AT1 receptor blockade attenuates insulin resistance and myocardial remodeling in rats with diet-induced obesity.
BACKGROUND
Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity.


METHODS
Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit β (βIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot.


RESULTS
Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group.


CONCLUSIONS
Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.
Botucatu Medical School, São Paulo State University, Botucatu, Brazil ; School of Physiotherapy, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
Silvio A
SA
Oliveira-Junior
Botucatu Medical School, São Paulo State University, Botucatu, Brazil ; School of Physiotherapy, Federal University of Mato Grosso do Sul, Campo Grande, Brazil.
Paula F
PF
Martinez
Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
Danielle M
DM
Guizoni
Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
Dijon H S
DH
Campos
School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
Tiago
T
Fernandes
School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
Edilamar M
EM
Oliveira
Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
Marina P
MP
Okoshi
Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
Katashi
K
Okoshi
Botucatu Biosciences Institute, São Paulo State University, Botucatu, Brazil.
Carlos R
CR
Padovani
Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
Antonio C
AC
Cicogna
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D002149:Energy Intake; D007333:Insulin Resistance; D019808:Losartan / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D020257:Ventricular Remodeling
D047228:Angiotensin II Type 1 Receptor Blockers; D000809:Angiotensins; D001786:Blood Glucose; D044140:Receptor, Angiotensin, Type 1; D058543:Class Ia Phosphatidylinositol 3-Kinase; D011972:Receptor, Insulin; D018995:Myosin Heavy Chains; D019808:Losartan