Exciting new research has determined that a variant of a drug used to treat pulmonary arterial hypertension induces weight-loss in obese mice. Among mice fed a high-fat diet, those who did not get the medication became obese while medicated mice did not.
The experimental drug used stimulates soluble guanylyl cyclase (sGC), and this drug is a member of the same class of novel drugs as the drug riociguat. The Food and Drug Administration approved riociguat in 2013 to treat high blood pressure in the lungs. Riocoguat is produced by Bayer HealthCare Pharmaceuticals, is marketed under the trade name Adempas.
In mice, the sCG stimulator stimulated a shift in fat tissue and turned stored white fat in the mice into brown fat, which burns up more energy and improves metabolic function. Beige or brown fat is a beneficial type of fat that is richly populated with mitochondria, which makes the tissue look brown under a microscope. White fat releases hormonal signals that prompt the storage of still more white fat, but brown fat burns up fat and protects against weight gain, even when caloric intake is high.
In this research, which was published in the journal Nature Communications, mice made obese by a high-fat, high-calorie diet were given the sCG stimulator. These mice not only experienced weight loss, but also showed improved glucose tolerance, reduced insulin levels and decreased the signs of fatty liver, which is a damaging consequence of established obesity. It also even shrunk white fat cells.
In plump mice on the sCG stimulator, circulating dietary fatty acids were increasingly drawn into the brown fat and burned up at high rates. Even muscle and white fat in those mice increased their use of the circulating fatty acids. These metabolic changes caused mice to burn more calories, and their abnormal metabolic function improved.
This new research was led by researchers at the University Hospital in Bonn, Germany, and it elucidated the biochemical pathway that generates brown fat. This brings potential targets into view that could shift white fat into brown fat.
The sCG stimulator used in this study, the authors concluded, “might be used to enhance weight loss induced by physical activity.”
If a drug related to riociguat is to enter broad use for obesity, however, it will need to be cheaper than its close chemical relative. At doses taken by those with pulmonary arterial hypertension, a typical month’s prescription of Adempas costs close to $2,800, or about $90,000 a year.
As a treatment for the nation’s more than 72 million obese adults, that cost could prove prohibitive, especially as obesity and its consequences are increasingly understood to be chronic conditions that will need long-term management.
McMaster University stem cell scientists have discovered a way to adult sensory neurons from human patients simply by having them roll up their sleeve and provide a blood sample. The McMaster scientists directly converted adult human blood cells to both central nervous system (brain and spinal cord) neurons and peripheral nervous system (rest of the body) neurons responsible for pain, temperature and itch perception. This means that how a person’s nervous system cells react and respond to stimuli can be determined from their blood.
This breakthrough was published online recently and was also featured on the cover of the journal Cell Reports. The leader of this research, Mick Bhatia, serves as the director of the McMaster and Cancer Research Institute and holds the Canada Research Chair in Human stem Cell Biology and is a professor in the Department of Biochemistry and Biomedical Sciences in the Michael G. DeGroote School of Medicine.
Scientists do not have a robust understanding of pain and how to treat it. Neurons in the peripheral nervous system is composed of different types of nerves that detect mechanical forces like pressure or touch, and others and detect temperature, such as heat. Pain is perceived by the brain when signals are sent by peripheral pain receptors.
“The problem is that unlike blood, a skin sample or even a tissue biopsy, you can’t take a piece of a patient’s neural system. It runs like complex wiring throughout the body and portions cannot be sampled for study,” said Bhatia.
“Now we can take easy to obtain blood samples, and make the main cell types of neurological systems — the central nervous system and the peripheral nervous system — in a dish that is specialized for each patient,” said Bhatia. “Nobody has ever done this with adult blood. Ever.
“We can actually take a patient’s blood sample, as routinely performed in a doctor’s office, and with it we can produce one million sensory neurons, that make up the peripheral nerves in short order with this new approach. We can also make central nervous system cells, as the blood to neural conversion technology we developed creates neural stem cells during the process of conversion.”
This new protocol uses a gene called “Oct4” to directly reprogram blood cells. Additionally, if two proteins (SMAD and GSK-3) are inhibited with small molecules while the cells are transfected with the Oct4 gene, then the resultant cells transdifferentiate into blood-derived induced neural progenitor cells (BD-iNPCs). Now the direct conversion of skin cells called fibroblasts into neural progenitor cells that look a great like neural crest cells. However, these BD-iNPCs have the ability to differentiate into glial cells (support cells in the nervous system, multiple central nervous system neurons, and pain receptors, which are normally found in the peripheral nervous system.
This new, revolutionary protocol that directly converts white blood cells into neurons with one gene has not only been patented, but has “broad and immediate applications,” according to Bhatia. He also added that it allows researchers to start asking questions about understanding disease and improving treatments. These cells could be used to determine why certain people feel pain instead of numbness, or whether or not the degree to which people perceive pain is genetically determines, or whether or not diabetic neuropathy ca be mimicked in a culture dish? Bhatia’s new protocol also provides a slick, new model system to find new pain drugs that don’t just numb the perception of pain, but completely block it.
“If I was a patient and I was feeling pain or experiencing neuropathy, the prized pain drug for me would target the peripheral nervous system neurons, but do nothing to the central nervous system, thus avoiding non-addictive drug side effects,” said Bhatia. “You don’t want to feel sleepy or unaware, you just want your pain to go away. But, up until now, no one’s had the ability and required technology to actually test different drugs to find something that targets the peripheral nervous system and not the central nervous system in a patient specific, or personalized manner.”
Bhatia’s team successfully tested their protocol by using fresh blood and frozen blood. This is an important piece of research since blood samples are usually taken and frozen. Freezing blood samples allows scientists or even physicians to create a kind of “time machine” that can show the evolution of a patient’s response to pain over a period of time.
For future studies, Bhatia and his colleagues would like to examine patients with Type 2 Diabetes to determine if his technique can help predict whether they will experience neuropathy by running tests in the lab using their own neural cells derived from their blood sample.
“This bench to bedside research is very exciting and will have a major impact on the management of neurological diseases, particularly neuropathic pain,” said Akbar Panju, medical director of the Michael G. DeGroote Institute for Pain Research and Care, a clinician and professor of medicine.
“This research will help us understand the response of cells to different drugs and different stimulation responses, and allow us to provide individualized or personalized medical therapy for patients suffering with neuropathic pain.”