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Biological Chemistry

Starving Fat

Targeted apoptosis technique turns mice from supersize to svelte

by Stu Borman
May 17, 2004 | A version of this story appeared in Volume 82, Issue 20

Credit: © 1999 NATURE MEDICINE
Model of a targeted apoptosis agent like the one used in the new study shows homing domain (blue), glycinylglycine linker (yellow), and apoptotic sequence D-enantiomeric (KLAKLAK)2, where K (red) is lysine and LA (green) is leucine-alanine.
Credit: © 1999 NATURE MEDICINE
Model of a targeted apoptosis agent like the one used in the new study shows homing domain (blue), glycinylglycine linker (yellow), and apoptotic sequence D-enantiomeric (KLAKLAK)2, where K (red) is lysine and LA (green) is leucine-alanine.

A technique in which an apoptosis (cell suicide-inducing) agent is directed specifically to the linings of blood vessels in fat tissue has been shown to be effective for reversing obesity in overfed mice. Mice that were given the agent while on a high-calorie diet were transformed from rotund to slender in four weeks.

The approach might also prove applicable for treating people who struggle with their weight. Such applicability is far from having been demonstrated, the researchers emphasize. But there is substantial motivation for developing such a therapy. In addition to obesity’s adverse effects on appearance and self-image, it is a major risk factor for developing cancer, diabetes, and cardiovascular disease.

The technique was devised by instructor Mikhail G. Kolonin and professors of medicine Renata Pasqualini and Wadih Arap of the University of Texas M. D. Anderson Cancer Center, in Houston, and coworkers [Nat. Med., published online May 9,]. “When you inject our drug into mice, it homes in on and promotes the death of blood vessels associated with white fat tissue, which is then reabsorbed and metabolized,” Arap says.

Credit: © 2004 NATURE MEDICINE
Credit: © 2004 NATURE MEDICINE

The strategy is based in part on an earlier technique for suppressing blood vessel growth in fat tissue, developed by cardiologist Maria A. Rupnick of Brigham & Women’s Hospital, Boston, and coworkers, including professor of chemical and biomedical engineering Robert Langer of Massachusetts Institute of Technology and antiangiogenesis pioneer M. Judah Folkman of Children’s Hospital Boston [Proc. Natl. Acad. Sci. USA, 99, 10730 (2002)]. Antiangiogenesis (blood vessel growth inhibition) has been investigated primarily for use against cancer. But Rupnick and coworkers believed it could also be used to perturb the extensive network of blood vessels required for growth and maintenance of fat tissue. They indeed found that giving known angiogenesis inhibitors to obese mice caused weight reduction and adipose tissue loss.

The M. D. Anderson study adds two elements to the antiangiogenesis strategy: use of an apoptosis agent and its highly selective targeting to fat tissue. The researchers used phage display to identify peptides that bind predominantly to protein receptors in the endothelium (linings) of blood vessels that sustain fat tissue. The most selective peptide homed in on the receptor prohibitin, a vascular marker of fat tissue. A glycinylglycine linker is used to connect the selective homing peptide to an apoptotic peptide in the group’s targeted apoptotic agent.

Mice that had gained a lot of weight from a high-calorie diet were treated with the agent while continuing on the diet. None of the mice were naturally fat or genetically altered to become obese. After one month of daily doses, the mice lost an average of over 30% of their body mass and generally returned to normal weight. However, “if you stop the treatment and keep the mice on the high-calorie diet, they will gain weight again,” Arap says. No toxic side effects were observed.

The M. D. Anderson researchers “used a powerful tool which, in essence, identifies a zip code for the blood vessels in fat tissue with which to send targeted apoptotic instructions,” Rupnick comments.

Much more experimentation will be needed to test the applicability of the strategy to people. The researchers are currently planning tests in obese nonhuman primates as a step toward human clinical trials.


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