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

Aw, Herling; S, Kilp; Hp, Juretschke; Neumann-Haefelin, Claudia; Gerl, Martin; Kramer, Werner

doi:10.1038/ijo.2008.105

Cited by 25 publications

(19 citation statements)

References 39 publications

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“…Indeed, visceral adiposity represents a major fat-associated risk factor. The decrease of epididymal fat mass in our study is in accord with a recent study that showed a decrease of visceral fat mass with rimonabant treatment in a candy-diet rat model (18).…”

Section: Discussionsupporting

confidence: 81%

“…The same result was observed concerning relative epididymal fat mass, which was decreased more in rimonabant-treated rats than in pair-fed rats, but the P value from ANOVA just approached significance. The majority of studies using pair-fed groups in rimonabant treatment showed a food intake's independent effect of rimonabant treatment on body weight and fat mass (15,17,27), especially visceral fat mass (18). It should be pointed out that the use of pair-fed groups in the case of rimonabant treatment may present a bias regarding the fact that the pair-fed group more likely than not ate all of their food in a relatively short period of time.…”

Section: Discussionmentioning

confidence: 99%

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Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

Flamment

Guéguen

Wetterwald

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The aim of this study was to investigate the effect of rimonabant treatment on hepatic mitochondrial function in rats fed a high-fat diet. Sprague-Dawley rats fed a high-fat diet (35% lard) for 13 wk were treated with rimonabant (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) during the last 3 wk and matched with pair-fed controls. Oxygen consumption with various substrates, mitochondrial enzyme activities on isolated liver mitochondria, and mitochondrial DNA quantity were determined. Body weight and fat mass were decreased in rats treated with rimonabant compared with pair-fed controls. Moreover, the serum adiponectin level was increased with rimonabant. Hepatic triglyceride content was increased, while serum triglycerides were decreased. An increase of mitochondrial respiration was observed in rats treated with rimonabant. The increase of mitochondrial respiration with palmitoyl-CoA compared with respiration with palmitoyl-L-carnitine stating that the entry of fatty acids into mitochondria via carnitine palmitoyltransferase I was increased in rats treated with rimonabant. Moreover, rimonabant treatment led to a reduction in the enzymatic activity of ATP synthase, whereas the quantity of mitochondrial DNA and the activity of citrate synthase remained unchanged. To summarize, rimonabant treatment leads to an improvement of hepatic mitochondrial function by increasing substrate oxidation and fatty acid entry into mitochondria for the ␤-oxidation pathway and by increasing proton leak. However, this increase of mitochondrial oxidation is regulated by a decrease of ATP synthase activity in order to have only ATP required for the cell function. cannabinoid receptor; mitochondria; liver; oxidative phosphorylation THE ENDOCANNABINOID SYSTEM appears to be an essential regulator of energy homeostasis and endocrine function (35). This system comprises the cannabinoid receptor (CB1 and CB2), the endogenous ligands (endocannabinoids), and the machinery for their biosynthesis and metabolism (12,36). Rimonabant (SR-141716), the first selective CB1 antagonist, leads to a decrease of food intake and body weight in various rodent models (38,39,47,48), and recent clinical studies in obese patients have shown that rimonabant not only reduced body weight but also improved cardiometabolic risk factors such as waist circumference, high-density lipoprotein, triglyceride, and glycated hemoglobin (13,19,37,43,46). An important aspect of rimonabant action is that a large part of its metabolic effects is independent of body weight reduction (13,43,46). Moreover, the reduction of food intake induced by CB1 blockade (KO or pharmacologically) is earlier and only transient, whereas reduction of body weight is sustained and higher than that expected from the inhibitory effect on food intake (4, 10, 14, 38, 39), so pathways other than reduction of food intake are implied in the decrease of body weight. Indeed, CB1 expression was demonstrated in various peripheral tissues involved in the control of energy homeostasis, such as adipose tissue, liver, pancreas, and skel...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

Flamment

Guéguen

Wetterwald

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…Similarly, rats treated with rimonabant for 10 -14 days showed a decrease in total body fat (9) and subcutaneous, retroperitoneal, mesenteric, and epididymal fat (11). A recent report has demonstrated a significant reduction in visceral fat in mice treated with rimonabant for 6 wk concomitant with a candy diet (16). However, what constitutes true visceral fat in the mouse model remains to be clearly identified.…”

mentioning

confidence: 94%

Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs

Richey¹,

Woolcott²,

Stefanovski³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg.kg(-1).day(-1), orally; n = 11) or placebo (n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight (P = 0.029), whereas in placebo dogs body weight increased by 6.2% (P < 0.001). Rimonabant reduced food intake (P = 0.027), concomitant with a reduction of SAT by 19.5% (P < 0.001). In contrast with the VAT increase with placebo (P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate (r(2) = 0.24; P = 0.154) or food intake (r(2) = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue.

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“…Whole-body Cb1r (also known as Cnr1) knockout (Cb1r −/− ) mice are resistant to dietinduced obesity, while wild-type littermates on the same diet with identical energy intake become obese [16]. In addition, there is direct experimental evidence that CB1R antagonism increases energy expenditure in peripheral tissues [14,17,18].…”

Section: Introductionmentioning

confidence: 99%

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

et al. 2011

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Aims/hypothesis Modulation of central nervous system (CNS) and extra-CNS cannabinoid receptor type 1 (CB1R) affects metabolic conditions, independently of weight loss. Here we examined the relative contributions of acute CNS and extra-CNS CB1R modulation on insulin sensitivity using pharmacological gain-and loss-of-function of CB1R in mice. Methods We assessed the effects of acute modulation of CB1R on insulin sensitivity and tissue glucose uptake by administering a CB1R agonist (HU210) and antagonist (AM251) (vs vehicle) i.v. in wild-type mice. In addition, we administered a CB1R agonist (vs vehicle) systemically (i.v.) to Cb1r (also known as Cnr1) knockout (Cb1r −/− ) mice or intracerebroventricularly (i.c.v.) in wild-type mice to elucidate the peripheral vs CNS-mediated regulatory effect of CB1R on insulin sensitivity.Results HU210 induced significant insulin resistance in wild-type mice with a reduction of whole-body glucose disappearance rate and muscle Akt phosphorylation, as well as of glucose uptake by skeletal muscle, but not by adipose tissue, changes that were prevented by pretreatment with AM251. HU210 did not affect insulin sensitivity in Cb1r −/− mice, suggesting that the observed effects were mediated through CB1R. HU210 administered i.c.v. did not induce insulin resistance, suggesting that acute stimulation of CNS CB1R was not required for this effect. Conclusions/interpretation Skeletal muscle insulin sensitivity is affected by acute CB1R modulation. These changes are mediated by extra-CNS CB1R, probably by the receptors in skeletal muscle tissue.

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

Cited by 25 publications

References 39 publications

Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

Rimonabant prevents additional accumulation of visceral and subcutaneous fat during high-fat feeding in dogs

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

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