By David N. Leff
"There is a widespread bias that people who are overweight must be over-eaters. Yet there is no solid evidence in the literature that obese people do in fact eat too much."
This observation comes from molecular geneticist Craig Warden, of the University of California, at Davis. "If that's not the case," Warden told BioWorld Today, "then all you're left with is that people who are obese must differ in some way in their energy-expenditure side of the intake-output sides of the energy equation."
On the molecular level, mammals play out that equation in and around their mitochondria, commonly known as the cell's power plant.
Warden is principal author of a paper in the March Nature Genetics, reporting discovery of a mammalian gene that diverts mitochondrias' job of supplying energy only for cellular functions, to burning off calories, in the form of excess body fat.
"What we have provided," Warden said, "is a gene that is involved in energy expenditure * burning calories. It encodes a protein that is not a hormone, not a receptor, but the actual worker molecule. What we suggest is that it looks like a likely drug target."
He and his co-authors have named their novel gene sequence "uncoupling protein2" (UCP2). What distinguishes it from long-known UCP1 is their strikingly different locations and functions in the body.
UCP1's gene product markedly influences energy expenditure, but dwells mainly, if not exclusively, in brown fat cells, which are few and far between in the adult human body. In contrast, its newly discovered homolog protein, UCP2, is widely expressed in human tissues, especially white fat cells and muscle.
"The whole problem with UCP1," Harvard endocrinologist Bradford Lowell observed, "has always been that it's important in rodents * and human neonates * but not in adult humans, who tend not to have very much brown fat." Lowell and his co-author Jeffrey Flier, at Beth Israel Deaconness teaching hospital in Boston, wrote a commentary on Warden's paper in Nature Genetics, titled: "Obesity research springs a proton leak."
Protons, positively charged particles of matter, are the least common denominator of the mitochondrion's power supply to the cell.
ATP (adenosine triphosphate) is the molecule that enables a mitochondrion to burn fuel * largely fats and carbohydrates * to provide its cell with energy, coupled to the actual energy needs of the cell to do its work.
"By uncoupling that relationship," Lowell told BioWorld Today, "the mitochondrion can simply burn fuel * that is, calories."
Because Warden's new UCP2 protein operates on widespread white adipose tissue, rather than scarce brown fat cells, Lowell pointed out, "and a dominant fuel floating around inside white fat cells are fatty acids, presumably there would be a marked effect on fatty acid fuel consumption."
He observed: "Just simply stated like that, somebody would have to be scientifically brain dead not to realize UCP2's significance."
If It Works In Mice, Humans Come Next
Qualifying that appraisal, Lowell added: "There'll need to be some proof-of-principle work done. For instance, transgenic mice expressing UCP2 should be skinny. Gene knockout mice that lack it should become obese."
Warden allowed that he and his group are "working on mouse experiments, doing transgenics and knockouts," as well as "very actively looking for the human sequence variants of UCP2, and asking whether these are associated with obesity."
As for the pharmacological potential, he said, "Obviously, large-scale drug screening isn't something I'm going to do in my lab * until we find a partner."
Lowell commented: "Assuming that his principle will be proved, people will be trying to find ways of increasing the expression of the UCP2 gene, or to pharmacologically alter the activity of its uncoupling protein UCP2."
Back in the wide-open medicine market of the 1920s, he recounted, an industrial chemical called dinitrophenol (DNP) was sold as a remedy for treating obesity. "What DNP does is, it leaks protons. It's a molecule that diffuses freely across cell membranes in a protonated and unprotonated state.
"So outside the mitochondrion," he continued, "DNB picks up a proton, releases it inside, goes back outside for another one. That way, the drug uncoupled mitochondrial respiration. So, in the humans who took it during the 1920s, it turned on their energy expenditure like crazy. Their body temperature was going way up, and it was killing them. One of the earliest things the FDA did was get DNP off the market."
From Old-Time Quackery To Modern Drug Design
This doesn't mean, Lowell pointed out, that stimulating UCP2 would provoke the same toxicity. "DNP," he pointed out, "doesn't interact with any proteins; it just does unlimited uncoupling of all mitochondria.
"So if one were to design activators of UCP2, * since it's a protein that's normally already there * you'd probably have a limited range, under which you could get, not total uncoupling, but a modest increase. That's obviously something that remains to be determined."
Lowell made the point that "if you were to increase energy expenditure by small amounts over time, that would have an enormous effect on body fat. Accumulation of body fat occurs when energy intake exceeds energy expenditure. If you could create a negative deficit of approximately 5 percent, you would lose a lot of fat over time."
As to a conceptual mechanism for how such a drug might work, Lowell declines comment. "The fact that we here are working on it shouldn't be a surprise to anybody. And I'm sure others are too." *