IL-25 treatment improves metabolic syndrome in high fat diet and genetic models of obesity

Authors: Smith, Allen; FAN, ANYA - University Of Maryland School Of Medicine; QIN,, BOLIN - University Of Maryland; DESAI, NEEMESH - University Of Maryland School Of Medicine; ZHAO, AIPING - National Institutes Of Health (NIH); SHEA, DONOHUE - National Institutes Of Health (NIH)

Submitted to: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/23/2021
Publication Date: 12/21/2021
Citation: Smith, A.D., Fan, A.X., Qin, B., Desai, N., Zhao, A., Shea-Donohue, T. 2021. IL-25 treatment improves metabolic syndrome in high-fat diet and genetic models of obesity. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 14:4875-4887. https://doi.org/10.2147/DMSO.S335761.
DOI: https://doi.org/10.2147/DMSO.S335761

Interpretive Summary: 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 immune cells, is a critical link between obesity and diabetes. IL-25, a substance made by the immune system, promotes development of an anti-inflammatory immune response called a Th2 immune response that can counteract low-grade inflammation associated with obesity and T2D. Administration of IL-25 to obese mice fed a high fat diet (HFD) led to weight loss and reversed glucose intolerance, a symptom of diabetes. Glucose absorption and expression of a protein that transports glucose in the small intestine, SGLT-1, were significantly reduced in obese mice fed a HFD. Giving IL-25 further lowered glucose absorption but normalized expression of the glucose transport protein SGLT-1. Importantly, the reversal of glucose intolerance in obese mice treated with IL-25 was maintained several weeks after treatment ended indicating IL-25 caused long-term changes to glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in ob/ob mice that get obese on normal mouse food. Both intestinal and skeletal muscle cells are important for controlling glucose regulation. Glucose absorption was reduced by giving IL-25 to an intestinal cell line called IPEC-J2 but increased glucose absorption in the skeletal muscle cell line called L6. This suggests that IL-25 may be acting to normalize glucose in obese mice by acting on intestinal and skeletal muscles cells. These results suggest that the IL-25 maybe a useful target for the treatment of diabetes.

Technical Abstract: 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 have anti-inflammatory properties and has the potential to counteract low-grade inflammation associated with obesity and T2D. Administration of IL-25 to obese mice fed a high fat diet (HFD) led to weight loss and reversed glucose intolerance. Glucose absorption and SGLT-1 expression in the small intestine were significantly reduced in obese mice fed a HFD. Administration of IL-25 further lowered glucose absorption but normalized expression of SGLT-1. Importantly, the reversal of glucose intolerance in obese mice treated with IL-25 was maintained several weeks post-treatment cessation even as mice regained body weight indicating IL-25 induced long-term changes to glucose metabolism in obese mice. Glucose intolerance was also reversed by IL-25 treatment in genetically obese ob/ob mice without inducing weight loss. Both gastrointestinal and skeletal muscle cells are important for whole body glucose regulation. Glucose absorption was inhibited by IL-25 treatment of the intestinal cell line IPEC-J2 but increased glucose absorption in the skeletal muscle cell line L6 thus providing a possible mechanism for glucose normalization in obese IL-25 treated mice. These results suggest that the IL-25 pathway maybe a useful target for the treatment of metabolic syndrome.