If you're like most people, you probably don't think about your skeleton much. But try, for a moment, to imagine life without bones. You'd be little more than a fleshy blob, unable to sit, stand, or walk around. The soft organs inside your body wouldn't stand a chance without a rib cage, pelvis and skull to protect them. And without bone marrow to churn out new blood cells, your body would have no way to get oxygen to your tissues.
Now a new study is adding one more to the list of jobs the skeleton performs. Scientists have revealed that bones secrete a chemical that controls body weight and food metabolism. That makes the skeleton an official member of the endocrine system, the organs and glands that send out chemical messengers known as hormones. By linking the skeleton to food metabolism, the new research promises to contribute to the treatment of diabetes. The research was conducted at Columbia University Medical Center and published in the August 10th issue of Cell.
Bones seem an unlikely player in controlling how the body responds to glucose , a simple sugar that, after a meal, moves from the stomach into the bloodstream. In order for your body to use glucose for energy, insulin is needed. Insulin is made by beta cells in the pancreas , and it travels from the pancreas into the bloodstream. Insulin's job is to shuttle glucose out of the blood and into the cells that need it for energy. Think of insulin like a key. It unlocks cells and allows glucose to enter, where the sugar can be burned for fuel.
Diabetes is a disease that develops when the insulin system fails. Sometimes diabetes occurs because the body stops making insulin altogether. That kind of diabetes is known as type 1 diabetes (historically this kind of diabetes was called juvenile diabetes , because people often—but not always—get the disease during childhood or adolescence). Another, more common, kind is called type 2 diabetes; it is linked to obesity and occurs when the cells of the body become insulin resistant, meaning insulin is present but the cells don't unlock properly. In either case, sugar builds up in the bloodstream, locked out of the cells that need it. These cells increasingly become energy starved at the same time as sugar in the blood reaches dangerously high levels; the consequences include kidney disease, blindness, amputation, coma, and even death.
The treatment for type 1 diabetes (and sometimes for type 2) is to supply insulin from an exogenous (not produced by the body) source, typically through shots or an insulin pump. This is a treatment, not a cure, since for one thing it's very difficult to exactly match the amount of insulin the body needs with the amount administered; supplying either too little or too much both have negative (but different) consequences. Type 2 diabetes can sometimes, but not always, be treated by diet and exercise. Diabetes is a widespread disease affecting nearly 7% of the US population, and obesity-related diabetes (along with obesity itself) is on the rise.
The Fat-Bone Connection
The new study shows the skeleton to be a surprising player in diabetes. But to understand the new research, it helps to first back up and look at a study that preceded it. In that study, Gerard Karsenty and a team of researchers at Columbia University showed that fat cells regulate how bones are constructed. Your body is constantly removing old, and building new, bone tissue. It is a process that goes on throughout your lifetime.
Karsenty's team discovered that bone rebuilding is controlled by leptin , a hormone made by fat cells. You may have heard of leptin. It has been widely reported that leptin suppresses appetite, and that mice with leptin gene defects become grossly fat.
What is less well known about leptin mutants is that, in addition to being obese, these mice are less prone to osteoporosis, the bone-wasting disease. That finding caused Karsenty and his colleagues to investigate the bone-fat connection, and they discovered that leptin acts on the skeletal system, inhibiting bone-building cells called osteoblasts . You can think of osteoblasts like bone construction workers. Their job is to pull minerals from the surrounding fluid and construct bones from the raw material.
The discovery that fat cells were regulating bone building was surprising and it led the team of researchers to a realization. Feedback loops —where one organ sends signals to another and the second organ sends signals back—are common in the body. The scientists realized that if fat cells were talking to bone cells, bone cells were probably talking back.
As Karsenty told The Scientist, "If fat speaks to bone, bone must speak to fat." So Karsenty and his team began to investigate whether bone cells were indeed sending out signals. They focused their attention on a bone protein called osteocalcin . It had been known for some time that osteocalcin is secreted by osteoblasts, those hard-working bone builders. But no one knew for sure what the osteocalcin protein did.
"Osteocalcin has been the flagship molecule of the bone field for decades," Karsenty told The Scientist. "It's the only molecule uniquely secreted by osteoblasts, but no one has been able to show what role it plays in the body."
Karsenty's team genetically engineered mice that no longer made osteocalcin. The team observed that the mutant mice were fatter than normal, and they appeared to have defects in their sugar-processing system. For instance, the mice developed type 2 diabetes even when fed a normal diet; they had increased levels of glucose in the bloodstream; and they were less sensitive to insulin, which is a key marker of diabetes.
The researchers then genetically engineered a second set of mice. These mutant mice, rather than lacking osteocalcin, made extra amounts of it. And what happened to them was the opposite of what happened to the first set of mutants. The second mutants had low, rather than high, blood sugar. Their cells were more, not less, sensitive to insulin. And the mice were resistant to obesity: even when they were fed a high-fat diet, they didn't pack on the pounds like normal mice.
A New Role for Old Bones
Karsenty and his colleagues then investigated what osteocalcin might actually be doing inside the body to explain these changes. They discovered that osteocalcin acts as a messenger. It leaves the bones and travels to the pancreas , where it stimulates beta cells to make more insulin and promotes the growth of new beta cells. Osteocalcin also stimulates fat cells to release a hormone that enhances insulin sensitivity.
These effects in the body make osteocalcin a bona fide hormone, which by definition is a substance made in one part of the body that works at a distant site. The discovery that osteocalcin works as a hormone means that the skeleton becomes an official part of the endocrine system, along with other hormone-secreting glands like the pituitary , the pancreas and the thyroid .
Markus Stoffel, who studies glucose metabolism at the Swiss Federal Institute of Technology in Zurich, told Nature, "The skeleton was always thought of as being for walking upright and as the location of the bone marrow, and that's it really. This is the first definite study that shows it's an endocrine organ."
"It's a sparkling observation," said Jake Kushner of the University of Pennsylvania in Philadelphia, speaking to The Scientist. "The findings show that bone is an endocrine organ, and that it affects glucose homeostasis . This concept is totally novel."
One particular feature of the mutant mice had diabetes researchers sitting up and taking notice. Usually when insulin levels go up, cells respond by becoming insulin resistant, complicating diabetes treatment. But in the skinny mutants, the ones that made extra osteocalcin, the mice made more insulin while simultaneously becoming insulin sensitive. It is the opposite of what usually happens, and it is a promising finding.
The current research took place in mice, so more work will need to be done to determine how the system functions in people. If osteocalcin works similarly in people—raising insulin levels and insulin sensitivity while lowering body fat—the discovery may open new avenues for treating an old disease.