Diabetes, Metabolic Syndrome and Obesity (Dec 2021)

IL-25 Treatment Improves Metabolic Syndrome in High-Fat Diet and Genetic Models of Obesity

  • Smith AD,
  • Fan A,
  • Qin B,
  • Desai N,
  • Zhao A,
  • Shea-Donohue T

Journal volume & issue
Vol. Volume 14
pp. 4875 – 4887

Abstract

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Allen D Smith,1 Anya Fan,2 Bolin Qin,1 Neemesh Desai,2 Aiping Zhao,2 Terez Shea-Donohue3 1Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USA; 2Department of Radiation Oncology University of Maryland School of Medicine, Baltimore, MD, USA; 3Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USACorrespondence: Allen D SmithDiet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD, USATel +1 301-504-8577Fax +1- 301 504-9062Email [email protected]: Endemic obesity is considered the driving force for the dramatic increase in incidence of type 2 diabetes (T2D). There is mounting evidence that chronic, low-grade inflammation driven by Th1/Th17 cells and M1 macrophages, is a critical link between obesity and insulin resistance. IL-25 promotes development of a Th2 immune response and M2 macrophages that counteract the inflammation associated with obesity and T2D.Methods: Mice were fed a high-fat diet (HFD) for 16 weeks and then treated with IL-25 or BSA as a control for 21 days. Body weight, blood glucose levels, intraperitoneal glucose tolerance, and gene expression were evaluated in mice treated with BSA or IL-25. Ob/ob mice fed a normal control diet were also treated with BSA or IL-25 and body weight and blood glucose levels were measured. Transepithelial electrical resistance and sodium-linked glucose absorption were determined in muscle-free small intestinal tissue and glucose absorption assessed in vitro in intestinal epithelial and skeletal muscle cell lines.Results: Administration of IL-25 to HFD fed mice reversed glucose intolerance, an effect mediated in part by reduction in SGLT-1 activity and Glut2 expression. Importantly, the improved glucose tolerance in HFD mice treated with IL-25 was maintained for several weeks post-treatment indicating long-term changes in glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. In vitro studies demonstrated that glucose absorption was inhibited by IL-25 treatment in the epithelial IPEC-1 cells but increased glucose absorption in the L6 skeletal muscle cells. This supports a direct cell-specific effect of IL-25 on glucose metabolism.Conclusion: These results suggest that the IL-25 pathway may be a useful target for the treatment of metabolic syndrome.Keywords: metabolic syndrome, glucose, ob/ob, rodent

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