Elevated T-helper 2 cytokine levels in high fat diet-fed C57BL/6 mice are attenuated by short-term 6-week treatment with a combination of low-dose aspirin and metformin

Abstract

Objective: To evaluate T-helper cytokine responses in a short-term high fat diet (HFD) induced impaired glucose metabolism. To further evaluate the modulation of T-helper 1 (Th₁) and T-helper 2 (Th₂) cytokines using short-term low-dose aspirin in combination with metformin.

Design: Two experiments were carried out in this study in order to evaluate the T-helper cytokine profiles in a state of impaired glucose metabolism. A total of 28 six-week-old male C57BL/6 mice were used in this study. In the first experiment, mice were fed either a high fat diet or low fat diet for a duration of 10 weeks. We then determined the Th₁, Th₂ and T-helper 17 (Th₁₇) cytokine profiles. In the second experiment, we evaluated whether the short term 6-week treatment with low-dose aspirin in combination with metformin modulates T-helper cytokine profiles of the HFD-fed mice.

Measurements: In the first experiment, we measured the body weights, blood glucose levels, insulin levels, lipid profiles and haematological parameters. We further performed oral glucose tolerance testing following an 8-hour fast and serum Th₁, Th₂ and Th₁₇ cytokine levels were also determined following short-term 8-week diet-feeding and 6-week low-dose aspirin and combined metformin with low-dose aspirin treatment.

Results: High fat diet-feeding caused a marked increase in circulating peripheral blood lymphocytes, which was attenuated by short-term low-dose aspirin treatment. Moreover, the HFD feeding resulted in 2-fold increase in total cholesterol and a 4-fold increase in low-density lipoprotein cholesterol when compared to the low-fat diet-fed group (p < 0.05). In the high fat diet group, impaired glucose metabolism was associated with skewed Th₂ responses without alterations in the Th₁ and Th₁₇ cytokine profiles. Interestingly the short-term treatment with low-dose aspirin showed no effect on the selected T-helper 1 cytokine IFN-Ƴ (P > 0.05). While the combination of low-dose aspirin with metformin considerably reduced the levels of serum IFN-Ƴ (P < 0.05). Furthermore low-dose aspirin treatment showed the modest attenuation of the selected Th₂ cytokines, IL-10 and IL-13 when compared to low-dose aspirin with metformin (P < 0.01).

Conclusion: The early immunological and metabolic changes that occur in a state impaired glucose tolerance are accompanied by the increased production of Th₂ cell cytokines. The short-term treatment using low-dose aspirin combined with metformin may provide therapeutic benefits in preventing complications associated with dysregulated Th₂ cell responses.

Keywords: Impaired glucose metabolism; Inflammation; T cell activation; T-helper cytokines.