Metabolic Disease in a Clinically Relevant Rodent Model of Spinal Cord Injury
Abstract
Obesity, diabetes, hypercholesterolemia, and cardiovascular disease are a serious health problem in the United States. But they are also a serious problem for spinal cord injured (SCI) persons. Typically, obesity and the other diseases that accompany obesity are the result of eating a diet rich in saturated fats and too little exercise. SCI persons typically have a reduction in exercise due to their injury. But when their physical activity is controlled for by matching to other injured persons without SCI, we see that there is still an undue burden of disease on individuals having SCI. This suggests there are mechanisms of pathology that are not straightforward after SCI that are driving metabolic problems. Though some basic characterizations have been done using rat models looking at food intake and body weight, there appears to be a significant gap in trying to understand the specific issues with obesity and diabetes that might afflict people with SCI. The current proposal uses methods that have been worked out in understanding obesity and diabetes in normal rats and superimposes these methods on a clinically relevant model of acute to chronic SCI. We hypothesize that because SCI causes a sustained state of full-body inflammation, the brain will be particularly sensitive to insult and result in activation of the resident immune cells, microglia. There is a whole body of literature that suggests that when these cells are activated, dysregulation of body weight control occurs. If we superimpose a palatable diet rich in fats to the SCI animals, we anticipate a greater inflammatory response in the brain. We also anticipate that this inflammatory response will break down the barrier that exists between the peripheral organs of the body and the brain, exposing sensitive brain regions responsible for regulating metabolic function to inflammatory signals. Thus, the brain will sense and experience the increased fluctuations of inflammation and causing a dysregulation in the brain s ability to response to dietary stressors. Additionally, there are key proteins in the brain (specifically hypothalamus) that respond to the level of fat and glucose in the body, which occur in the hypothalamus. It is possible that through the increased inflammation and barrier permeability, these peptides no longer signal properly. Not only do we want to know how the brain is signaling with respect to the pathways that control food intake, but how SCI rats gain weight by offering them palatable foods that are high in fat. In the present proposal, we will place animals on a diet that is relatively higher in fat and similar to the American diet. We will test whether the SCI rats can control their food intake and fasting normally. We will determine how much food they eat and how much weight they gain for the food they eat and where the fat is stored. We will test some basic parameters in circulation by performing tail vein bleeds to see if the normal mechanisms that control body weight regulation are in place. In SCI rats maintained on a very low fat diet, it appears that SCI rats overeat. This is very important to understand further because it suggests that something is not functioning properly with respect to the control of food intake. Finally, we will determine whether animals can control their glucose similar to non-injured animals. If fed a very low fat diet, SCI rats perform normally. But in order to understand if there really is a dysfunction, we need to stress the system. This again is carried out by placing the animals on a palatable saturated fat diet. We will examine the response of the animals to glucose and insulin and fasting, but also examine their hormone responses and the architecture of the pancreas to determine if there is unidentified damage. All persons with SCI are at risk for metabolic disease, and their reduced activity places them in an even greater risk. Metabolic disease does not appear overnight. M
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610387
Entities
People
- Bernadette E Grayson
Organizations
- United States Army
- University of Mississippi