Cannabinoid Receptor Stimulation Impairs Mitochondrial Biogenesis in Mouse White Adipose Tissue, Muscle, and Liver The Role of eNOS, p38 MAPK, and AMPK Pathways

Integrated Laboratories Network, Center for Study and Research on Obesity, and Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, University of Milan, Milan, Italy.
Diabetes (Impact Factor: 8.1). 11/2010; 59(11):2826-36. DOI: 10.2337/db09-1881
Source: PubMed


Cannabinoid type 1 (CB1) receptor is involved in whole-body and cellular energy metabolism. We asked whether CB1 receptor stimulation was able to decrease mitochondrial biogenesis in different metabolically active tissues of obese high-fat diet (HFD)-fed mice.
The effects of selective CB1 agonist arachidonyl-2-chloroethanolamide (ACEA) and endocannabinoids anandamide and 2-arachidonoylglycerol on endothelial nitric oxide synthase (eNOS) expression were examined, as were mitochondrial DNA amount and mitochondrial biogenesis parameters in cultured mouse and human white adipocytes. These parameters were also investigated in white adipose tissue (WAT), muscle, and liver of mice chronically treated with ACEA. Moreover, p38 mitogen-activated protein kinase (MAPK) phosphorylation was investigated in WAT and isolated mature adipocytes from eNOS(-/-) and wild-type mice. eNOS, p38 MAPK, adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial biogenesis were investigated in WAT, muscle, and liver of HFD mice chronically treated with ACEA.
ACEA decreased mitochondrial biogenesis and eNOS expression, activated p38 MAPK, and reduced AMPK phosphorylation in white adipocytes. The ACEA effects on mitochondria were antagonized by nitric oxide donors and by p38 MAPK silencing. White adipocytes from eNOS(-/-) mice displayed higher p38 MAPK phosphorylation than wild-type animals under basal conditions, and ACEA was ineffective in cells lacking eNOS. Moreover, mitochondrial biogenesis was downregulated, while p38 MAPK phosphorylation was increased and AMPK phosphorylation was decreased in WAT, muscle, and liver of ACEA-treated mice on a HFD.
CB1 receptor stimulation decreases mitochondrial biogenesis in white adipocytes, through eNOS downregulation and p38 MAPK activation, and impairs mitochondrial function in metabolically active tissues of dietary obese mice.

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    • "PEA and, particularly, OEA activation of PPARa, unlike CB1, may lead to food-intake inhibition, lipolysis in the liver and adipose tissue, and induction of satiety via small intestine-mediated mechanisms (Schwartz et al., 2008). Also, activation of TRPV1, a potential target for OEA, PEA, and AEA (Di Marzo and De Petrocellis, 2010), stimulates lipolysis and improves mitochondrial activity in the skeletal muscle (Luo et al., 2012), two effects that are again the opposite of those exerted by CB1 activation (Tedesco et al., 2010). On the other hand, MAGs such as 2-oleoyl-and 2-linoleoyl-glycerol activate GPR119 in the small intestine, with subsequent stimulation of GLP-1 release and inhibitory and stimulatory effects of food intake and insulin secretion, respectively (Lan et al., 2012; Hansen et al., 2012). "
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    ABSTRACT: Endocannabinoids and cannabinoid CB1 receptors are known to play a generalized role in energy homeostasis. However, clinical trials with the first generation of CB1 blockers, now discontinued due to psychiatric side effects, were originally designed to reduce food intake and body weight rather than the metabolic risk factors associated with obesity. In this review, we discuss how, in addition to promoting energy intake, endocannabinoids control lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in skeletal muscle and pancreas are also emerging. This knowledge may help in the design of future therapies for the metabolic syndrome.
    Cell metabolism 04/2013; 17(4):475-90. DOI:10.1016/j.cmet.2013.03.001 · 17.57 Impact Factor
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    • "This elevation of the PGC-1α expression level suggests a role for the eCB-system in regulating metabolism because PGC-1α is an established marker of mitochondria biogenesis as well as glucose and fatty acid metabolism [51]. It is noteworthy that the observed elevation of PGC-1α may not be explained based on other, previous studies [52], [53]. These discrepancies could be due to differences in the experimental procedures (chronic and persistent infusion versus chronic injections once or twice daily), but they also suggest that further investigations are required to analyse the effects of eCB on lipid metabolism. "
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    ABSTRACT: Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels) and altered endocannabinoid (eCB)-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. Mice were treated with either a cannabinoid (CB) receptor agonist (HU210) or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT) diet, one-half of each group of mice were challenged with a high fat (HF) diet for the following 3-week period. Under basal conditions (control diet), chronic CB receptor agonist treatment (i.e., 6 weeks) induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression) in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression) in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle's lipid content without affecting the body weight or the fat mass. Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.
    PLoS ONE 02/2013; 8(2):e55963. DOI:10.1371/journal.pone.0055963 · 3.23 Impact Factor
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    • "eNos has been linked to the induction of PGC-1α expression [38]–[39] and both PGC-1α [40] and Ucp2 [41] are involved in mitochondrial biogenesis, reduction of which may contribute to lowering ROS production. In contrast, the p38 MAPKα gene (Mapk 14) was up-regulated and mitochondrial biogenesis is reduced by p38 MAPK activation [42], a target of GIP signaling. The marked reduction in expression of genes coding for proinflammatory proteins and enzymes involved in mitochondrial biogenesis was unexpected, since previous studies showed that GIP stimulated adipocyte resistin release [16], an effect that has been interpreted as pro-inflammatory. "
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    ABSTRACT: Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert β-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced β-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.
    PLoS ONE 07/2012; 7(7):e40156. DOI:10.1371/journal.pone.0040156 · 3.23 Impact Factor
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