Obesity has become a common comorbidity among transplant recipients that is linked to inferior transplant outcome through far-reaching effects on metabolism, inflammation and immunity. Increasingly, weight-loss surgery is being considered for prospective transplant recipients to reduce these peri- and postoperative risks.

Fully mismatched skin transplantations were performed in diet-induced obese (DIO) C57/Bl6 mice and lean littermates. Sleeve gastrectomies (SGx) were performed prior to transplantation to induce weight loss.

While obese graft recipients showed significantly accelerated allograft rejection, bariatric surgery prolonged allograft survival to levels even beyond those of lean animals, associated with a shift in systemic cytokine balance towards protective IL-10-skewed conditions. Quantitative metabolomic profiling identified a secondary bile acid and a proteinogenic amino acid as upregulated after bariatric surgery. Strikingly, combined application led to weight loss comparable to bariatric surgery and resulted in significant prolongation of graft survival. Of note, lean littermates did not lose weight with metabolic treatment. Improved graft survival was associated with reduced pro-inflammatory responses in splenic CD4⁺ T cells and a significant reduction in splenic M1-like antigen-presenting cells through activation of the bile acid receptor TGR5.

CLAMS analysis subsequently demonstrated reduced oral intake of obese animals with metabolic treatment, while maintaining regular physical activity and energy expenditure. In line with significantly lowered respiratory exchanged ratios indicating heightened fat metabolism, both subcutaneous inguinal and visceral epididymal adipose tissue decreased with treatment. In addition, insulin resistance was reversed in intraperitoneal glucose tolerance testing. Mechanistically, metabolic treatment led to decreased expression of hypothalamic orexigenic peptides AgRP and NPY with increased levels of serum leptin.

Administration of two metabolic compounds associated with sleeve gastrectomy centrally regulated feeding and energy metabolism through hypothalamic neuropeptides and systemic leptin levels, leading to weight loss, increased insulin sensitivity, dampened systemic immune responses, and prolonged allograft survival.

CITATION INFORMATION: Quante M., Heinbokel T., Minami K., Nian Y., Elkhal A., Tullius S. Metabolic Regulation of Neuropeptides Induces Weight Loss and is Linked to Prolongation of Allograft Survival Am J Transplant. 2017;17 (suppl 3).

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