Summary: A new study demonstrates how spinal cord injuries can lead to significant metabolic disruptions, including the onset of conditions such as diabetes and heart disease.
Key Facts: The study identifies a link between spinal cord injuries and metabolic dysfunctions due to abnormal neuronal activity affecting fat tissue.
Previous research has found that cardiometabolic diseases are among the leading causes of death in people who have experienced a spinal cord injury.
As soon as we disrupt sensory processing as a result of spinal cord injury, we see changes in the fat,” Tedeschi said.
Results also showed an increase in blood flow in fat tissue and recruitment of immune cells to the environment.
“CGRP is also a potent vasodilator, and we saw increased vascularization of the fat – new blood vessels forming as a result of the spinal cord injury.
Tedeschi’s lab has previously shown in animal studies that gabapentin helped restore limb function after spinal cord injury and boosted functional recovery after stroke.
“α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury” by Andrea Tedeschi et al.
In summary, a recent study shows how serious metabolic disturbances resulting from spinal cord injuries can cause the onset of diseases like diabetes and heart disease. The research discovered that, following an injury, aberrant neural activity causes an excessive breakdown of triglycerides in adipose tissue, which releases toxic substances into organs such the liver.
Researchers were able to successfully avert these metabolic effects in animal models by giving the nerve painkiller gabapentin. This finding may lead to the development of novel therapies that lessen the side effects of spinal injuries.
Important Information:.
The research finds a connection between metabolic dysfunctions brought on by aberrant neural activity that affects adipose tissue and spinal cord injuries.
By inhibiting problematic neural proteins and preventing the excessive breakdown of fats, gabapentin was successful in returning mice’s metabolic processes to normal.
Scientists have had to modify dosing strategies to maintain therapeutic effects while minimizing side effects because gabapentin, despite its advantages, caused insulin resistance.
The Ohio State University is the source.
According to a recent animal study, abnormal post-injury neuronal activity that leads to the leakage and pooling of abdominal fat tissue compounds in the liver and other organs is the cause of conditions like diabetes, heart attacks, and vascular diseases that are frequently diagnosed in people with spinal cord injuries.
Once the relationship between the breakdown of triglycerides in mice’s fat tissue and dysregulated neuron function was established, researchers discovered that a brief course of gabapentin, a medication often prescribed for nerve pain, could stop the spinal cord injury’s harmful metabolic effects.
In this case, the overactive neural protein that results from damage to the nervous system impairs communication between sensory neurons and the fat tissue in the abdomen to which they are sending signals. Gabapentin blocks this neural protein.
“We think there is a maladaptive reorganization of the sensory system that causes the fat to undergo changes, starting a chain of reactions – triglycerides start breaking down into glycerol and free fatty acids that are released in circulation and taken up by the liver, the heart, the muscles, and accumulate, setting up conditions for insulin resistance,” stated senior author Andrea Tedeschi, an assistant professor of neuroscience at The Ohio State University College of Medicine’s.
“We were able to restore normal metabolic function by administering gabapentin.”. “.
In Cell Reports Medicine, the study was published today, April 24, 2024.
Cardiometabolic disorders rank among the top causes of death for individuals with spinal cord injuries, according to earlier research.
In addition to having a complex metabolic role that involves storing energy and releasing fatty acids when needed for fuel, visceral white fat, also known as adipose tissue, may be malfunctioning in these frequently chronic disorders. Adipose tissue also helps to maintain stable blood sugar levels.
Previous studies on these disorders in individuals with neuronal damage have concentrated on the function of adipose tissue and the role of the sympathetic nervous system, which is responsible for both regulating the adipose tissue that surrounds the abdominal organs and eliciting the “fight or flight” response.
Rather, Debasish Roy, a postdoctoral scholar in Tedeschi’s lab and the paper’s first author, chose to concentrate on sensory neurons in this particular setting. Tedeschi and associates have previously demonstrated that following spinal cord injury, the neuronal receptor protein alpha2delta1 is overexpressed. This increased activation of the protein interferes with the post-injury function of axons, which are the long, slender extensions of nerve cell bodies that carry messages.
In this new study, scientists first looked at the connections between sensory neurons and adipose tissue in healthy mice. Then, they developed a spinal cord injury mouse model that specifically targeted those neurons, leaving the sympathetic nervous system intact.
Within seven days following the injury, experiments in visceral fat tissue and neurons (albeit only in their communication function, not in their regrowth or structure) showed a cascade of abnormal activity.
While communicating with the fat tissue through synaptic transmission, sensory neurons expressed more alpha2delta1 receptors and over-secreted CGRP, a neuropeptide that, in a dysregulated state, increased the levels of a receptor protein that interacted with the CGRP.
