Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR

LA-cp rat model of prediabetic metabolic syndrome

James C. Russell, Sandra E. Kelly, Abdoulaye Diane, Ye Wang, Rabban Mangat, Susan Novak, Donna F. Vine, Spencer D. Proctor

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Rimonabant (SR141716) 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-1·day -1, 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume299
Issue number2
DOIs
Publication statusPublished - 1 Aug 2010
Externally publishedYes

Fingerprint

rimonabant
Lipid Metabolism
Blood Vessels
Kidney
Haptoglobins
Apolipoprotein B-48
Body Weight
Triglycerides
Eating
Cannabinoid Receptor Antagonists
Insulin
Intestinal Secretions
Intestinal Diseases
Acute-Phase Proteins
Plasminogen Activator Inhibitor 1
Hyperinsulinism
Sclerosis
Cardiomyopathies
Vascular Diseases

Keywords

  • Apolipoprotein B48
  • Chylomicron overproduction
  • Glomerular sclerosis
  • Inflammation
  • Metabolic syndrome
  • Microalbuminuria
  • Plasminogen activator inhibitor-1

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR : LA-cp rat model of prediabetic metabolic syndrome. / Russell, James C.; Kelly, Sandra E.; Diane, Abdoulaye; Wang, Ye; Mangat, Rabban; Novak, Susan; Vine, Donna F.; Proctor, Spencer D.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 299, No. 2, 01.08.2010.

Research output: Contribution to journalArticle

Russell, James C. ; Kelly, Sandra E. ; Diane, Abdoulaye ; Wang, Ye ; Mangat, Rabban ; Novak, Susan ; Vine, Donna F. ; Proctor, Spencer D. / Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR : LA-cp rat model of prediabetic metabolic syndrome. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2010 ; Vol. 299, No. 2.
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