DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Mechanisms of Gastrointestinal Neuropeptide Signaling in an Animal Model of SCI Following Weight Loss Surgery

Principal Investigator: HAJNAL, ANDRAS
Institution Receiving Award: PENNSYLVANIA STATE UNIVERSITY, MILTON S. HERSHEY MEDICAL CENTER
Program: SCIRP
Proposal Number: SC160171
Award Number: W81XWH-17-1-0197
Funding Mechanism: Investigator-Initiated Research Award
Partnering Awards:
Award Amount: $773,297.91


PUBLIC ABSTRACT

The prevalence of obesity and the accompanying risk for developing type 2 diabetes, hyperlipidemia, and cardiometabolic pathologies are reaching epidemic proportions in the United States. The causative factors of this aggregate of diseases, a so-called metabolic syndrome (MS), in the able-bodied population are often considered to be a result of a high fat “Western diet” coupled with physical inactivity. Unlike the able-bodied population, the evidence identifying what factors provoke the onset of metabolic syndrome in individuals with spinal cord injury (SCI) is often speculative and draws upon inferences made from the able-bodied population. The profound alterations in the physiology of a SCI individual are not representative of any other single disease process, and preclinical research must employ experimental SCI models in order to begin to understand the mechanisms leading to SCI-induced obesity in order to produce effective therapeutic interventions.

The likelihood of an individual with SCI developing obesity and metabolic syndrome is 16%-44% greater than a similar-aged individual without SCI. In healthy individuals who have just eaten a meal, the gastrointestinal tract releases a wide array of peptide hormones that serve to regulate local and whole-body reflexes and nutrient set points. For example, in response to the glucose-containing portion of a meal, cells responsive to glucose secrete the gastrointestinal hormone glucagon-like peptide-1 (GLP-1). This peptide hormone is detected by sensory fibers in the gut as well as directly by neurons at multiple levels of the brain. GLP-1 signaling is but one critical component in the regulation of glucose homeostasis, reflexive control of the stomach following eating as well as feeding itself.

For obese individuals, 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 loss that occurs after surgery does not appear to reflect mechanical restriction of food intake or malabsorption of nutrients but a change in the bi-directional regulatory signaling between the brain and the gut (the so-called gut-brain axis). One example of these changes includes the increased release of gut hormones that inhibit food intake such as GLP-1.

Given the risk factors for developing obesity following SCI, WLS offers an attractive intervention for SCI-induced obesity. It is unknown how bariatric surgical intervention for the able-bodied population translates to the SCI population. Specifically, do the control mechanisms that normally limit eating (and promote weight loss following bariatric surgery) function to the same extent in the SCI individual?

Our proposal combines methods derived from our expertise in experimental models of obesity, weight loss surgery, and clinically relevant SCI. Our own preliminary research has demonstrated that the WLS procedure is tolerated by obese rats with SCI at the third thoracic (T3) spinal level. We also superimposed a very high fat (60% of calories) within these surgical groups as a successful test of feasibility.

Specifically, we will mechanistically investigate the effect of SCI and SCI coupled with WLS on the gut-brain axis at the level of (1) the neural signals emanating from the gut; (2) the brain site where gut signaling is integrated; and (3) the resulting behavior that is modulated by these neural circuits.

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.