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. 2021 Dec 21:14:4875-4887.
doi: 10.2147/DMSO.S335761. eCollection 2021.

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

Allen D Smith  1 , Anya Fan  2 , Bolin Qin  1 , Neemesh Desai  2 , Aiping Zhao  2 , Terez Shea-Donohue  3
Affiliations

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

Allen D Smith et al. Diabetes Metab Syndr Obes. .

Abstract

Introduction: 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: glucose; metabolic syndrome; ob/ob; rodent.

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Conflict of interest statement

This work was prepared while Aiping Zhao was employed at University of Maryland School of Medicine and his current address is Center for Scientific Review, National Institutes of Health, Bethesda, MD, USA. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Dr Aiping Zhao reports a patent US9724392B2 issued to University of Maryland Baltimore. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
IL-25 treatment induces body weight loss in mice fed the HFD. Mice were fed the NCD or HFD for 16 weeks followed by ip injection with IL-25 at a dose of 2 μg/kg three times weekly or 5 μg/kg twice weekly for 21 days and periodically weighed. Panel (A) change in body weight in grams over 21 days in mice fed the NCD or HFD and treated with IL-25. (B) percent changes in body weight over time in BSA or IL-25-treated mice fed the HFD (% of pretreatment weight); mean±SEM, n=7–8 *p<0.05, **p<0.01 versus NCD; ф p<0.05 versus BSA treated HFD.
Figure 2
Figure 2
IL-25 treatment reduces fasting blood glucose levels and improves glucose tolerance in mice fed the HFD. Mice were fed the NCD or HFD for 16 weeks. (A) Fasting blood glucose levels measured before and after IL-25 treatment for 21 days, **p<0.01 versus pretreatment value (day 0); (B) intraperitoneal glucose tolerance test (IPGTT) administered 21 days after IL-25 treatment; and (C) calculated area under the IPGTT curve. Mean±SEM, n=7–8 **p<0.01 versus NCD.
Figure 3
Figure 3
Body weight loss and improvement in glucose tolerance is not simply the results of decreased food consumption. Mice were fed the HFD for 16 weeks and treated with BSA or IL-25 and feed intake measured. One group of mice receiving BSA had their feed restricted to levels consumed by the IL-25 treated mice. (A) Daily feed intake in BSA, IL-25 treated and BSA-feed matched groups; (B) changes in body weight in BSA, IL-25 treated and BSA-feed matched groups, *p<0.05, **p<0.01 vs BSA-treated HFD group, ф p<0.05 vs IL-25 group; (C) glucose levels during an intraperitoneal glucose tolerance test (IPGTT) in NCD or HFD fed mice treated with BSA, with or without feed restriction, or IL-25; and (D) calculated area under the curve (AUC) of the IPGTT curves in (C) mean±SEM, n=7–8 *p<0.05, **p<0.01 vs NCD group, ф p<0.05 vs NCD.
Figure 4
Figure 4
Feeding mice the HFD reduces sodium linked glucose transport and SGLT1 expression that are further changed by IL-25 treatment. (A) Sodium-linked glucose transport was reduced significantly in BSA-treated mice fed the HFD compared to mice fed a NCD and was inhibited further by both doses of IL-25. (B) SGLT1 expression was significantly reduced in mice fed the HFD compared to mice fed a NCD but was reversed by IL-25 treatment. Mean±SEM, n=5 *p<0.05, **p<0.01 vs NCD.
Figure 5
Figure 5
Body weight is regained by post IL-25 treated mice fed the HFD but the beneficial effects on glucose tolerance were maintained. (A) Body weight in HFD-fed mice was monitored after cessation of IL-25 treatment for 48 days; (B) fasting blood glucose post cessation of IL-25 treatment in HFD fed mice. mean±SEM, n=7 **p<0.01 vs 0 days post treatment.
Figure 6
Figure 6
IL-25 treatment improves glucose tolerance in genetically obese ob/ob mice. WT or ob/ob mice were treated with BSA or IL-25 for 21 days and the effect of IL-25 treatment on glucose levels during intraperitoneal glucose tolerance test (IPGTT), (A) and the area under the curve (AUV) of the IPGTT curves determined, (B) mean±SEM, n=8–10 **p<0.01 vs WT BSA; ф p<0.05, ф ф p<0.01 vs ob/ob BSA.
Figure 7
Figure 7
IL-25 has a direct effect on glucose uptake in iPEC-1 cells and skeletal smooth muscle cells. Differentiated iPEC-1 cells (A) or L6 skeletal cells (B) were incubated with IL-25 at two concentrations (50, 100 ng/mL) for two hours and then with the fluorescent glucose analog 2-NBDG for 2 hours to measure cellular glucose uptake. 2-NBDG uptake was measured using an Eclipse TE2000-S microscope and the fluorescence intensity was quantified by ImageJ software (NIH Image). Mean±SEM, n=5–6 **p<0.01 vs 0.
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