopkins] university has licensed C75 and similar compounds to the company in exclusivity."