Endocannabinoid Dysregulation in the Pancreas and Adipose Tissue of Mice Fed With a High‐fat Diet

Starowicz, Katarzyna; Cristino, Luigia; Matias, Isabel; Capasso, Raffaele; Racioppi, Alessandro; Izzo, Angelo A.; Marzo, Vincenzo Di

doi:10.1038/oby.2007.106

Cited by 181 publications

(194 citation statements)

References 62 publications

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“…This conclusion is built on our findings of lower levels of 2-AG in AT in the obese The endocannabinoid system in adipose tissue MF Bennetzen et al individuals, low levels that increase/normalise in association with weight loss, and low levels of CB1 expression in SAAT in the obese group, which also increases after weight loss. The finding of low levels of ECs in SAT from obese subjects is well in line with studies in obese rodents, 31,32 demonstrating a pronounced reduction in subcutaneous EC in obese rodents, whereas the change in ECs in VAT was more modest after diet-induced obesity. Animal studies do indicate hyperactivity of the ECS in obesity in the intra-abdominal (epididymal) AT depot.…”

Section: Discussionsupporting

confidence: 72%

Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss

et al. 2011

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Context: Endocannabinoids (ECs) have a role in obesity by affecting appetite and through peripheral effects. Obesity is associated with a dysregulation of the endocannabinoid system (ECS). Objective: We aimed to determine the ECS in subcutaneous adipose tissue (AT) in obese subject and investigate the influence of diet-induced weight loss on this system. Design: The obese study participants underwent a 12 weeks diet regimen resulting in 10-12% weight loss. All study participants underwent fasting blood samples and AT biopsies from abdomen and gluteal region, the obese subjects both before and after weight loss. Setting and participants: A total of 21 healthy obese individuals (10 men/11 women, age 39.5 ± 1.6 years, body mass index (BMI): 37.5±0.8 kg m À2 ) and 21 age-and gender-matched lean subjects (BMI: 23.8±0.4 kg m À2 ) were studied. Main outcome measures: The activity of ECS in AT was determined by measuring arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine/anandamide in AT by mass spectrometry and gene expressions of enzymes and receptors involved in the ECS. Results: The EC, 2-AG was reduced in obese individuals in the gluteal AT depot (Po0.01). Moreover, 2-AG increased in both depots in the obese subjects following weight loss (Po0.05). The gene expression of the CB1 was either not affected by the obese state (in the gluteal AT depot) or reduced (in the abdominal depot, Po0.05) and significantly affected by weight loss. The expression of the degrading enzymes FAAH, FAAH2, MGL and MGL2 was differently affected by obesity, AT depot and weight loss. Conclusion: We found reduced levels of 2-AG in subcutaneous AT in obesity, which increased after weight loss. In abdominal AT, the low CB1 expression was normalised after weight loss, whereas in gluteal AT the CB1 expression was reduced after weight loss. These findings support the concept of a dysregulated ECS in AT in association with obesity.

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Section: Discussionsupporting

confidence: 72%

Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss

et al. 2011

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“…36,37 A higher endocannabinoid tone is detected in the visceral fat relative to the subcutaneous fat in both human and mice. 10,12,13 Treatment of rimonabant exhibits a preferential loss of abdominal fat over subcutaneous fat, 38 which was also observed in the treatment with BPR697. In this regard, repeated stimulation of fatty acid oxidation in addition to inhibition of lipid accumulation decreased abdominal fat mass and hepatic lipids, as observed in other studies.…”

Section: Discussionmentioning

confidence: 89%

“…4--7 On the other hand, the CB1 receptor found in many peripheral tissues involved in metabolism, such as liver, adipose tissue, skeletal muscle, pancreas and the gastrointestinal tract, promotes anabolic pathways, such as de novo lipogenesis and glucose uptake, to regulate energy homeostasis. 5,8--11 The endocannabinoid system is dysregulated after chronic perturbation of energy balance, as can be seen in mice fed a high-fat diet, and in obese and diabetic patients, 10,12,13 thus contributing to the exacerbation of these disorders and the associated cardiometabolic indices.…”

