Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

Abstract

Vine DF, Proctor SD. Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 299: G507-G516, 2010. First published May 27, 2010 doi:10.1152/ajpgi.00173.2010 is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro-and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg·kg Ϫ1 ·day Ϫ1 , 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction. metabolic syndrome; chylomicron overproduction; inflammation; microalbuminuria; glomerular sclerosis; plasminogen activator inhibitor-1; apolipoprotein B48 EXCESSIVE WEIGHT GAIN, PARTICULARLY in the form of abdominal (visceral) adipose tissue, is a major public health problem in prosperous societies worldwide (16,65). The resultant abdominal obesity has driven a developing epidemic of prediabetic insulin resistance and cluster of associated metabolic abnormalities that are termed the metabolic syndrome (9, 35). Insulin resistance leads to chronic hyperinsulinemia and has been implicated as a major determinant of early development of macro-and microvasculopathy, including atherosclerosis, ischemic cardiovascular disease (CVD), and renal damage, which are strongly associated with the metabolic syndrome (9, 26). The contribution of the metabolic syndrome to the development of cardiovascular and re...

Blockade of kinin B1 receptor reverses plasma fatty acids composition changes and body and tissue fat gain in a rat model of insulin resistance

“…One-week treatment with SSR240612 reduced by 15 g the gain in body weight when compared to vehicle in glucose-fed rats. A similar effect could be achieved only after 4-week treatment with the cannabinoid CB1 receptor antagonist rimonabant (10 mg/kg/day) in obese and insulino-resistant JCR:LA-cp rats [52]. The monoamine reuptake inhibitor sibutramine (10 mg/kg/day) reduced significantly body weight after 2 weeks in the model of monosodium glutamate-treated obese rats [53].…”

“…A similar effect could be achieved only after 4-week treatment with the cannabinoid CB1 receptor antagonist rimonabant (10 mg/kg/day) in obese and insulino-resistant JCR:LA-cp rats [52]. A similar effect could be achieved only after 4-week treatment with the cannabinoid CB1 receptor antagonist rimonabant (10 mg/kg/day) in obese and insulino-resistant JCR:LA-cp rats [52].…”

Role of the endocannabinoid system in diabetes and diabetic complications

“…The first evidence was provided in murine models of the metabolic syndrome. Treatment with rimonabant prevented proteinuria, ameliorated renal function and reduced the glomerular damage in obese ZDF rats and improved both albumin-creatinine ratio and glomerulosclerosis in JCR : LA-cp rats (a strain which is a close model of the human syndrome characterized by obesity, hyperlipidaemia, insulin resistance and a high risk for cardiovascular disease) (Janiak et al, 2007;Russell et al, 2010). More recently, a study performed in db/db mice, a model of T2DM, has shown that rimonabant markedly decreases urinary albumin excretion and mesangial expansion and suppresses synthesis of profibrotic and proinflammatory cytokines (Nam et al, 2012).…”

Chronic Treatment With the Cannabinoid 1 Antagonist Rimonabant Altered Vasoactive Cyclo-oxygenase-Derived Products on Arteries From Obese Zucker Rats

“…Recent studies have found that RM improved endothelial function of ApoE -/-mice 11 and vascular renal damage in JCR:LA-cp rats. 12 In Apo E -/-mice, the CB1 antagonist also improved insulin sensitivity and reduced vascular reactive oxygen species production. 11 That decrease of reactive oxygen species is also described in vascular smooth muscle cells 11 and endothelial cells.…”

“…11 In another animal model, the JCR:LA-cp rats, only microvascular function was protected after treatment with rimonabant. 12 We have recently reported that chronic treatment with RM of obese Zucker rats (OZR) partially prevents the systolic blood pressure increase associated with weight gain without affecting the endotheliumdependent vasodilatation 13 but altering the participation of cyclooxygenase (COX)-derived products on endothelial response. Thus, the first aim of this work is to clarify the nature and source of the COX products involved in such effects.…”