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Researchers Discover Possible Connection Between Infant Hormone Exposure, Lifelong Weight Issues

   Portland, Ore.

Work helps explain how hormones involved in fetal development may influence obesity risk and may offer hope of future treatments to prevent weight problems

Scientists at Oregon Health & Science University have discovered a link between exposure to the hormone leptin early in life, and brain formation that likely impacts weight regulation later in life.

The research was conducted in mice at the OHSU Oregon National Primate Research Center. Results of the study are printed in the April 2 edition of the journal Science.

"We're excited about this finding because it shows how exposure to leptin can directly affect development of brain structures involved in regulating body weight," said Richard Simerly, Ph.D., a senior scientist at ONPRC and a faculty member in the Department of Cell and Developmental Biology in the OHSU School of Medicine. "While the full impact of this information is not currently known, our findings suggest a link between the developmental actions of leptin and early onset obesity."

The OHSU work is based on an earlier finding that mice experience a natural surge in leptin levels during the first weeks of life. This same surge occurs prior to birth in humans. In adult mammals, which includes both mice and humans, leptin acts on the brain to reduce food intake, a natural form of weight regulation. Until now, however, little was known about the impact of leptin early in life on the development of brain mechanisms regulating body weight.

Specifically, the OHSU scientists wanted to determine the effects of this early-life leptin surge on brain development. The researchers studied two types of mice: leptin-deficient mice and normal mice. Leptin-deficient mice are typically obese because they lack this important hormone that limits food intake.

"We were shocked by how clear the result was," explained Simerly. "Leptin plays an important role in brain development, by acting specifically on the clusters of brain cells that regulate food intake. In other words, the same hormone that helps regulate food intake later in life also regulates formation of weight control brain mechanisms very early in life."

OHSU scientists tracked development of neurons located in a region known as the arcuate nucleus of the hypothalamus (ARH). They found that brain circuits associated with the ARH were less developed in mutant mice that lack leptin when compared to normal mice. Specifically, they noted diminished development of axons from ARH neurons in the leptin-deficient mice. Axons are considered the "arms" of a brain cell, acting as the pathways for cell communication.

To further test the theory that leptin plays an important role in brain development, Sebastien Bouret, Ph.D., a postdoctoral fellow working in the Simerly lab, investigated whether leptin-deficient mice would be affected by the lab's introduction of leptin early in life.

"We found that by introducing the hormone in these leptin-deficient mice at approximately the same time early in life as the natural leptin-surge in normal animals, brain development was essentially normal," said Bouret.

Bouret also tested the brain structure impacts of the hormone on adult leptin-deficient mice. In that case, leptin did not affect brain cell development. This demonstrates there is a specific window of time early in life when leptin impacts axon development in the ARH.

"This work raises significant questions about the role of leptin that still need to be answered," explained Simerly. "For instance, nutritional or other environmental factors that suppress leptin during brain development may have lasting effects on an individual's ability to regulate body weight. It will be particularly important to identify aspects of maternal and prenatal nutrition that affect the occurrence, duration and intensity of the leptin surge."

While the full impact of this research is hard to predict, it is conceivable that after much more research, leptin-based therapeutic approaches may proactively reduce the risk of early onset obesity. However, scientists are quick to point out that much more research is required before these types of therapies are tested in humans.

In addition to his post at ONPRC, Simerly is a researcher in the new OHSU Center for Weight Regulation and Associated Disorders. The center conducts research into causes of and treatments for obesity. Prior to the creation of this center, OHSU has been involved in a number of key weight regulation discoveries, including the identification of specific cells in the brain involved in weight control. OHSU researchers have also identified hormones involved in weight loss and weight gain.

The ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International.

OHSU includes the schools of dentistry, medicine, nursing and science and engineering; OHSU Hospital and Doernbecher Children's Hospital; numerous primary care and specialty clinics; multiple research institutes; and several outreach and community service units.


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