Drs. Ming-Jer and Sophia Tsai, professors of molecular and cellular biology at BCM, have studied COUP-TFII (Chicken Ovalbumin Upstream Promoter Transcription Factor II) for decades, but only when they bred mice that had only one gene copy for the factor did they find that the animals had smaller fat cells and increased energy metabolism as well as enhanced response to insulin.

"If a mouse loses one copy of the gene, the animal becomes lean," said Ming-Jer Tsai. "It is more sensitive to the effects of insulin and resistant to obesity from a high fat diet."

Their studies raise the likely possibility that one can use COUP-TFII as a potential drug target for diabetes and obesity treatment.

Identifying a drug that could reduce the effect of COUP-TFII activity has become a future focus for their research, said Sophia Tsai.

"We don't need to inhibit it totally," she said. "Partial inhibition will do the trick as when you lose one copy of the gene, your fat cells are already much smaller and the animal is lean."

The animals not only have less fat, they also have more muscle and burn more energy, said Ming-Jer Tsai.

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Working first with mice made obese through a high-fat diet, they demonstrated that the animals developed ER stress in the hypothalamus, the main area of the brain where leptin signals. This in turn initiated the unfolded-protein response, rendering the mice extremely leptin-resistant. The team also created a strain of mice whose ER was weakened in the brain through deletion of a gene called XPB1 specifically in the neurons. These mice also developed ER stress and leptin resistance, and also became obese, despite having some of the highest leptin levels ever reported. As expected, the mice also ate more and gained more weight.

But when Ozcan and colleagues pretreated either group of mice with a chemical chaperone (either 4-PBA or TUDCA) leptin sensitivity increased as much as 10-fold, and the mice had significant weight loss with leptin treatment even when fed a high-fat diet.

Children's researchers hope to eventually move the discovery to human trials. Both 4-PBA and TUDCA are safe in humans and already FDA-approved for clinical use. 4-PBA (Buphenyl) used in urea cycle disorders and in cystic fibrosis; TUDCA (tauroursodeoxycholic acid), used for centuries in traditional Chinese medicine, is currently used in some liver diseases. Both agents are under study for use in neurologic disorders such as Alzheimer's disease and Huntington's disease.

In related work in 2006, Ozcan and colleagues reported in Science that chemical chaperones reduce ER stress in a mouse model of type 2 diabetes, normalizing blood sugar and restoring insulin sensitivity.

In 1995, Amgen, Inc. (Thousand Oaks, CA) paid $20 million for commercial rights to recombinant human leptin, a record amount for a deal with an academic institution. In 2006, Amgen sold the rights to Amylin Pharmaceuticals (San Diego, CA). Amylin is testing leptin in combination with its diabetes drug, pramlintide.

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