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

Sun, Zheng; Ernsberger, Paul

doi:10.1124/jpet.106.111153

Cited by 11 publications

(11 citation statements)

References 25 publications

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“…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.…”

Section: Discussionmentioning

confidence: 70%

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

Weiss

Bouchoucha

Aiad

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome.

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Section: Discussionmentioning

confidence: 70%

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

Weiss

Bouchoucha

Aiad

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…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.…”

Section: Effects Of S43126 On Erk1/2 and Pkb Phosphorylationmentioning

confidence: 60%

“…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.…”

Section: Introductionmentioning

confidence: 99%

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

Tesfai

Crane

Baziard-Mouysset

et al. 2011

Pharmacological Reports

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Abstract:The I 1 -imidazoline receptor is a novel target for drug development for hypertension and insulin resistance, major disorders associated with type 2 diabetes. In the present study, we examined the effects of a novel imidazoline agonist S43126, on phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK1/2) in PC12 cells. We further examined the effects of S43126 on insulin stimulated PKB and ERK phosphorylation. PC12 cells were treated with varying doses of S43126 (10 -10 to 10 -6 M) or insulin (10 -10 to 10 -6 M) or combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) for 10 min. Western blot analysis of treated samples showed that S43126 increased both ERK1/2 and PKB phosphorylation by 5 fold. Combination treatment with insulin (10 -6 M) and varying doses of S43126 (10 -6 -10 -11 M) enhanced phosphorylation of PKB and ERK1/2 above the level of insulin alone, in a dose and time dependent manner. Treatment with siRNA against Nischarin (mouse homologue of I 1 -imidazoline receptor) reduced the phosphorylation of both ERK and PKB following combination treatments. These results indicate that S43126 has the potential to augment insulin action and should be further studied as a possible candidate drug for the treatment of insulin resistance states.

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“…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].…”

Section: Pharmacological Treatments For Hypertension In Obesitymentioning

confidence: 96%

Pharmacological Treatments for Obesity-Related Hypertension

Masuo¹

2010

CHYR

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Obesity, hypertension and obesity-related hypertension are growing health problems. Hypertension is an important risk factor for cardiovascular disease (CVD), particularly in patients with obesity, diabetes, and metabolic disease. Obese subjects are frequently associated with hypertension, diabetes mellitus, metabolic disease, and end-organ damage (i.e. end-stage renal damage). An integrated cardiovascular risk management approach is being adopted: aggressive blood pressure (BP) control is important in patients with high CVD risk, and well-tolerated antihypertensive agents with protective benefits beyond BP lowering are advantageous. The identification and management of these CVD risk factors is an important part of the overall management of hypertensive patients. Because patients in these special populations such as subjects with obesity or metabolic syndrome are more predisposed to target organ damage, stringent targets for blood pressure control have been set in clinical guidelines, however clinical trial and real-life evidence suggest that these targets are difficult to achieve.The first line of treatment of obesity and metabolic syndrome associated with obesity are weight loss with a lifestyle modification such as low caloric diet and exercise (see the previous chapter) or gastric band/gastric bypass surgery or bariatric surgery. Recently, anti-obesity drugs (Orlistat, Sibutramine) have been developed, but the precise effects on blood pressure and neurohormonal parameters have not been fully clarified. In addition, leptin administration (pegylated recombinant leptin; PEG-OB) as theoretical treatment for obesity has been examined in overweight or obese human and in animal models. Central leptin gene therapy was also examined in animal models. However, the anti-obesity effects of leptin administration were controversial.Recently, many clinical and epidemiological studies have shown that angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) are highly efficacious, persistent, well-tolerated antihypertensive agents, with additional benefits in obesity-related hypertension, cardiovascular pathogenesis, end-organ damage, and in metabolic syndrome. For example, the Irbesartan/HCTZ combination therapy Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial has shown comparable antihypertensive efficacy and tolerability regardless of BMI or diabetes status. Another observation is emerging that Telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)-gamma, a well-known target for treatment of the metabolic syndrome and diabetes. This clinical evidence perhaps argues against this, with the The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showing no benefit for Telmisartan compared with Ramipril, in prevention of new diabetes development.Another antihypertensive drug class with favourable properties are the centrally acting Imidazolin, M...

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

Cited by 11 publications

References 25 publications

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

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

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

Pharmacological Treatments for Obesity-Related Hypertension

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