Increased Energy Expenditure Contributes More to the Body Weight-Reducing Effect of Rimonabant than Reduced Food Intake in Candy-Fed Wistar Rats

Abstract

The CB1 receptor antagonist, rimonabant, affects the endocannabinoid system and causes a sustained reduction in body weight (BW) despite the transient nature of the reduction in food intake. Therefore, in a multiple-dose study, female candy-fed Wistar rats were treated with rimonabant (10 mg/kg) and matched with pair-fed rats to distinguish between hypophagic action and hypothesized effects on energy expenditure. Within the first week of treatment, rimonabant reduced BW nearly to levels of standard rat chow-fed rats. Evaluation of energy balance (energy expenditure measured by indirect calorimetry in relation to metabolizable energy intake calculated by bomb calorimetry) revealed that increased energy expenditure based on increased fat oxidation contributed more to sustained BW reduction than reduced food intake. A mere food reduction through pair feeding did not result in comparable effects because animals reduced their energy expenditure to save energy stores. Because fat oxidation measured by indirect calorimetry increased immediately after dosing in the postprandial state, the acute effect of rimonabant on lipolysis was investigated in postprandial male rats. Rimonabant elevated free fatty acids postprandially, demonstrating an inherent pharmacological activity of rimonabant to induce lipolysis and not secondarily postabsorptively due to reduced food intake. We conclude that the weight-reducing effect of rimonabant was due to continuously elevated energy expenditure based on increased fat oxidation driven by lipolysis from fat tissue as long as fat stores were elevated. When the amount of endogenous fat stores declined, rimonabant-induced increased energy expenditure was maintained by a re-increase in food intake.

Reversal of visceral adiposity in candy-diet fed female Wistar rats by the CB1 receptor antagonist rimonabant

“…This speculation is supported by recently published data that energy expenditure based on whole body fat oxidation measured by indirect calorimetry was increased during treatment with rimonabant in this animal model. 26 The differences observed in the patterns of LCACoAs, grouped as SFA, MUFA and PUFA, reflected only in part the ingredients of fatty acid species of the different diets. SFA and MUFA were elevated, similarly to their content in the candy-diet.…”

“…It has recently been reported that increased energy expenditure based on increased fat oxidation contributed more to the sustained body weight reducing effect of rimonabant than reduced food intake. 26 The HepCL signal measured by MRS as about 9-10% of water signal corresponds to about 15 mg triglyceride per Visceral adiposity and rimonabant AW Herling et al gram of liver (1.5% liver fat) for the candy-diet control as well as for the rimonabant-treated group; this indicates that these values are far below a fatty liver (45% liver fat). In this study, no reduction of the HepCL (Figure 2c) was observed at the end of the study in the rimonabant candy-diet group.…”

“…This has already been postulated indirectly by gene expression studies in mice 36 as well as recently demonstrated by indirect calorimetric studies in rats. 26 As IMCL, a biomarker for muscle insulin resistance, was reduced, it seems likely that skeletal muscle represents the site of fatty acid oxidation. Malonyl-CoA represents the endogenous inhibitor of carnitin-palmitoyl-CoA transferase-1, the key enzyme of mitochondrial fatty acid oxidation.…”

“…[21][22][23][24][25] The transience of reduced food intake in the presence of persistent reduction of body weight caused by rimonabant in rodent models has recently been elucidated to be caused by increased energy expenditure based on increased fat oxidation measured by indirect calorimetry, which contributed more to the sustained body weight reducing effect of rimonabant than reduced food intake. 26 In the diet-induced obese mice rimonabant caused a reduction of total body weight, which predominantly was the result of reduced subcutaneous fat depots. In contrast in the genetically obese rat studies rimonabant caused more a reduced 'body weight development' compared with untreated control rats, than really an absolute decrease in body weight.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…increased energy expenditure) mechanisms (Cota et al ., 2003; Jbilo et al ., 2005; Herling et al ., 2008; Nogueiras et al ., 2008). Whilst this present study did not permit us to discriminate between these two different modes of action directly, our findings indicate that rimonabant is unlikely to convey its metabolic improvements in aged mice by increasing energy expenditure.…”