With just one enzyme missing, mice show 'global' metabolic improvements

"It was a surprising and unexpected finding," said Richard Lehner of the University of Alberta. "With this gene deleted, not only was there a decline in very low-density lipoproteins in the whole mouse, it also affected metabolism in fat tissue. The insulin-secreting cells became smaller, suggesting that they didn't have to work as hard to secrete insulin, and the mice became more insulin sensitive." The animals ate more, but they also expended more energy and showed no change in body weight.

Very low-density lipoproteins (VLDLs) are a form of "bad" cholesterol, Lehner explained. TGH normally frees up triglycerides from their storage place in the liver, releasing them for assembly into VLDLs. Therefore, one might expect that loss of TGH would have ill effects on the liver, as triglycerides would build up there. Indeed, he says, similar experiments with other enzymes have shown such an effect.

"We didn't observe that here," Lehner said. "Instead of being stored in liver, triglycerides were directed for oxidation." In other words, they were burned. The liver also compensated by synthesizing less fat.

The studies demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels, with possible far-reaching beneficial side effects throughout the body. That may be especially worthy of note, given that drug companies already have a TGH blocker. In fact, Lehner's team earlier showed that the TGH-inhibiting drug can lower the secretion of VLDLs from liver cells. But it wasn't clear whether the drug was really acting only on TGH. The new findings add support to the notion that loss of TGH activity alone can have very significant and positive effects.

"But there is a still a lot more work to do," Lehner says. They plan to see what happens when mice on a high-fat diet lose the enzyme, noting that the mice in the current study were eating regular chow. They also want to find out what happens when the enzyme is lost only in specific tissues -- fat tissue, for example -- instead of throughout the body.

One would also want to be careful that the chemical inhibitor targets TGH and not other enzymes in the same family. For the most part, scientists don't know what those other enzymes are doing, he says, and -- at least until they do -- specificity will be key.

"We've answered a small piece of the puzzle, and this is or could be a good target," Lehner says, although he emphasizes caution. "Would it be a magic bullet? Now, that's something else that has yet to be seen."

The researchers include Enhui Wei, University of Alberta, Edmonton, Canada; Yassine Ben Ali, University of Alberta, Edmonton, Canada; James Lyon, University of Alberta, Edmonton, Canada; Huajin Wang, University of Alberta, Edmonton, Canada; Randy Nelson, University of Alberta, Edmonton, Canada; Vernon W. Dolinsky, University of Alberta, Edmonton, Canada; Jason R.B. Dyck, University of Alberta, Edmonton, Canada; Grant Mitchell, CHU Sainte-Justine, Universite´ de Montreal, Montreal, Canada; Gregory S. Korbutt, University of Alberta, Edmonton, Canada; and Richard Lehner, University of Alberta, Edmonton, Canada.