The Intriguing Relationship Between Fat and Bone
Clifford Rosen, MD, is the director of clinical and translational research and a senior scientist at Maine Medical Center Research Institute. He is also an adjunct staff scientist at the Jackson Laboratory, a professor of nutrition at the University of Maine (Orono), and a professor of medicine at Tufts University School of Medicine. Rosen is interested in bone metabolism, including the genetics and mechanisms involved in bone marrow stem cell differentiation into bone or bone marrow fat. The goal of his research is to inform the design of treatments for bone diseases such as osteoporosis.
Rosen earned his MD from Upstate Medical Center (SUNY–Syracuse) and did postgraduate training in medicine and internal medicine at Berkshire Medical Center (Pittsfield, MA) and in endocrinology at Dartmouth-Hitchcock Medical Center (Hanover, NH). He has held academic appointments at UMass–Worcester, Dartmouth-Hitchcock Medical Center, Eastern Maine Medical Center, and Boston University School of Medicine.
“Our laboratory is very interested in understanding the relationship between fat and bone,” says Rosen. Throughout life, bone marrow stem cells respond to signals that tell them to differentiate into cells such as blood, bone, or fat. Rosen’s work focuses on bone and bone marrow fat cells and how they affect bone health. Fat in bone appears to increase and decrease throughout life in response to circadian rhythms, diet, stage of life, and injury. In some instances, increases in bone marrow fat correspond to decreases in bone mass.
Evidence is mounting that fat cells in bone are different from adipocytes found elsewhere in the body. “They’re very responsive to different signals,” says Rosen. “Like after bone marrow transplantation, you see these bone marrow fat cells, and they’re there for a couple of days, and then they go away. Then you see the flourishing of the cells that you need for your blood and for your bone. So we think they’re a special type of fat cell and we’re trying to define what these cells are, what they’re doing, what they’re responsive to, and how they either help or hurt the bone-forming cells.” Rosen suggests that these fat cells may assist bone marrow stem cells in some way, possibly by acting as placeholders until the stem cells differentiate into the cell type that is needed.
Bone marrow fat may also play a role in energy storage and thermogenesis. “Some of these fat cells make a substance called uncoupling protein 1, and that is what generates heat for cells,” says Rosen. “You can generate heat by shivering, but you can also generate it by certain types of fat cells called brown fat cells. One of our ideas is that, at least under certain circumstances, fat cells may be generating heat that is necessary to keep the bone marrow working well.”
Levels of bone marrow fat increase with age, and the marrow fat of aging appears different from marrow fat found earlier in life. Rosen and his group primarily use mouse models to investigate the function of marrow fat cells at different stages of life and under various conditions. “What we’ve been able to do very recently is take magnetic resonance imaging and actually define the fatty composition in the bone marrow of two strains of mice—one that has lots of marrow fat and one that doesn’t—and the composition of fatty acids, saturated versus unsaturated fat, is quite different,” says Rosen. “So the fat is probably functioning differently.”
Rosen and his research group have recently identified in mice a circadian-regulated gene called nocturnin that strongly influences the amount of fat in bone and liver. Hepatic expression of this gene increases in the early evening when mice tend to be feeding, and this increase is associated with increased hepatic fat, leading to the idea that nocturnin is important in the disposition of dietary fat. Mice lacking nocturnin are resistant to hepatic steatosis (buildup of fat) and diet-induced obesity, and they display an altered sensitivity to glucose and insulin. Increased expression of nocturnin in bone is associated with increased marrow fat and decreased bone mass. A common diabetes drug appears to increase nocturnin expression, and hence could decrease bone density—a significant concern if a causal relationship between nocturnin expression and bone mass is confirmed in human studies.
Rosen has several projects underway to investigate marrow fat and its effects on bone mass. He would like to find a collaborator with access to micro-PET functional imaging to explore the metabolism of marrow fat cells in mouse models. “We have the animal models with lots of marrow fat,” says Rosen. “The question is, can we tell what it’s doing? Micro-PET imaging would be one way to do it. Could we see glucose taken up in the fat cells in certain animal models? Or, conversely, can we use a tag for a PET scan that is not glucose, something else that is metabolically active, and ask the same question?” Further studies of bone and marrow fat metabolism, including studies of nocturnin and associated mechanisms, could lead to the development of new therapeutic agents for osteoporosis, diabetes, metabolic syndrome, and obesity.