Study in mice finds that a widely-used medication prevents damage to fat tissue from injuries
A new animal study suggests that conditions like diabetes, heart attacks, and vascular diseases, commonly diagnosed in individuals with spinal cord injuries, may be linked to unusual neuronal activity following the injury. This activity can cause abdominal fat tissue compounds to leak and pool in the liver and other organs, a new animal study has found.
After discovering the connection between dysregulated neuron function and the breakdown of triglycerides in fat tissue in mice, researchers found that a short course of the drug gabapentin, commonly prescribed for nerve pain, prevented the damaging metabolic effects of the spinal cord injury.
Gabapentin inhibits a neural protein that, after the nervous system is damaged, becomes overactive and causes communication problems – in this case, affecting sensory neurons and the abdominal fat tissue to which they’re sending signals.
Mechanism of Action
“We believe there is maladaptive reorganization of the sensory system that causes the fat to undergo changes, initiating 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 accumulating, setting up conditions for
“Through administration of gabapentin, we were able to normalize metabolic function.”
The study was recently published in the journal helped restore limb function after spinal cord injury and boosted functional recovery after stroke.
But in these experiments, Roy discovered something tricky about gabapentin: The drug prevented changes in abdominal fat tissue and lowered CGRP in the blood – and in turn prevented spillover of fatty acids into the liver a month later, establishing normal metabolic conditions. But paradoxically, the mice developed insulin resistance – a known side effect of gabapentin.
The team changed drug delivery tactics, starting with a high dose and tapering off – and stopping after four weeks.
“This way, we were able to normalize metabolism to a condition much more similar to control mice,” Roy said. “This suggests that as we discontinue administration of the drug, we retain beneficial action and prevent spillover of lipids in the liver. That was really exciting.”
Finally, researchers examined how genes known to regulate white fat tissue were affected by targeting alpha2delta1 genetically or with gabapentin, and found both of these interventions after spinal cord injury suppress genes responsible for disrupting metabolic functions.
Tedeschi said the combined findings suggest starting gabapentin treatment early after a spinal cord injury may protect against detrimental conditions involving fat tissue that lead to cardiometabolic disease – and could enable discontinuing the drug while retaining its benefits and lowering the risk for side effects.
Reference: “α2δ1-mediated maladaptive sensory plasticity disrupts adipose tissue homeostasis following spinal cord injury” by Debasish Roy, Elliot Dion, Jesse A. Sepeda, Juan Peng, Sai Rishik Lingam, Kristy Townsend, Andrew Sas, Wenjing Sun and Andrea Tedeschi, 24 April 2024, Cell Reports Medicine.
DOI: 10.1016/j.xcrm.2024.101525
This work was supported by grants from the National Institute of Neurological Disorders and Stroke and the