“These are some pretty quick changes. We see changes in the fat as soon as we disrupt sensory processing due to spinal cord injury, according to Tedeschi. “A vicious cycle is created; it’s as if you’re driving and depressing the gas pedal to allow your car to run out of gas, but someone else keeps filling it up so it never does.”. “.
The process known as lipolysis, which has gotten out of control, is what leads to the overflow of free fatty acids and glycerol from fat tissue. The recruitment of immune cells to the environment and an increase in blood flow in fat tissue were also observed in the results.
“Lipolysis is being activated by the fat’s reaction to the presence of CGRP,” stated Tedeschi. Since the spinal cord injury caused new blood vessels to form, we observed increased vascularization of the fat. CGRp is also a potent vasodilator. Additionally, the influx of monocytes may contribute to the establishment of a persistent pro-inflammatory state. “.
Since gabapentin targets both alpha2delta1 and its partner, alpha2delta2, it was a good candidate for treatment. Normal function was restored to the fat tissue by silencing the genes encoding the alpha2delta1 receptor.
Previous animal studies conducted by Tedeschi’s lab have demonstrated that gabapentin enhances functional recovery following a stroke and aids in the restoration of limb function following spinal cord damage.
But Roy found something interesting about gabapentin in these experiments: the medication stopped changes in the fat tissue around the abdomen and decreased the blood level of CGRP, which prevented fatty acid spillover into the liver a month later and restored normal metabolic conditions. Paradoxically, though, the mice experienced the known gabapentin side effect of insulin resistance.
The team used a different approach to administering the medication, beginning with a high dose, tapering it off, and ending after four weeks.
“In this manner, we were able to restore metabolism to a state that was considerably closer to that of control mice,” Roy stated. This implies that when the medication is stopped, its beneficial effects are maintained and the accumulation of lipids in the liver is stopped. That was incredibly thrilling. “.
Finally, researchers looked at the effects of genetically targeting alpha2delta1 or using gabapentin on genes known to regulate white fat tissue. They discovered that both of these interventions, when applied after spinal cord injury, suppress the genes that cause disruptions in metabolic processes.
Tedeschi stated that the collective results indicate that initiating gabapentin therapy soon after a spinal cord injury may guard against harmful conditions involving fat tissue that result in cardiometabolic disease. It may also allow for the drug to be stopped with all of its advantages and a decreased chance of side effects.
Funding: The Ohio State Chronic Brain Injury program, grants from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke, and other contributions were used to support this work.
Elliot Dion, Jesse Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas, and Wenjing Sun were the other co-authors. All of them were Ohio State alumni.
Regarding this news article on metabolism and spinal cord injury.
Writer: Emily Caldwell.
University of Ohio is the source.
Ohio State University’s Emily Caldwell can be reached.
Photo credit: This image is courtesy of Neuroscience News.
Original Study: Disclosed under open license.
According to Andrea Tedeschi et al., “α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury.”. Cell Reports: Medical.
Inabst.
Upon spinal cord injury, adipose tissue homeostasis is disturbed by maladaptive sensory plasticity mediated by α2δ1.
Highlights.
Lipolysis in epididymal white adipose tissue (eWAT) is made worse by SCI.
Increased expression of α2δ1 is observed in CGRP-positive DRG neurons that innervate eWAT following SCI.
Following SCI, eWAT lipolysis returns to normal in DRG neurons with conditional deletion of Cacna2d1.
After SCI, eWAT lipolysis returns to normal when gabapentin is administered to block α2δ1.
In brief.
The risk of cardiometabolic disorders, such as insulin resistance, dyslipidemia, and hypertension, is elevated in individuals with spinal cord injuries (SCI). Side effects of stroke include ectopic lipid accumulation in organs crucial for insulin and glucose metabolism in addition to the pathological enlargement of adipose tissue. It is unknown what pathophysiological alterations cause adipose tissue dysfunction following SCI.
In epididymal white adipose tissue (eWAT), we find that SCI exacerbates lipolysis.
In dorsal root ganglia neurons that project to eWAT and express the α2δ1 subunit of voltage-gated calcium channels, eWAT lipolysis is restored following SCI when the α2δ1 gene is conditionally deleted in these neurons.
Moreover, gabapentin systemic administration normalizes eWAT lipolysis following SCI and prevents ectopic lipid accumulation in the liver by pharmacologically blocking α2δ1.
Our findings thus aid in the development of strategies to lessen metabolic and cardiovascular complications following SCI by shedding light on the molecular causes of maladaptive sensory processing in eWAT.
