Abstract
The obese spontaneously hypertensive rat (SHROB) is a model of marked insulin resistance with normoglycemia. We sought to determine whether insulin resistance extends to adipocytes and the impact of an insulin-sensitizing imidazoline, moxonidine (4 mg/kg/days for 21 days). Gonadal adipocytes were isolated from SHROB and lean spontaneously hypertensive rat (SHR) littermates. In lean SHR adipocytes, Akt activation by 100 nM insulin peaked at 3 min at 25-fold, whereas SHROB adipocytes showed only 4-fold activation. In dose-response experiments, the maximal response (Emax) was markedly reduced 18.8 ± 2.3 versus 3.7 ± 0.8. Insulin sensitivity was also attenuated, with higher concentrations required for responses (EC50 = 3.5 ± 0.5 versus 29 ± 3.8 nM). Glucose uptake as determined with [3H]2-deoxyglucose was also less responsive to insulin in SHROB relative to lean SHR. Moxonidine had little or no effect when applied acutely in vitro, but adipocytes isolated from SHROB treated with moxonidine in vivo showed significantly improved responses to insulin, both in terms of Akt activation and facilitation of glucose uptake. Chronic but not acute moxonidine treatment partially restores insulin sensitivity in SHROB adipocytes, suggesting an indirect action of this agent.
Footnotes
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This study was supported by Grant HL44514 from the National Institutes of Health. It was submitted in partial fulfillment of the requirements for a doctorate in Nutrition from Case Western Reserve University School of Medicine.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.111153.
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ABBREVIATIONS: SHROB, spontaneously hypertensive rat(s), obese substrain; IRS-1, insulin receptor substrate 1; PI3K, Phosphatidylinositol 3-kainse; BSA, bovine serum albumin.
- Received July 20, 2006.
- Accepted November 8, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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