NIH News Release
National Institute of Dental
and Craniofacial Research

National Institute of Arthritis and
Musculoskeletal and Skin Diseases

Thursday, January 20, 2000
5:00 p.m. EST

Contact: Wayne Little

Obesity Gene Controls Bone Density Via Brain Pathway

The obesity gene, which helps maintain body weight and fertility, also plays a key role in controlling bone density, according to a report in the January 21 issue of Cell. Leptin, the hormone product of the obesity gene, acts as a natural bone inhibitor by telling the brain to slow down the rate of bone formation. The Cell study is the first to show that the brain has a central role in controlling bone formation and density. Bone researchers are excited about this finding as it reveals a novel pathway that perhaps can be manipulated in ways to increase bone density and treat or even prevent osteoporosis.

An international team of investigators, led by Dr. Gerard Karsenty from the Baylor College of Medicine, with support from the National Institutes of Health, discovered the link between leptin, the brain, and bone density.

"This is a very significant finding because it identifies an entirely new avenue for targeting osteoporosis therapies," said Dr. Karsenty. "Bone mass is essentially the product of a balancing act between cells that form new bone and other cells that digest old bone. Osteoporosis results from an imbalance in this equilibrium--specifically, an increase in bone resorption. Current therapies are aimed at slowing down resorption, but little is known about the formation side of maintaining bone mass. Identification of the leptin pathway, where the brain acts as the central component in building bone mass, opens a new realm of treatment approaches."

The link between leptin, the brain, and bone formation is another chapter in the story of this recently discovered hormone. It is known that leptin, which is produced by fat cells, acts on a region of the brain called the hypothalamus to help reduce body fat and maintain fertility. Karsenty and his colleagues unraveled the leptin-brain-bone connection by studying two groups of genetically obese mice.

One group of mutant animals was unable to make leptin; the other group could make leptin, but was unable to make the leptin receptor normally present in the hypothalamus. Both strains of mice were obese, but were also observed by X-ray analysis to have unusually dense bones. Further experiments confirmed that the leptin pathway had to be intact (both leptin and its brain receptor present) for bone formation to proceed at a normal rate. If the circuit is broken, by the absence of either leptin or its receptor, the brain directs bone-forming cells to become more active and make more bone.

The bones formed by leptin-deficient mice appear normal in terms of length and thickness, but the honeycombed interior is unusually dense, made up of thick, bony walls that surround areas of marrow. Not only are the bones dense, they are also as strong and flexible as normal bone. The situation is the reverse of what occurs in osteoporosis, where the honeycombed bone becomes thin and weak.

While the absence of a functioning leptin circuit may be beneficial for building dense bone, the animals suffer the adverse effects of obesity and infertility. However, there is some encouraging evidence that leptin may use a separate pathway to control bone mass. Mice that produced half the normal amount of leptin were of normal weight, but also had dense bones. Yet another strain of mouse that was unable to produce either fat or leptin, nonetheless had very dense bones.

"It may be possible to manipulate the leptin pathway in a way that increases bone mass, but avoids the adverse effects on weight and fertility," said Dr. Karsenty.

Working with Dr. Karsenty were Drs. Patricia Ducy, Shu Takeda, and Jianhe Shen from the Baylor College of Medicine in Houston, Texas; Drs. Michael Amling, Matthias Priemel, Arndt Schilling, Frank Beil, and Johannes Rueger from the University of Hamburg, Germany; and Dr. Charles Vinson from the National Cancer Institute (NCI). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). NCI, NIDCR, and NIAMS are components of the federal National Institutes of Health located in Bethesda, Maryland.