Better intelligence for the battle of the bulge

ILLINOIS - Few people want to be obese, but growing numbers are, and the problem is proving increasingly difficult to conquer. Obesity is obviously associated with taking in more calories than a person burns off. But fighting fat also means understanding how and why it develops, and two new studies have taken a giant step in coming up with some ideas. The studies, published in January 1 Genes and Development, have pinpointed a master switch that directs the formation of fat cells. They have also suggested a new strategy for treating obesity, and a way to improve on a class of widely prescribed diabetes drugs.The studies showed that a steroid hormone receptor protein - the peroxysome proliferator-activated receptor g (PPAR-γ), specifically an isoform of the protein called PPAR-γ-2 - enables laboratory-grown fat cell precursors to form fat cells in response to signaling molecules. Earlier work had shown that gene-regulatory proteins PPAR-γ and C/EBP-α promoted fat-cell formation, or adipogenesis, but it wasn't clear if one protein directed the whole show or if they worked independently. It also wasn't clear if just one of the two isoforms of the receptor, PPAR-γ-1 or PPAR-γ-2, played a key role."These papers really cement that it's this specific factor, [PPAR-γ], specifically the γ-2 form" said Mitch Lazar, director of the diabetes center at the University of Pennsylvania School of Medicine, Philadelphia.The results open up the possibility of an anti-obesity drug that blocks fat-cell formation, he suggested. This strategy might complement existing and planned anti-obesity drugs, which reduce appetite, such as the 5HT/noradrenaline reuptake inhibitor sibutramine, or reduce nutrient absorption, such as the lipase inhibitor orlistat. Some over-the-counter remedies claim to increase the rate of metabolism, but there's little scientific evidence that they help people lose weight, Lazar argued.In the first new study, a team led by Bruce Spiegelman of Harvard Medical School and Dana-Farber Cancer Institute generated a mouse embryonic fibroblast (MEF) cell line that lacked a working copy of the PPAR-γ gene. Normally, a cocktail of insulin and other molecules stimulate MEF cells to morph into fat cells in culture dishes, but the cocktail didn't work on the cells lacking PPAR-γ. Adding back a retrovirus with the PPAR-γ gene restored the ability of the cells to become fat cells. But adding back a retrovirus with the C/EBP-α gene did not. "These findings mean that there is one pathway, not two, to differentiation," Spiegelman suggested.In the second study, a team led by Heidi Camp of Pfizer's Global Research and Development Division, Ann Arbor, Michigan, probed deeper into the system to see which of the two versions of PPAR-γ was responsible for fat-cell differentiation (adipogenesis). Both proteins are made in fat cells, but earlier work had hinted at a special role for PPAR-γ-2 in fat cells, although the precise mechanism remained unknown.Both isoforms are made from the same gene, but from two different promoters, which results in different messenger RNAs that encode slightly different receptors. The Pfizer team took advantage of specially engineered DNA-binding proteins called zinc-finger proteins that blocked expression of the PPAR-γ gene, while leaving other genes unaffected. The zinc-finger proteins turn individual genes on or off by binding to nearby DNA sequences called promoters. They were designed by collaborators at Sangamo BioSciences, Inc., Pt. Richmond, California.A zinc-finger protein that eliminated both types of PPAR-γ prevented cultured fat-cell precursors from forming fat cells. And adding back PPAR-γ-2, but not PPAR-γ-1, restored fat-cell formation. "This shows that γ-2 is really directing fat-cell formation," Camp reported.Together with earlier results, the findings suggested that a compound that targeted PPAR-γ-2 might help to 'fight the battle of the bulge', Lazar suggested. Although it was once thought that all fat cells were formed by the time a person reached adolescence, researchers now know that fat cells die and are replaced in adults. "If you could block additional ones, that would actually be a reasonable strategy after puberty," he added.But Lazar cautioned that a total blockade of fat cell formation would make people very ill. Mice and people that can't make fat cells develop diabetes and severe cholesterol problems. "The goal of any kind of therapy would be to reduce or prevent making any new fat but not get rid of all fat," he said. He also cautioned: "It's a long way from fat cells...in a tissue culture dish to doing it a complicated organism like a mouse or a person."Compounds that block PPAR-γ are already being developed by drug companies. Researchers can then test whether they reduce fat cell size or number. "I'm sure that's going to be answered pretty soon," Camp indicated.The findings from the two new studies could also lead to improved ways of treating diabetes. One class of diabetes drugs — the glitazones, which includes pioglitazone (Actos) and rosiglitazone (Avandia) - also affect PPAR-γ. But instead of blocking it, they activate it. This boosts the ability of muscle, liver, and fat cells to respond to insulin and take up sugar from the blood. But in activating PPAR-γ, the drugs also spur on fat cell development, and patients tend to gain weight.It might also now be possible to design a glitazone or related drug that cuts insulin resistance without making people fatter, Lazar suggested. This would work only if glitazones altered the insulin response by activating the γ-1 isoform rather than the γ-2 isoform. "Otherwise," he explained, "you're not going to be able to push the same button and do two different things."Despite the years of research on glitazones, no one yet knows which isoform of PPAR-γ they target, Camp pointed out. But she's interested. "The next question is which isoform is responsible for insulin sensitization," she said. The best scenario would be if it turned out to be PPAR-γ-1, Lazar suggested. In that case, a new drug could block fat formation and reduce the risk of type 2 diabetes. People with more fat cells, for unknown reasons, are more likely to develop insulin resistance and diabetes. "A drug that blocked the production of more fat cells but didn't independently make diabetes worse would probably make diabetes better," he concluded.

Better intelligence for the battle of the bulge

Identification of the factor that stimulates fat cell development could help fight obesity and diabetes.

Interested in reading more?

Become a Member of