Discovery of Possible New Weight Control Role for Leptin Announced by Yale University School of Medicine Researchers

Researchers at Yale University School of Medicine and the Institutes for Pharmaceutical Discovery in Branford, Conn., have discovered a possible new mechanism for the body to control its fat stores by inducing the growth of new blood vessels, which suggests a new avenue for weight regulation.

The mechanism involves the action of leptin, a naturally occurring hormone known for its hunger-blocking effect on the hypothalamus, a region in the brain. According to a study published in the Sept. 11 issue of the journal Science, leptin also triggers the formation of new vessels in fat tissue, which may be a crucial adaptive response that provides more efficient release of metabolic energy and, thereby, weight loss.

The discovery was made by M. Rocio Sierra-Honigmann, M.D., Ph.D., associate research scientist in the Yale pathology department, and her husband Jaime Flores-Riveros, Ph.D, of the Institutes for Pharmaceutical Discovery (IPD), along with their colleagues.

“Now we have strong evidence for the existence of functional leptin receptors outside the brain, which could give us new insights into how leptin controls body fat besides blocking hunger,” Sierra-Honigmann said.

“We were certainly puzzled by our initial observation that leptin receptors were present in endothelial cells lining blood vessels, a location never suspected to be a site of leptin action,” said Flores-Riveros, a research director at IPD and previously a scientist in the Bayer Research Center in West Haven, Conn.

Other members of the research team were Anjali K. Nath, Chiaki Murakami, Guillermo Garcia-Cardena, Andreas Papapetropoulos, William C. Sessa, Lisa A. Madge, Jeffrey S. Schechner and Michael B. Schwabb of the Boyer Center for Molecular Medicine, Yale School of Medicine; and Peter J. Polvernini of the University of Michigan School of Dentistry.

According to Sierra-Honigmann, the growth of new blood vessels might also serve as a “cooling system” that dissipates heat generated as stored fat breaks down – especially in “brown fat” found in hibernating animals, and fat stores found in human newborns and cold-acclimatized individuals.

“Because leptin is produced mainly in fat cells, it is reasonable to speculate that formation of new blood vessels – a process called angiogenesis – may actively occur around those cells,” said Sierra-Honigmann. Angiogenesis normally occurs during early development in infants and children, and during wound healing and female reproductive functions, such as the menstrual cycle, placenta formation and in the breast tissue of nursing mothers. Angiogenesis also takes place as cancer progresses in order to build a network of new blood vessels to feed a growing tumor.

By acting on the vascular system, as well as through the hypothalamus and other brain centers, leptin may provide comprehensive control of energy balance, thereby achieving intricate control of fat stores, the researchers said. “This is the first unequivocal evidence for cross-talk between fat cells and endothelial cells,” said Flores-Riveros of IPD, who added that the discovery is likely to be helpful in the development of new pharmaceuticals to treat obesity.

In addition to revealing new mechanisms of weight control, the discovery also could help scientists understand more about defective wound healing and alterations of the blood vessels in diabetic patients. “Whether leptin angiogenesis plays a role in tumor formation and female reproduction is currently the focus of our research,” Sierra-Honigmann said.

While leptin appears promising for the treatment of obesity, she cautioned that weight disorders have many causes and not all people react in the same way to leptin. The research was performed with cultured human cells at Yale as well as with experiments in rats.

The discovery four years ago of a gene that produces leptin in mice triggered a flurry of research aimed at harnessing leptin to treat obesity in humans. The subsequent discovery that obese people actually had more leptin than normal-weight people led researchers to speculate that the problem lies instead in inefficient leptin receptors – a problem that might not respond to more leptin.

However, a recent study at Tufts University buoyed hopes for leptin therapy by showing that appropriate doses can produce moderate weight loss in some people.

Since its founding in 1810, Yale University School of Medicine has made major contributions to public health by isolating the polio virus, promoting the early use of cancer chemotherapy, adding to the arsenal of AIDS medications, developing a promising Lyme disease vaccine, discovering genes that contribute to skin cancer and high blood pressure, and making breakthroughs in the treatment of Parkinson’s disease, depression and other mental disorders. Yale ranks fourth among American medical schools in research dollars granted by the National Institutes of Health.

IPD operates the Institute for Diabetes Discovery, which is developing drugs for the treatment of diabetic complications, diabetes and related disorders, and the Institute for Diagnostic Research, which develops and validates customized diagnostic assays either for research or as a tool to help pharmaceutical companies launch new drugs.

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