Cerebrum Summer 2020

NES T HE STORY BEGINS VERY FAR FROM NEUROSCIENCE. In the early 1990s, as an assistant professor of molecular genetics, I was interested in the molecular basis of bone mineralization. This led me to osteocalcin, a bone-derived hormone found at high concentrations in the skeleton. But there were obstacles to this research. For one, making a knock-out mouse lacking osteocalcin to help determine its functions was anything but easy. More generally, entering a new field made it extremely difficult to find funding, gain acceptance among my peers, and address other real-life issues.

Eventually, we were able to engineer mice that lacked osteocalcin, and we anticipated that we would find problems with their bones. But their skeletons appeared essentially normal, a result I found intriguing as well as discouraging. Equally intriguing were a number of other issues we found. The mice had unusually fatty abdomens; they had trouble breeding and, unlike typical rodents, never rebelled or tried to bite or escape. The lack of osteocalcin, apparently, had wide-ranging effects on mice’s fat stores, livers, muscles, pancreases, and testes. Based on such observations, in 1995 I hypothesized that osteocalcin is a hormone that regulates fertility and some aspects of energy metabolism, including fat mass. If so, does this make bone an endocrine organ that directly influences the physiology of other organs, starting with reproductive functions and energy metabolism? At that time, I was not bold enough to follow this hypothesis, and it took me ten years to muster the courage to explore it further. Evidence eventually suggested that the brain, too, is impacted—and that osteocalcin is a messenger, sent by bone to regulate crucial processes all over the body, including how we respond to danger. The narrative of how these discoveries—much of which controverted accepted scientific dogma—were made over 25 years is anything but linear. Early Findings Skeletons do a lot more than just give our bodies their shape. In 2007, we were able to show that through osteocalcin, bones play a crucial role in regulating blood sugar: mice engineered to lack the hormone were essentially diabetic; they were less sensitive to insulin and produced less of it than wild- type mice. When we provided osteocalcin, their insulin sensitivity and blood sugar normalized. When we first presented these findings at a conference, endocrine experts were surprised by the potential implications for the treatment of metabolic diseases, chief among them being type 2 diabetes. Our work also raised provocative questions about the skeleton’s role in fertility. In 2011, we discovered that bones play a crucial role in male reproduction: mice that did not produce osteocalcin had abnormally low levels of testosterone and were sterile, while those producing high levels of osteocalcin had abundant testosterone and bred frequently. (The finding did not appear to be relevant to females.) Neuroscience came to the fore in our 2013 paper, published in the journal Cell , when we showed that bone plays a direct role in memory and mood . Mice, whose skeletons did not produce osteocalcin as a result of genetic manipulation, were anxious, depressed, and almost completely unable to master a test of spatial memory. When we infused them with the missing hormone, however, their moods improved and their performance on the memory test nearly normalized. We also found that, in pregnant mice,

Research by geneticist Gérard Karsenty at Columbia University Medical center has revealed that our bones do much more than provide protection and support. A protein called osteocalcin—released as a hormone by the skeleton—has been linked to sugar levels, exercise, and male fertility. More recently, he has shown that osteocalcin triggers a “fight or flight” response to threat.

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