Science Editor

The discovery, quite frankly, sounds more Elle than Cell: In the April 15, 2010, edition of Cell Metabolism, scientists reported that knocking out a gene in mice led to increased food and water intake, decreased activity and weight loss.

Senior author Randall Johnson's lab at the University of California at San Diego primarily studies breast cancer, and was interested in HIF because it induces angiogenesis. They created a knockout of Factor inhibiting HIF-1-alpha or FIH, a regulator that chemically modifies HIF by acetylating one specific amino acid.

"Other regulators [of HIF] result in highly vascularized mice," Johnson told BioWorld Today. "We didn't see any of that. It was a head-scratcher."

The clue to what FIH did do came from an initial observation that the knockouts seemed to be "a bit smaller and leaner" than their wild-type counterparts. And digging into that observation ultimately led to the realization that, physiologically speaking, the knockouts were acting like they were on a permanent mountain vacation.

At high altitude, the lower oxygen content of the air kicks off a "classical response to hypoxia;" breathing and heart rate increases, as does metabolism. That response "typically goes on for a day or two, and then you adjust," Johnson said. But the FIH knockout mice "are acting as if they are in an acute hypoxic state, and they just never adapt to it."

At the same time, Johnson and his team wrote in their paper, FIH "has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis or development," suggesting that targeting the protein could be used specifically to alter metabolism.

Because of their low body weight combined with what seemed like good health, Johnson and his team tested the animals' metabolic functions in more detail, and found that they were highly sensitive to insulin.

One of the biggest surprises, Johnson said, was that the mice were impervious to the effects of a diet that contained 60 percent fat. On such a high-fat diet, he said, "you can watch normal mice become insulin-resistant - that just wasn't happening with these guys."

And while both groups of animals gained weight on the tub-o-lard meal plan, the knockouts did so to a lesser degree than wild-type animals.

As a final insult (at least from a dieter's perspective), the knockouts ate and drank 30 percent to 40 percent more than wild-type mice.

Johnson and his colleagues next created animals that were missing FIH specifically in their brains. Animals that were missing FIH only in neurons showed many of the same effects as the global knockouts. Specifically, they weighed less to begin with, had increased insulin sensitivity and gained less weight on a high-fat diet, leading Johnson and his team to conclude that "FIH acts to a significant degree through the nervous system to regulate metabolism."

Johnson pointed out that the findings are on a protein that is "very druggable" - companies exploring therapeutic HIF manipulation include Akebia Therapeutics Inc., where Johnson is on the scientific advisory board, and FibroGen Inc. - and "unexplored from this perspective."

Of course, at this point, the desirable metabolic effects come with side effects of hyperventilation and increased heart rate. Johnson said that one goal of his team is to see whether blocking HIF pharmacological can specifically induce the desired effects on metabolism while avoiding the undesirable ones. "Can insulin sensitivity be manipulated through this pathway in a way that separates them? We just have to find out."