Steiner tracks complex role of leptin in relation to reproduction

Robert Steiner

For thousands of years, humankind has known that there is some connection between nutrition, body fat and fertility. The more fat on an animal, the more fertile it is likely to be; the more fat on a cow, the more milk it produces.

Conversely, anorexic and thin animals, including humans, are less fertile. Women athletes involved in sports that have high metabolic demands, such as long-distance running, ballet dancing and gymnastics, often have amenorrhea (no menstrual cycles) and may have difficulty becoming pregnant.

How does the body decide if it has sufficient fat reserves to commit to the metabolic demands of pregnancy and lactation? In other words, how does the reproductive system “know” the nutritional status of the body?

In 1995, during an illuminating conversation with Dr. Scott Weigle, an associate professor of medicine, Dr. Robert Steiner, professor of physiology and biophysics and of obstetrics and gynecology, theorized that the reproductive system could be cued by plasma levels of a newly discovered hormone called leptin.

Steiner will discuss his discoveries of leptin’s role in a Science in Medicine Lecture, “Leptin as a Metabolic Signal to the Reproductive System,” on Friday, Jan. 22, from noon to 1 p.m. in room T-625, Health Sciences Center.

Leptin is a hormone secreted by fat cells. The story of this hormone began in December of 1994 when a research group at the Rockefeller Institute first identified it as a satiety factor and named it after the Greek word leptos, meaning “thin.” Studies showed that leptin circulates in the blood at levels that are proportional to the degree of fat found in adipose tissue.

It was also discovered that rising blood levels of leptin reduce appetite and speed up metabolism and that falling levels of leptin do the opposite. This early research suggested leptin could be the ticket to curing obesity. Pharmaceutical companies vied for the patent, which eventually went to Amgen for $20 million.

Studies by other researchers, however, including Drs. Richard Palmiter, UW professor of biochemistry, and Mike Schwartz, associate professor of medicine, have since revealed that although leptin does play an important role in regulating appetite and metabolism, it is unlikely to be the “magic bullet” for treating obesity.

“The brain’s circuitry for mediating leptin’s effect on feeding and metabolism is highly complex,” said Steiner.

Steiner and his colleagues, notably Dr. Don Clifton, professor of obstetrics and gynecology; graduate students Clement Cheung, John Hohmann, and Matt Cunningham; postdoctoral fellow Dr. Pattie Finn, and Joe Kuijper of ZymoGenetics, have shown that leptin does act as a metabolic signal to the reproductive system. Weigle, now at ZymoGenetics, is also working on the problem.

More recently, the group has shown that leptin reverses the delay in sexual maturation caused by food restriction in developing animals and triggers the secretion of sex hormones in animals whose reproductive system has been shut down by fasting.

The team has also discovered that leptin acts on special cells in the hypothalamus to “turn on” a particular gene for a protein called proopiomelanocortin. Products of this large protein eventually lead to a “down regulation” of feeding, Steiner said.

Exactly how leptin regulates reproduction, as well as body weight, at the molecular level, remains a mystery. “We’re slowly unraveling the neuronal circuitry and trying to identify all of the various cells and molecules involved, so we can reassemble it and understand the ensemble as a whole,” Steiner said.

Years of painstaking, yet rewarding research lie ahead. “The low apples on the leptin tree have been picked,” he added.

Steiner came to the UW in 1975 after earning a Ph.D. in physiology at the Oregon Health Sciences University in Portland. After a senior fellowship in physiology and biophysics, he became a faculty member with appointments in that department and in obstetrics and gynecology, as well as an adjunct appointment in zoology.

He is also a research affiliate of the Regional Primate Research Center and the Diabetes Research Center, and co-director of the Population Center for Research in Reproduction, as well as director of the Reproductive Biology Training Program.

He has received several awards for teaching, including the UW Distinguished Teaching Award in 1996. ¶

Will Morton