MECHANISMS OF GASTROINTESTINAL NEUROPEPTIDE SIGNALING IN AN ANIMAL MODEL OF SCI FOLLOWING WEIGHT LOSS SURGERY

Background: Approximately two-thirds of spinal cord injured (SCI) individuals become overweight or obese. The greatest increase from normal to overweight or obese has been reported to occur during the first year after acute rehabilitation. In addition to limiting self-help techniques (e.g., wheelchair transfer), these individuals are susceptible to obesity-related conditions including type 2 diabetes. As the life span of SCI individuals continues to increase, these chronic conditions diminish the quality of life while increasing the financial healthcare burden for Veterans with SCI.Weight loss surgery (WLS), including sleeve gastrectomy (SG) and the Roux-en-Y gastric bypass (RYGB) surgery, is regarded as highly effective in the long-term treatment of obesity and remission of type 2 diabetes. The weight reduction after WLS does not appear to reflect mechanical restriction of food intake or malabsorption of nutrients, but a change in the regulatory signaling within the gut-brain axis. Examples of these changes include the increased release of anorexigenic gut hormones such as glucagon-like peptide-1 (GLP-1) and alterations in gastrointestinal (GI) transit.Given the risk factors for developing obesity following SCI, WLS offers an attractive intervention for SCI-induced obesity. SCI individuals, however, should not be regarded as similar to able-bodied individuals. In addition to the immediate loss of motor control, SCI results in impairment of autonomic nervous system function, including the regulation and integrity of the GI tract. These comorbidities combine to challenge metabolic homeostasis of the SCI individual. Due to current knowledge gaps, it is unknown if obese individuals with SCI respond to WLS similarly to the able-bodied. Therefore, efficacy assessments regarding the mechanisms behind successful bariatric surgical intervention in this special population group are warranted before performing surgery on potentially high-risk individuals.Our own observations in an animal model of SCI identify persistent GI dysmotility, a transient reduced sensitivity to gut hormones, increased adiposity and reduction of lean tissue mass, upregulation of inflammatory markers, intestinal histopathology, and reduced superior mesenteric artery (SMA) blood flow. We have verified that obese rats with an SCI can tolerate the increasingly preferred SG procedure, which is more tolerable by patients and provides similar benefits to those of RYGB surgery at lower costs. Thus, the rodent model is a viable tool for addressing fundamental questions regarding the mechanisms leading to the development of obesity and the efficacy of intervention strategies.The proposed studies are based upon the central hypothesis that diminished sensitivity of the vagal gut-brain axis to nutrient-associated GI signaling provokes the development of obesity prior to SG in an animal model of SCI. SG bariatric surgery will reverse this blunted sensitivity even in the radically altered physiology that accompanies SCI.Research Idea and Strategy: Following SCI, the sensitivity of neural circuits to our target GI peptide, GLP-1, before and after SG intervention will be investigated in SCI rats with the following specific aims:Specific Aim 1 will test the hypothesis that sensitivity of the gut-brain axis to nutrient-associated signaling is diminished in SCI rats, thus elevating the risk to developing obesity.Specific Aim 2 will test the hypothesis that SG intervention in obese SCI rats will restore sensitivity of the gut-brain axis to nutrient signaling and reduce adiposity.Impact: Complications of SCI include reduced GI integrity and motility (ileus), poor energy homeostasis, and an increased risk for obesity. It is unknown how bariatric surgical intervention for the able-bodied population translates to the SCI population. Our proposal for a neurophysiological study of the beneficial mechanisms of SG in an animal model of SCI is singular, novel, and likely to provide significant evidence-based data for applying this intervention to persons with SCI.Innovation and Military Relevance: We are only just beginning to understand the multi-organ responses following SCI. This proposal will combine GI physiology and animal models of WLS to explore the efficacy of SG to reverse the effects of obesity in an experimental model of SCI. Success of this proposal will develop evidence-based strategies for the treatment of obesity following SCI.