Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

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 (E max ) was markedly reduced 18.8 Ϯ 2.3 versus 3.7 Ϯ 0.8. Insulin sensitivity was also attenuated, with higher concentrations required for responses (EC 50 ϭ 3.5 Ϯ 0.5 versus 29 Ϯ 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.Obese spontaneously hypertensive rats (SHROB) are markedly insulin-resistant, showing a greater than 20-fold elevation fasting insulin levels in the presence of normal fasting glucose (Friedman et al., 1997;Velliquette et al., 2005). At the cellular level, defects in insulin action have been noted in skeletal muscle and the liver, as indicated by reduced insulin receptor protein, reduced levels of its substrate protein IRS-1, and impaired insulin-induced tyrosine phosphorylation of both proteins (Friedman et al., 1997). In adipocytes and in skeletal muscle, the stimulation of glucose transport by insulin is impaired. However, insulin signaling in adipocytes in the SHROB model has not yet been characterized.Akt (protein kinase B) is a 57-kDa Ser/Thr kinase that plays a key role in the insulin induced PI3K-Akt pathway (Hanada et al., 2004;Osaki et al., 2004). The binding of insulin to its receptors leads to the phosphorylation of PI3K, which then phosphorylates phosphatidylinositols at the 3-position. Then, Akt is recruited to the inner side of plasma membrane due to the interaction between its pleckstrin homology domain and the phosphatidylinositol-(3,4,5)-trisphosphate produced by PI3K. The Thr308 and Ser473 on Akt are then phosphorylated by 3-phosphoinositide-dependent protein kinase 1/2 and mammalian target of rapamycin (Hresko and Mueckler, 2005). Once activated, Akt regulates many cellular functions related to insulin action (Hanada et al., 2004). As a key element in insulin signaling, Akt could be an efficient indicator for cellular insulin response. Here, we measured the phosphorylation level of Akt in corresponding to insulin stimulation as an indicator of insulin sensitivity in isolated rat adipocytes. We hypothesized that the inherent defe...

Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance

“…The following transduction cascade can therefore be proposed: I 1 R ¡ inactivation of adenylate cyclase ¡ 2cAMP ¡ inactivation of SIRT1/ FOXO1 ¡ activation of PPAR␥ ¡ 1adiponectin synthesis. The direct peripheral modulation of adiponectin and AMPK signaling highlighted in the present study probably contributes to the overall beneficial effect on insulin resistance of sympathoinhibitory antihypertensive agents (39,43) and I 1 R ligands (7). Nevertheless, additionnal non-adiponectin mechanisms of action cannot be ruled out.…”

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

“…Our present results showed that like moxonidine, S43126 also cause increased phosphorylation of ERK and PKB. Ernsberger's lab showed that in adipocytes isolated from SHROB treated with moxonidine in vivo, there was an improved response to insulin, both in terms of PKB activation and facilitation of glucose uptake [26]. Since receptors are defined by their signaling pathways, our data suggest that S43126 is an agonist at the imidazoline binding site.…”

“…Moxonidine has been shown to ameliorate elements of metabolic syndrome in both animals and humans. Moxonidine treatment improved glucose disposal and increased insulin-stimulated phosphorylation of key insulin signaling intermediates [6,8,10,26] in the spontaneously hypertensive rat (SHROB; Koletsky rat) model of metabolic syndrome. The beneficial effects of moxonidine on elements of the metabolic syndrome extend to humans with similar disorders.…”

Pharmacological Treatments for Obesity-Related Hypertension

“…In obese spontaneously hypertensive rat adipocyte that chronic, but not acute, selective moxonidine treatment partially restores insulin sensitivity [49]. Moxonidine reduced blood pressure associated with improving insulin sensitivity in obese hypertensive patients [50].…”