Section: Introductionmentioning

confidence: 99%

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg À1 , BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg À1 resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors. Keywords: fatty acid oxidation; peripheral CB1 antagonist; food intake; body weight; cardiometabolic risk factors INTRODUCTION Energy homeostasis, the balance between energy intake and energy expenditure, is regulated by coordinated interaction between the central nervous system and peripheral tissues. Elucidation of the metabolic factors influencing energy balance, and lipid and glucose metabolism has been a major focus of research interest, and many studies of the underlying mechanisms have revealed the importance of communication between the central nervous system and the periphery. 1--3 Among various factors involved in energy balance, endocannabinoids (for example, anandamide and 2-arachidonoylglycerol) mediate a positive energy balance via activation of their receptor, cannabinoid receptor 1 (CB1). The brain CB1 receptor, a G proteincoupled receptor, is present at a high level in brain tissue, and enhances appetite a...

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“…[14][15][16]18,21 It is, however, rather surprising in light of the findings by others showing that HF diets given to mice cause dysregulation of the ECS, either via alterations in the expression of CB 1 receptors, via alterations in the levels of endogenous ligands, or both. 17,[40][41][42] Also the fatty acid composition of dietary fat may influence endocannabinoid action. 43 For example, the presence or absence of n-3 PUFAs in the diet affects endocannabinoid levels in the brain, as shown by Berger et al 44 and Watanabe et al 45 Batetta et al 46 recently found that dietary n-3 PUFAs can reduce inflammatory markers and liver triglyceride levels, and these effects were associated with lower levels of endocannabinoid ligands in peripheral organs.…”

Section: Discussionmentioning

confidence: 99%

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

et al. 2009

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Background and objectives:The antiobesity effects of suppressed endocannabinoid signaling may rely, at least in part, on changes in lipid fluxes. As fatty acids exert specific effects depending on their level of saturation, we hypothesized that the dietary fatty acid composition would influence the outcome of treatment with a CB 1 -receptor antagonist (rimonabant). Methods: Mice were treated with rimonabant (10 mg kg À1 body weight per day) or vehicle while equicalorically fed either a low-fat diet (LF), a high-fat (HF) diet or an HF diet in which 10% of the saturated fatty acids (SFAs) were replaced by polyunsaturated fatty acids (PUFA) from fish oil (FO). Food intake and body weight were registered daily. Indirect calorimetry was performed and feces were collected. After 3 weeks, mice were killed for blood and tissue collection. Results: Relative to the LF diet, the HF diet caused anticipated metabolic derangements, which were partly reversed by the HF/FO diet. The HF/FO diet, however, was most obesity-promoting despite inhibiting lipogenesis as indicated by low gene expression levels of lipogenic enzymes. On all three diets, rimonabant treatment improved metabolic derangements and led to significantly lower body weight gain than their respective controls. This latter effect appeared largest in the HF/FO group, but occurred without major changes in nutrient absorption and energy expenditure. Conclusion: The effects of chronic rimonabant treatment on body weight gain occurred irrespective of diet-induced changes in lipogenic activity, food intake and daily energy expenditure, and were, in fact, most pronounced in HF/FO mice. The effects of dietary PUFA replacement in an HF diet on expansion of adipose tissue might allow the favorable effects of dietary PUFA on dyslipidemia and hepatic steatosis. In light of other disadvantageous effects of weight gain, this might be a risky trade-off.

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Endocannabinoid Dysregulation in the Pancreas and Adipose Tissue of Mice Fed With a High‐fat Diet

Cited by 181 publications

References 62 publications

Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss

Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Metabolic responses to long-term pharmacological inhibition of CB1-receptor activity in mice in relation to dietary fat composition

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