Fat Screen Delivers Plant-derived Chemical With Antidiabetic Effects

The work suggests a new approach for treating insulin resistance that might complement the use of preexisting drugs and, more generally, provides validation for fat cell screens as a promising strategy for identifying new metabolic drugs, according to the researchers.

While harmine itself has effects on the central nervous system that may preclude its use, "it may eventually be possible to separate the nervous system and metabolic effects of harmine through optimization of the chemical structure," said Peter Tontonoz, a Howard Hughes Medical Institute investigator at the University of California, Los Angeles. Harmine has been known to induce hallucinations, convulsions, and tremors.

The principal class of drugs prescribed for obesity-related diabetes, called thiazolidinediones or TZDs, work through a counterintuitive mechanism: they restore insulin sensitivity by activating a central promoter of fat tissue production called peroxisome proliferator-activated receptor ã (PPARã).

"The current explanation for this paradoxical mode of action is the idea that the body needs a place to store lipids," Tontonoz said. "If the body becomes less able to store lipids in fat, it may deposit in other tissues," where it can spur disease.

Despite their efficacy, the development and clinical use of TZDs is limited by adverse effects such as fluid retention, weight gain, congestive heart failure, liver toxicity, and potential cancer risks, the researchers said. Therefore, alternative approaches to treating insulin resistance are needed.

The researchers speculated that other small molecules that promote fat tissue by distinct mechanisms could be candidates for novel insulin sensitizers. By running a technologically advanced screen of more than 500 bioactive compounds, the researchers found that harmine has such a positive effect on fat. The fat cells under examination were manipulated such that they literally lit up when fat-boosting PPARã became active.

Further study of harmine's effects in diabetic mice found that the chemical increases insulin sensitivity in a manner similar to, though more roundabout than, the predominant antidiabetes drugs. Rather than triggering PPARã directly, the chemical blocks a pathway that normally inhibits fat cells' production. "Harmine inhibits an inhibitor for a net positive effect on fat" that ultimately appears to restore insulin response without some of the side effects attributed to TZDs, Tontonoz said.

The findings provide "a second example of a small molecule that both promotes fat cell differentiation in vitro and improves glucose tolerance in vivo," Tontonoz's team concluded. The biological activities of harmine and TZDs underscore the fact that links between fat tissue and insulin resistance are complex and are likely to involve not only changes in fat tissue differentiation and cell number but also changes in the fat cells' function, they said.

The researchers include Hironori Waki, Kye Won Park, Nico Mitro, Liming Pei, Damien C. Wilpitz, Peter Tontonoz, Robert Damoiseaux, and Karen Reue of University of California, Los Angeles in Los Angeles; Enrique Saez of The Scripps Research Institute, La Jolla.

This work was supported by a Bristol-Myers Squibb Freedom to Discover Award.

Waki et al.: "The Small Molecule Harmine Is an Antidiabetic Cell-Type-Specific Regulator of PPARg Expression." Publishing in Cell Metabolism 5, 357--370, May 2007. DOI 10.1016/j.cmet.2007.03.010 http://www.cellmetabolism.org.