Addition of a low dose of rimonabant to orlistat therapy decreases weight gain and reduces adiposity in dietary obese rats Sawsan A Zaitone* and Soha Essawy † *Department of Pharmacology and Toxicology, Faculty of Pharmacy, and † Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt SUMMARY 1. The aim of the present study was to determine whether the addition of a subeffective dose of rimonabant (1 mg/kg) to orlistat would be beneficial in the treatment of diet-induced obesity in rats compared with orlistat monotherapy. 2. Male rats were divided into five groups: (i) rats fed a low-fat diet for 4 months; (ii) rats fed a high-fat diet (HFD) for 4 months and treated daily with vehicle (0.2% Tween-80 solution); (iii) orlistat (10 mg/kg per day)-treated HFD-fed rats; (iv) rimonabant (1 mg/kg per day)-treated HFD-fed rats; and (v) HFD-fed rats treated with a combination of orli- stat plus rimonabant. Fasting blood glucose, serum insulin, leptin and adiponectin levels were measured. Liver and adi- posity indices were calculated and liver and adipose tissues were processed for histological examination. 3. Over the 4 months of the study, vehicle-treated HFD-fed rats exhibited increased cumulative food intake, bodyweight and liver and adiposity indices. Moreover, vehicle-treated HFD-fed rats exhibited a deterioration in liver function and an abnormal lipid profile. Insulin resistance and serum leptin were increased in this group, whereas serum adiponectin levels were decreased. Orlistat monotherapy or combination therapy with orlistat plus rimonabant improved all these parameters. 4. The addition of the low subeffective dose of rimonabant to orlistat therapy ameliorated HFD-induced obesity to a much greater extent than orlistat monotherapy. This combination showed better weight control and metabolic profile compared with orlistat alone. Therefore, the results of the present study encourage reassessment of the use of a low dose of rimonabant to potentiate the effect of orlistat in the clinical management of obesity if proper clinical safety data are available. Key words: adipose tissue, high-fat diet, liver, obesity, orlistat, rimonabant. INTRODUCTION Obesity is a complex metabolic disorder resulting from an imbal- ance in energy intake and expenditure. This dysregulation may have either genetic and/or behavioural origins, depending on the type and quantity of food ingested, as well as lifestyle. Obesity is defined in terms of adiposity. 1,2 Obesity is often associated with dysregulation of tissue and plasma levels of pro- and anti-inflam- matory cytokines, such as tumour necrosis factor-a, and dysregu- lation of hormones such as adiponectin and insulin. 3 Obesity increases the disposition to diabetes and cardiovascular diseases; weight loss has been reported to ameliorate these conditions. 4 Reducing weight by caloric restriction generally fails because most obese patients regain their lost weight thereafter. 5 Very few drugs have been developed for the treatment of obesity and those that have been approved for use have limited success. Marked increases in the prevalence of obesity, in addition to the consequent health and economic burdens, heighten the need for new insights into the mechanisms of anti-obesity medi- cations. 6 Orlistat is a non-centrally acting anti-obesity drug that acts locally in the gastrointestinal tract by inhibiting intestinal lipase, an enzyme involved in the breakdown of dietary fat. 7 Animal studies have demonstrated the ability of orlistat to inhibit the absorption of fats and triglycerides. 8 Previous studies in mice suggest that orlistat treatment reduces interest in the consumption of dietary fat and decreases aortic atherosclerosis. 9,10 Moreover, orlistat treatment reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance, and decreases the required dose of antidiabetic drugs and improves the lipid profile in patients with type 2 diabetes. 11 The reported side-effects of orlistat include flatus and oily stool. Severe problems, such as faecal urgency, incontinence and abdominal pain, can also occur. 12 Conversely, the endocannabinoid system is reported to be involved in the central regulation of feeding. 13 Endocannabinoids, through CB 1 receptors, stimulate hypothalamic orexigenic neu- rons, enhance appetite and facilitate feeding behaviour. 14 There is compelling evidence that the beneficial metabolic effects of CB 1 receptor blockade may exceed the anorexigenic effect. 15,16 For example, rimonabant, an inverse agonist of CB 1 receptors, has been reported to decrease food-motivated behaviour in laboratory animals, 17 increase energy expenditure 18 and to reduce body- weight gain in Zucker rats 19 and diet-induced obesity (DIO) in mice. 20 These findings are further strengthened by the notion that Correspondence: Dr SA Zaitone, Department of Pharmacology and Toxicology, Suez Canal University, Ismailia 41522, Egypt. Email: Sawsan_zaytoon@pharm.suez.edu.eg Received 9 January 2012; revision 17 April 2012; accepted 19 April 2012. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd Clinical and Experimental Pharmacology and Physiology (2012) 39, 551–559 doi: 10.1111/j.1440-1681.2012.05717.x