The Skeleton: A Regulator of Energy Metabolism?
Safety Assessment
Susan Y. Smith

The Skeleton: A Regulator of Energy Metabolism?

During the evolution of man, we were subject to famine and feasting largely driven by the seasons and changing environmental conditions. When food was plentiful, metabolism functioned one way, and when man hit the hard times of famine, metabolism switched gears. It is this ability to accommodate and adjust to varying environmental conditions that has helped us survive as a species.

Nowadays, we rarely experience these radical fluctuations in our diet, and in this regard, our metabolism goes largely unchallenged. So this is a good thing, right? Probably not… Obesity and diabetes are approaching epidemic proportions, mostly as a consequence of poor diet, and this is without mentioning things like food additives (over 4,000) which wreak havoc with our metabolism.

There is abundant evidence emerging to indicate that the skeleton functions as an endocrine organ and is central to the regulation of energy metabolism. One thing we are learning is that fat is bad for bone. But not all fat, it seems. Apparently just visceral fat is likely detrimental, while subcutaneous fat may be protective. This is because the progenitors that make bone cells can be redirected to make fat cells. With this one primary cell source, the body, based on its demands, will concentrate its efforts down one pathway or another, possibly introducing an imbalance which could lead to bone loss (and osteoporosis) or even fat disorders.

When we eat, the GI tract releases a variety of signals, including incretin hormones that stimulate insulin release. Hormones such as these help us to efficiently digest our meals and store fuel for future needs. Skeletal muscle and fat evolved into robust factories for acquiring, burning and storing fuel.  Given the common cellular origin of osteoblasts (bone forming cells), muscle and fat cells, it may not be surprising that the skeleton has a role in energy metabolism. Osteocalcin, produced only by osteoblasts, is the first bone-derived energy hormone identified, and there may be others. It seems the skeleton achieves its role to maintain glucose homeostasis by interacting with multiple organ systems, including the glucose-regulating functions of the pancreas, liver, white adipose tissue and muscle.

How the Skeleton Regulates Energy Metabolism…
There are 3 bone cell types: the bone forming cells, osteoblasts; the bone resorbing cells, osteoclasts; and the osteocytes, the most abundant yet least understood bone cell. The osteocyte, formed once its life as an osteoblast is complete, becomes embedded in the bone tissue in its own lacuna (pit or cavity) and while doing so produces many dendrites that, through minute channels called cannaliculi, allow it to stay in contact with other osteocytes, and importantly, with other bone cells. In this way, the osteocyte forms a network of cells to orchestrate the function of the skeleton. Through its cannaliculi the osteocyte senses fluid flow from the stresses and strain put on the skeleton as we move.  In this way, it is thought to act as a mechanosensor. The osteocyte network likely functions to integrate these mechanical signals with its role as an endocrine organ (via hormonal and growth factor signaling) to regulate bone mass and energy balance.

Having seen a glimpse of what our skeleton does, maybe we can appreciate it a little more and possibly wonder about what we put into our bodies, be it food or medication, and consider what affect it will have on the skeleton. Also, in drug development we can start to use our understanding of systems biology to address any potential for liability, or benefit, in bone–a difficult task that can only be accomplished in vivo.