Long-term treatment with an angiotensin II receptor blocker decreases adipocyte size and improves insulin signaling in obese Zucker rats.
BACKGROUND
Angiotensin II (Ang II) has been shown to contribute to the pathogenesis of hypertension and insulin resistance. In addition, administration of selective Ang II type-1 receptor blockers has been shown to improve insulin sensitivity. However, only a few studies have addressed the molecular mechanisms involved in this association.


OBJECTIVE
The current study was undertaken to determine whether an Ang II receptor blocker (irbesartan) is effective in improving insulin resistance in adipose tissue from obese Zucker rats, a model of metabolic syndrome.


METHODS
Ten-week-old male obese Zucker rats (fa/fa) were treated daily with either vehicle or 50 mg/kg irbesartan for 6 months, and their age-matched lean (+/?) (lean Zucker rats) was used as a control. We determined systolic blood pressure (SBP), together with plasma levels of insulin, triglycerides, cholesterol and glucose. In addition, we evaluated insulin signaling through the insulin receptor/insulin receptor substrate-1/phosphatidylinositol 3 kinase/Akt/glucose transporter 4 pathway as well as the inflammatory status of adipose tissue.


RESULTS
Obese Zucker rats displayed hyperglycemia, hypertriglyceridemia, hyperinsulinemia and hypercholesterolemia and increased SBP together with decreased activation of insulin signaling through the insulin receptor/insulin receptor substrate-1/phosphatidylinositol 3 kinase/Akt pathway in adipose tissue as well as increased adipocytes size, macrophage infiltration and augmented levels of inflammatory mediators such tumor necrosis factor-alpha, monocyte chemoattractant protein-1 and Ang II. Chronic irbesartan treatment resulted in an improvement of all alterations.


CONCLUSIONS
The present study provides substantial information that demonstrates that long-term selective Ang II blockade ameliorates insulin resistance in adipose tissue from a model of metabolic syndrome via a mechanism that could involve the modulation of insulin signaling.
Muñoz
Marina C
MC
Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina. marinacmg@hotmail.com
Giani
Jorge F
JF
Dominici
Fernando P
FP
Turyn
Daniel
D
Toblli
Jorge E
JE
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000077405:Irbesartan; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D008055:Lipids; D013777:Tetrazoles; D019869:Phosphatidylinositol 3-Kinases; D000077405:Irbesartan