Effect of metformin on adipose tissue resistin expression in db/db mice

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Abstract

Resistin, a novel adipose-derived protein, has been proposed to cause insulin-resistant states in obesity. To evaluate whether an insulin-sensitizing drug, metformin, regulates adipose tissue resistin expression, murine models of obesity and diabetes, db/db mice, were treated with metformin (metformin group), insulin (insulin group), and vehicle (control group) for 4 weeks, followed by analyzing resistin protein expression in their adipose tissues. Unexpectedly, resistin protein expression was increased by 66% in the metformin group relative to the control group, while it did not differ between the insulin and control groups. Hyperinsulinemia was improved in the metformin group, while the insulin group exhibited severe hyperinsulinemia, similar to the control group. Furthermore, in comparison between obese mice (db/db mice) and age-matched lean controls, resistin protein expression was reduced by 58% in the obese mice with severe hyperinsulinemia. These data collectively suggest that resistin expression may be suppressed by hyperinsulinemia and that metformin may upregulate resistin expression via the improvement of hyperinsulinemia in obesity.

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Materials and methods

Animals. All animals were treated in accordance with the Animal Welfare Guideline of Akita University. Male obese diabetic db/db mice (C57BL/KsJ-leprdb/leprdb) and male C57BL/6J wild-type mice were obtained at 10 weeks of age from Nippon Clea (Tokyo, Japan). The mice were housed (n=3–4 per cage) in a room with relative humidity of 50% and a 12/12-h light/dark cycle at 20–22 °C, and allowed unrestricted access to standard rodent chow and water.

Metformin or insulin treatment. The db/db mice (10

Clinical characteristics

Table 1 shows the clinical characteristics of metformin-treated db/db mice (metformin group), insulin-treated db/db mice (insulin group), and vehicle-treated db/db mice (control group). As expected, fasting blood glucose and serum insulin levels were significantly reduced in the metformin group compared to the control group. In contrast to the metformin group, the insulin group exhibited high serum insulin levels, similar to the control group, although the insulin group showed a marked

Discussion

Originally, resistin was identified as an adipose-derived protein which may contribute to insulin resistance in murine models [7]. In the original paper, adipocyte resistin gene expression was shown to be downregulated by treatment with TZDs, and serum resistin levels were reported to be elevated in both genetic and diet-induced obese mice [7]. Therefore, we expected that resistin expression in adipose tissue would be reduced also by treatment with metformin, an insulin-sensitizing drug, in

Acknowledgements

This project was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (14770595).

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