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 (E(max)) was markedly reduced 18.8 +/- 2.3 versus 3.7 +/- 0.8.
Insulin sensitivity was also attenuated, with higher concentrations required for responses (EC(50) = 3.5 +/- 0.5 versus 29 +/- 3.8 nM).
Glucose uptake as determined with [(3)H]
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.