Nina L. Cluny

Gastric Bypass Increases Energy Expenditure in Rats

BACKGROUND & AIMSnMechanisms underlying weight loss maintenance after gastric bypass are poorly understood. Our aim was to examine the effects of gastric bypass on energy expenditure in rats.nnnMETHODSnThirty diet-induced obese male Wistar rats underwent either gastric bypass (n = 14), sham-operation ad libitum fed (n = 8), or sham-operation body weight-matched (n = 8). Energy expenditure was measured in an open circuit calorimetry system.nnnRESULTSnTwenty-four-hour energy expenditure was increased after gastric bypass (4.50 +/- 0.04 kcal/kg/h) compared with sham-operated, ad libitum fed (4.29 +/- 0.08 kcal/kg/h) and sham-operated, body weight-matched controls (3.98 +/- 0.10 kcal/kg/h, P < .001). Gastric bypass rats showed higher energy expenditure during the light phase than sham-operated control groups (sham-operated, ad libitum fed: 3.63 +/- 0.04 kcal/kg/h vs sham-operated, body weight-matched: 3.42 +/- 0.05 kcal/kg/h vs bypass: 4.12 +/- 0.03 kcal/kg/h, P < .001). Diet-induced thermogenesis was elevated after gastric bypass compared with sham-operated, body weight-matched controls 3 hours after a test meal (0.41% +/- 1.9% vs 10.5% +/- 2.0%, respectively, P < .05). The small bowel of gastric bypass rats was 72.1% heavier because of hypertrophy compared with sham-operated, ad libitum fed rats (P < .0001).nnnCONCLUSIONSnGastric bypass in rats prevented the decrease in energy expenditure after weight loss. Diet-induced thermogenesis was higher after gastric bypass compared with body weight-matched controls. Raised energy expenditure may be a mechanism explaining the physiologic basis of weight loss after gastric bypass.

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.

Cannabidiolic acid prevents vomiting in Suncus murinus and nausea‐induced behaviour in rats by enhancing 5‐HT1A receptor activation

To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5‐HT1A receptor activation in animal models.

The identification of peroxisome proliferator-activated receptor alpha-independent effects of oleoylethanolamide on intestinal transit in mice

Abstractu2002 Oleoylethanolamide (OEA) is an endogenous lipid produced in the intestine that mediates satiety by activation of peroxisome proliferator‐activated receptor alpha (PPARα). OEA inhibits gastric emptying and intestinal motility, but the mechanism of action remains to be determined. We investigated whether OEA inhibits intestinal motility by activation of PPARα. PPARα immunoreactivity was examined in whole mount preparations of mouse gastrointestinal (GI) tract. The effect of OEA on motility was assessed in wildtype, PPARα, cannabinoid CB1 receptor and CB2 receptor gene‐deficient mice and in a model of accelerated GI transit. In addition, the effect of OEA on motility was assessed in mice injected with the PPARα antagonist GW6471, transient receptor potential vanilloid 1 antagonist SB366791 or the glucagon‐like peptide 1 antagonist exendin‐3(9‐39) amide. PPARα immunoreactivity was present in neurons in the myenteric and submucosal plexuses throughout the GI tract. OEA inhibited upper GI transit in a dose‐dependent manner, but was devoid of an effect on whole gut transit or colonic propulsion. OEA‐induced inhibition of motility was still present in PPARα, CB1 and CB2 receptor gene‐deficient mice and in the presence of GW6471, SB366791 and exendin‐3(9‐39) amide, suggesting neither PPARα nor the cannabinoids and other likely receptors are involved in mediating the effects of OEA. OEA blocked stress‐induced accelerated upper GI transit at a dose that had no effect on physiological transit. We show that PPARα is found in the enteric nervous system, but our results suggest that PPARα is not involved in the suppression of motility by OEA.

Distribution and function of monoacylglycerol lipase in the gastrointestinal tract.

The endogenous cannabinoid system plays an important role in the regulation of gastrointestinal function in health and disease. Endocannabinoid levels are regulated by catabolic enzymes. Here, we describe the presence and localization of monoacylglycerol lipase (MGL), the major enzyme responsible for the degradation of 2-arachidonoylglycerol. We used molecular, biochemical, immunohistochemical, and functional assays to characterize the distribution and activity of MGL. MGL mRNA was present in rat ileum throughout the wall of the gut. MGL protein was distributed in the muscle and mucosal layers of the ileum and in the duodenum, proximal colon, and distal colon. We observed MGL expression in nerve cell bodies and nerve fibers of the enteric nervous system. There was extensive colocalization of MGL with PGP 9.5 and calretinin-immunoreactive neurons, but not with nitric oxide synthase. MGL was also present in the epithelium and was highly expressed in the small intestine. Enzyme activity levels were highest in the duodenum and decreased along the gut with lowest levels in the distal colon. We observed both soluble and membrane-associated enzyme activities. The MGL inhibitor URB602 significantly inhibited whole gut transit in mice, an action that was abolished in cannabinoid 1 receptor-deficient mice. In conclusion, MGL is localized in the enteric nervous system where endocannabinoids regulate intestinal motility. MGL is highly expressed in the epithelium, where this enzyme may have digestive or other functions yet to be determined.

Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Peripherally Restricted Cannabinoid CB1/CB2 Receptor Agonist, Inhibits Gastrointestinal Motility but Has No Effect on Experimental Colitis in Mice

The endocannabinoid system is involved in the regulation of gastrointestinal (GI) motility and inflammation. Using the peripherally restricted cannabinoid (CB)1/CB2 receptor agonist naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), we investigated the role of peripheral cannabinoid receptors in the regulation of GI motility and the development of colitis in mice. The actions of SAB378 on whole gut transit, upper GI transit, colonic propulsion, and locomotor activity were investigated in C57BL/6N, CB1 receptor knockout, and CB2 receptor knockout mice. The potential for SAB378 to modify inflammation was studied by using dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) models of experimental colitis. SAB378 did not modify locomotor activity. SAB378 slowed all parameters of GI motility, and these effects were significantly reduced by the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 carboxamide (AM251), but not by the CB2 receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H- indol-3-yl](4-methoxyphenyl)methanone (AM630). SAB378 did not inhibit GI transit or colonic propulsion in CB1 receptor knockout mice, whereas its effects were observed in CB2 receptor knockout mice. SAB378 did not reduce the degree of colitis induced by DSS or TNBS. The actions of SAB378 on GI motility are mediated by peripherally located CB1 receptors. SAB378 was not effective against two models of experimental colitis, which may indicate that peripheral cannabinoid receptor stimulation alone may not be sufficient to mediate the anti-inflammatory effects of cannabinoids.

Cannabinoid signalling regulates inflammation and energy balance: The importance of the brain–gut axis

Energy balance is controlled by centres of the brain which receive important inputs from the gastrointestinal tract, liver, pancreas, adipose tissue and skeletal muscle, mediated by many different signalling molecules. Obesity occurs when control of energy intake is not matched by the degree of energy expenditure. Obesity is not only a state of disordered energy balance it is also characterized by systemic inflammation. Systemic inflammation is triggered by the leakage of bacterial lipopolysaccharide through changes in intestinal permeability. The endocannabinoid system, consisting of the cannabinoid receptors, endogenous cannabinoid ligands and their biosynthetic and degradative enzymes, plays vital roles in the control of energy balance, the control of intestinal permeability and immunity. In this review we will discuss how the endocannabinoid system, intestinal microbiota and the brain-gut axis are involved in the regulation of energy balance and the development of obesity-associated systemic inflammation. Through direct and indirect actions throughout the body, the endocannabinoid system controls the development of obesity and its inflammatory complications.

The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat

The aim of this study was to determine if the neutral cannabinoid CB₁ receptor antagonist, AM4113, regulates body weight in the rat via changes in food intake. We confirmed that the AM4113-induced reduction in food intake is mediated by CB₁ receptors using CB₁ receptor knockout mice. In rats, intraperitoneally administered AM4113 (2, 10 mg kg⁻¹) had a transient inhibitory effect on food intake, while body weight gain was suppressed for the duration of the study. AM4113-induced hypophagia was no longer observed once the inhibitory effect of AM4113 on body weight stabilized, at which time rats gained weight at a similar rate to vehicle-treated animals, yet at a lower magnitude. Pair-feeding produced similar effects to treatment with AM4113. Food intake and body weight gain were also inhibited in rats by oral administration of AM4113 (50 mg kg⁻¹). Dual energy x-ray absorptiometry (DEXA) was used to measure lean and fat mass. The AM4113 treated group had 29.3±11.4% lower fat mass than vehicle-treated rats; this trend did not reach statistical significance. There were no differences in circulating levels of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG), glucose, triglycerides, or cholesterol observed between treatment groups. Similarly, 2-AG hypothalamic levels were not modified by AM4113 treatment. These data suggest that blockade of an endocannabinoid tone acting at CB₁ receptors induces an initial, transient reduction in food intake which results in long-term reduction of body weight gain.

The Effects of Cannabidiol and Tetrahydrocannabinol on Motion-Induced Emesis in Suncus murinus

The effect of cannabinoids on motion-induced emesis is unknown. The present study investigated the action of phytocannabinoids against motion-induced emesis in Suncus murinus. Suncus murinus were injected intraperitoneally with either cannabidiol (CBD) (0.5, 1, 2, 5, 10, 20 and 40 mg/kg), Delta(9)-tetrahydrocannabinol (Delta(9)-THC; 0.5, 3, 5 and 10 mg/kg) or vehicle 45 min. before exposure to a 10-min. horizontal motion stimulus (amplitude 40 mm, frequency 1 Hz). In further investigations, the CB(1) receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251; 5 mg/kg), was injected 15 min. prior to an injection of Delta(9)-THC (3 mg/kg). The motion stimulus was applied 45 min. later. The number of emetic episodes and latency of onset to the first emetic episode were recorded. Pre-treatment with the above doses of CBD did not modify the emetic response to the motion stimulus as compared to the vehicle-treated controls. Application of the higher doses of Delta(9)-THC induced emesis in its own right, which was inhibited by AM 251. Furthermore, pre-treatment with Delta(9)-THC dose-dependently attenuated motion-induced emesis, an effect that was inhibited by AM 251. AM 251 neither induced an emetic response nor modified motion-induced emesis. The present study indicates that Delta(9)-THC, acting via the CB(1) receptors, is anti-emetic to motion, and that CBD has no effect on motion-induced emesis in Suncus murinus.

Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats

Oligofructose (OFS) is a prebiotic that reduces energy intake and fat mass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending on predisposition to obesity. The aim of this study was to examine the effect of OFS in diet‐induced obese (DIO) and diet‐resistant (DR) rats.