The Secret’s Out

Secretin was the first hormone to be discovered, back in 1902. For decades, its actions were thought to be limited to gastro-intestinal functions. But this century, thanks in part to the work of Professor Billy Chow Kwok-chong, Chair of Endocrinology in the School of Biological Sciences, it was also shown that secretin is expressed in the brain. That finding was recently developed further with the discovery at HKU that secretin not only affects functions related to the gut, but also to the bones.

Professor Chow and Professor Kelvin Yeung Wai-kwok of the Department of Orthopaedics and Traumatology teamed up to show that secretin in the ventromedial hypothalamus (VMH) of the brain plays a vital role in controlling both energy balance and bone density, in a study published in Nature Communications.

Using both whole body and VMH-specific knockout mice that had secretin and secretin receptors removed, they found that a lack of secretin increased appetite, leading to obesity, and triggered bone loss, leading to osteoporosis. Conversely, if secretin was added back in, the appetite was controlled and bone mass increased. The findings applied to both male and female mice.

“Our study opens new doors to treating metabolic and bone diseases. The ability to control appetite and bone density through the brain has significant implications for tackling obesity and osteoporosis,” Professor Chow said.

Connecting across disciplines

An interesting feature of the study is the collaboration between two seemingly distinct research streams. Professor Chow has been looking at secretin and energy balance for the past decade and previously made important findings on how secretin controls salt and water balance in the body. He also developed the knockout mice about 10 years ago and showed that secretin injections could inhibit food intake, but he had not identified the mechanism involved.

Meanwhile, Professor Yeung has been investigating the role of VMH in controlling bone regeneration. He had found that if there is a bone fracture, signals are sent to the brain via the central nervous system, which then sends signals back ordering that new bone be formed.

The two came together via a postdoctoral student of Professor Yeung’s, who had become aware of Professor Chow’s work and wondered whether they should collaborate. The two professors had known each other for years and, together with their postdocs, met over drinks and sealed the deal.

“Basically, with this study, we have identified the magic,” Professor Yeung said. “Once the signal from the secretin is received, it can modulate both the bone loss and obesity.”

On the energy intake side, Professor Chow looked at how food intake, obesity and fat metabolism were affected when secretin and the secretin receptor were removed. Appetite increased, there was evidence of obesity, and the overall fat content in the body increased, while at the same time browning of the fat cells, which increases the basic metabolic rate, decreased. The lack of secretin also reduced both glucose tolerance and insulin sensitivity, which has implications for diabetes. He further tested a diabetes-induced obesity animal model and found that when secretin was removed, all the bad pathologies aggregated.

“It’s a breakthrough because it allows us to understand that secretin plays an overlapping role in all these different physiological mechanisms,” he said. 

Looking for treatment 

Professor Yeung said the correlation between appetite and bone loss also helped explain a clinical observation that obese people can experience osteoporosis, because it showed that the lack of secretin triggered hunger or lack of satiety while at the same time inducing bone loss. Before, the mechanism for this combination was unknown. 

“The implication is that we could simply treat people with obesity and osteoporosis at the same time by controlling secretin,” he said. 

How to turn that finding into actual treatment, though, is another challenge. The two labs are collaborating on this, but it will take time. Professor Yeung said he would also welcome pharmaceutical companies or others using the findings to develop new treatments or drugs with them. “The information is in the public domain and everyone can read it. I think this is something a university needs to do to serve the public,” he said. 

Professor Chow, meanwhile, is developing several treatments based on the current study and on an earlier discovery of a small molecule that can work with secretin to stimulate the secretin receptor. He also values working with industry through contract research. 

“Contract research is very important to me because I get to know the industry people and what kind of experiments they’re doing and what kind of problems they would like to solve. Contract research is very important for HKU as well to work together with industry and have an impact on society,” he said.