Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-δ

doi:10.1016/j.bbrc.2006.12.213

Biochemical and Biophysical Research Communications

Volume 354, Issue 2, 9 March 2007, Pages 427-433

https://doi.org/10.1016/j.bbrc.2006.12.213 Get rights and content

Abstract

Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-δ (PPAR-δ)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor.

Section snippets

Materials and methods

Animals and experimental procedures. All of the experimental procedures were performed in accordance with protocols approved by the Institutional Animal Care and Research Advisory Committee. Male Wistar rats obtained from an in-house breeding colony were randomized at 1 months of age into two groups; one group received standard laboratory chow ad libitum and the other a safflower oil-based high-fat diet ad libitum [12]. The high-fat diet supplied 59% of the calories as fat and 20% of the

Results

We used a rat model of metabolic syndrome. We first analyzed the biometrical and biochemical characteristics of rats on control diet and high-fat diet without and with exercise. Fig. 1 shows the biometric characteristics of the control rats, rats on high-fat diet, control rats plus exercise, and rats on high-fat diet plus exercise. At the age of 32 weeks, rats on high-fat diet had significantly higher body weight (557 ± 16 g; n = 12) compared to control rats (442 ± 8 g; n = 10) or rats on high-fat diet

Discussion

There are three major findings of the present study. First, rats on high-fat diet showed the typical characteristics of the metabolic syndrome, including obesity and hypertension. In addition, endurance exercise improved these signs of the metabolic syndrome. Second, rats on high-fat diet had increased adipocyte size in adipose tissue which was associated with increased CB1 expression. In addition, endurance exercise reduces adipocyte size and CB1 expression. Third, PPAR-δ directly regulates

Conflict of interests

There are no conflicts to disclose.

Acknowledgments

This study was supported by grants for Natural Science Foundation of China (No. 30470830) and 973 Program 2006CB503804 and 2006CB503905.

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Alterations in lipid metabolism play a significant role in the pathogenesis of obesity-associated disorders, and dysregulation of the lipidome across multiple diseases has prompted research to identify novel lipids indicative of disease progression. To address the significant gap in knowledge regarding the effect of age and diet on the blood lipidome, we used shotgun lipidomics with electrospray ionization-mass spectrometry (ESI-MS). We analyzed blood lipid profiles of female C57BL/6 mice following high-fat diet (HFD) and low-fat diet (LFD) consumption for short (6 weeks), long (22 weeks), and prolonged (36 weeks) periods. We examined endocannabinoid levels, plasma esterase activity, liver homeostasis, and indices of glucose tolerance and insulin sensitivity to compare lipid alterations with metabolic dysregulation. Multivariate analysis indicated differences in dietary blood lipid profiles with the most notable differences after 6 weeks along with robust alterations due to age. HFD altered phospholipids, fatty acyls, and glycerolipids. Endocannabinoid levels were affected in an age-dependent manner, while HFD increased plasma esterase activity at all time points, with the most pronounced effect at 6 weeks. HFD-consumption also altered liver mRNA levels of PPARα, PPARγ, and CD36. These findings indicate an interaction between dietary fat consumption and aging with widespread effects on the lipidome, which may provide a basis for identification of female-specific obesity- and age-related lipid biomarkers.
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Une session d’exercice aérobie modérée ou intense est capable d’augmenter les concentrations plasmatiques d’un des ligands du système endocannabinoïde, l’anandamide (AEA) alors que celles de sn-2-arachidonylglycérol (2-AG) ne varient pas. Quelques études in vitro suggèrent un effet bénéfique possible de l’AEA sur le métabolisme musculaire (e.g. sensibilité à l’insuline et biogenèse mitochondriale) via une action sur des récepteurs non cannabinoïdes – les récepteurs aux cannabinoïdes CB1 ayant au contraire des effets métaboliques délétères. Ces CB1 pourraient être hyperactivés dans certains tissus périphériques dans le cadre de l’obésité et l’exercice chronique pourrait alors en réduire l’expression (e.g. dans le tissu adipeux viscéral). Au niveau central, les études chez l’animal montrent que l’activation des CB1 en réponse à l’entraînement pourrait augmenter la prolifération cellulaire hippocampale et la mémoire spatiale. Enfin, l’activation des CB1 dans le striatum et le mésencéphale pourrait participer respectivement au phénomène d’addiction à l’exercice et à l’effet analgésique de ce dernier.
In humans, acute aerobic exercise, if intense enough, increases plasma concentrations of the endocannabinoid Anandamide (AEA) whereas sn-2-arachidonylglycerol (2-AG) remains stable. From several in vitro and animal studies, it could be postulated that high AEA levels would rather elicit beneficial metabolic effects in skeletal muscle (e.g. insulin sensitivity, mitochondrial biogenesis) through their action on non-cannabinoid receptors, contrary to the effects of cannabinoid receptors CB1 activation. In case of obesity and hyperglycemia, peripheral CB1 receptors might be overactivated with subsequent metabolic dysfunctions, while exercise training seems to be a promising strategy to reduce CB1 over-expression (e.g. in visceral adipose tissue). At the central level, CB1 activation during exercise and training might have positive effects on neuronal plasticity in hippocampus, rewarding systems in striatum and analgesia in midbrain. Thus, modulating endocannabinoid system activity through exercise manipulations could represent promising strategies for prevention and care of metabolic and neurodegenerative diseases.
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This study aimed to determine whether Cannabinoid receptor 1 (CB1) is involved in mammalian target of rapamycin (mTOR) signaling and skeletal muscle protein synthesis.
This study used human vastus lateralis skeletal muscle biopsies obtained before and after a resistance exercise (RE) bout in young men (n = 18). The signaling mechanisms were studied in vitro in human myotubes. Protein expression was determined by Western blot and confocal microscopy, and gene expression by quantitative PCR. Protein synthesis was measured in vitro using puromycin-based SuNSET technique.
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¹: These authors contributed equally to this work.

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Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-δ

Abstract

Section snippets

Materials and methods

Results

Discussion

Conflict of interests

Acknowledgments

Cell

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Therapy insight: adipocytokines in metabolic syndrome and related cardiovascular disease

Nat. Clin. Pract. Cardiovasc. Med.

Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome

Endocr. Rev.

Endocannabinoid control of food intake and energy balance

Nat. Neurosci.

The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis

J. Clin. Invest.

The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance

FASEB J.

CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity

Int. J. Obes.

Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors

Endocrinology