Effects of Inhibition of Angiotensin Converting Enzyme, Blocking Angiotensin Type 1 (AT1) Receptor, and Blocking Aldosterone Receptor on High Fat Fructose Diet Feeding Induced-Changes in Body Weight, Insulin Resistance, and Hepatic Steatosis
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- Category: Vol. 82, June 2014
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Effects of Inhibition of Angiotensin Converting Enzyme, Blocking Angiotensin Type 1 (AT1) Receptor, and Blocking Aldosterone Receptor on High Fat Fructose Diet Feeding Induced-Changes in Body Weight, Insulin Resistance, and Hepatic Steatosis, MOHAMMAD H.G.E. MOSTAFA, MOSHERA RATEB, MOHAMMAD E. SALEH and REHAM MOHAMMED
Abstract
Objective: The food industry has evolved, providing a supply of increasingly rich diet in terms of fatty acids and fructose. This shift is not without consequences on general health including increase risk of developing obesity, insulin resistance, hepatic steatosis and diabetes. Expression of all components of the renin-angiotensin-aldosterone-system has (RAAS) been shown in adipose tissue of human and rodent models. The present work aimed at studying the effects of inhibition of angiotensin converting enzyme, blocking angio-tensin II type 1 receptor, and blocking aldosterone receptor on high fat fructose diet (HFFD) feeding induced-changes in body weight, insulin resistance, and hepatic steatosis in male albino rats.
Material and Methods: 50 male albino rats with body weight 100-115gm were randomly divided into 5 groups. Each group contained 10 rats and with equal average body weights: Group I (control group) in which rats were fed standard rat chow for the entire study duration, Group II (HFFD) in which rats were fed HFFD for the entire study duration, Group III (HFFD+ACE inhibitor) in which rats were fed (HFFD) and treated orally with angiotensin converting enzyme inhibitor, captopril, at a dose of 40mg/kg/day, for the entire study duration, Group III (HFFD+AT1 blocker) in which rats were fed HFFD and treated orally with angiotensin II type 1 (AT 1) receptor blocker, losartan, at a dose of 10mg/kg/ day for the entire study duration, Group V (HFFD+Aldosterone receptor blocker) in which rats were fed HFFD and treated orally with Aldosterone receptor blocker, spironolactone, at a dose of 16mg/kg/day for the entire study duration. At the end of study period (10 weeks), rats were weighted then sacrificed. Serum was prepared for fasting glucose and insulin levels, insulin resistance was assessed using HOMA-IR, liver was removed, weighted, separated into 2 parts for real-time quantitative polymerase chain reaction for tumor necrosis alpha (TNF-a), Interleukin 6 (IL-6), Carbohydrate Response element binding protein (ChREBP), and Sterol response element binding protein-1c (SREBP) gene expression and for histopathological examination for non-alcoholic steatohepatitis called the NAFLD activity score (NAS) and fibrotic changes.
Results: Feeding rats with HFFD (group II) for 10 weeks produced significant increase in the mean values of body weight, fasting serum glucose and insulin levels. HOMA-IR, liver weight, % liver weight/body weight ratio, hepatic gene expression of TNF-a, (IL-6), and SREBP while hepatic gene expression of ChREBP significantly decreased. Moreover, NAS score and fibrotic changes significantly increased com-pared to group I.
Oral administration of angiotensin converting enzyme inhibitor (group III), angiotensin II type 1 receptor blocker (group IV), and aldosterone receptors blocker (group V) in rats fed HFFD can attenuate HFFD-induced changes as evident by significant decreases in mean values of body weight, fasting serum glucose and insulin levels, HOMA-IR, liver weight, hepatic gene expression of TNF-a, IL-6, SREBP, NAS score and fibrotic liver changes compared to group II. However, the mean values of % liver weight/body weight ratio signifi-cantly decreased in group III and IV but insignificantly changed in group V. Hepatic gene expression of ChREBP insignificantly changed in group III, IV, and V compared group II. The ability of interference with RAAS to modify HFFD-induced changes is partial as evident by significant increases in body weight, fasting serum glucose and insulin levels, HOMA-IR, liver weight, hepatic gene expression of TNF-a, IL-6, SREBP, and NAS score compared to control group. However % liver weight/body weight ratio insignificantly changed in group III and IV but significantly increased in group V compared to group I. Hepatic gene expression of ChREBP significantly decreased which is not related to interference with RAAS. Hepatic gene expression of ChREBP significantly decreased also in HFFD compared to control group and insignificantly changed with interference with RAAS.
Summary and Conclusion: High fat fructose diet partici-pates in the development of obesity, insulin resistance, hepatic steatosis, steatohepatitis, and even hepatic fibrosis. Interference with RAAS system by inhibiting angiotensin converting enzyme, blocking angiotensin II type 1 receptor, or blocking aldosterone receptor can partially improve HFFD induced changes. In conclusion, the established role of both circulating and local RAAS on the pathogenesis of obesity induced insulin resistance, NAFLD, and NASH created considerable interest on the effect of RAAS inhibitors since they are widely used, reasonably inexpensive, and with excellent safety profile.
Despite the encouraging evidence from animal studies, data from human studies are limited and contradictory and most data are from retrospective studies. Accordingly, more studies are needed to directly assess the effectiveness of ACE inhibitor, ARBs, and mineralocorticoid receptor blockers re in obese subjects.