Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice

Vujić, Nemanja; Schlager, Stefanie; Eichmann, Thomas O.; Madreiter‐Sokolowski, Corina T.; Goeritzer, Madeleine; Rainer, Silvia; Schauer, Silvia; Rosenberger, Angelika; Woelfler, Albert; Doddapattar, Prakash; Zimmermann, R.; Höefler, Gerald; Lass, Achim; Graier, Wolfgang F.; Radović, Branislav; Kratky, Dagmar

doi:10.1016/j.atherosclerosis.2015.10.109

Cited by 33 publications

(50 citation statements)

References 44 publications

(57 reference statements)

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“…Although Cnr1 was not overexpressed in our experiments, maybe as a consequence of a standard diet feeding, the increased endocannabinoid levels could reflect hyperactivation of CB1 receptors. On the other hand, the deficiency of Mgll has been linked to attenuation of diet-induced obesity and improvement of atherosclerosis via CB2 receptor activation [80,81]. Accordingly, we noticed that the liver of females from both perinatal groups displayed higher Cnr2 gene expression.…”

Section: Discussionmentioning

confidence: 86%

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

Ramírez-López¹,

Arco²,

Decara³

et al. 2016

PLoS ONE

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Recent studies have linked gestational exposure to highly caloric diets with a disrupted endogenous cannabinoid system (ECS). In the present study, we have extended these studies by analyzing the impact of the exposure to a palatable diet during gestation and lactation on a) the adult expression of endocannabinoid-related behaviors, b) the metabolic profile of adult offspring and c) the mRNA expression of the signaling machinery of the ECS in the hypothalamus, the liver and the adipose tissue of adult offspring of both sexes. Exposure to a palatable diet resulted in a) sex-dimorphic and perinatal diet specific feeding behaviors, including the differential response to the inhibitory effects of the cannabinoid receptor inverse agonist AM251, b) features of metabolic syndrome including increased adiposity, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia and c) tissue and sex-specific changes in the expression of both CB1 and CB2 receptors and in that of the endocannabinoid-degrading enzymes FAAH and MAGL, being the adipose tissue the most affected organ analyzed. Since the effects were observed in adult animals that were weaned while consuming a normal diet, the present results indicate that the ECS is one of the targets of maternal programming of the offspring energy expenditure. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include the ECS. The potential relevance of these alterations for the current obesity epidemic is discussed.

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Section: Discussionmentioning

confidence: 86%

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

Ramírez-López¹,

Arco²,

Decara³

et al. 2016

PLoS ONE

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“…These data suggest that inhibition of MAGL may limit the production of proinflammatory prostaglandins in the setting of inflammatory disorders 22 32. MAGL inhibitors reduce inflammation and colon alterations in a model of colitis,33 reduce macrophage content and improve atherosclerotic plaque alterations,34 attenuate neuroinflammation in astrocytes22 and display anti-inflammatory and protective effects during acute lung or muscle injury 35 36. Surprisingly, very little is known about the role of MAGL in the liver.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Habib

Chokr

Wan

et al. 2018

Gut

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ObjectiveSustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL -/- ), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL -/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

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“…Interestingly, the CB2 receptor activation was associated with anti-obesity effects (Verty et al, 2015) and a decreased risk for cardiovascular diseases. For instance, the gene deletion of the 2-AG-degrading enzyme Mgll has been linked to attenuation of diet-induced insulin resistance and improvement of atherosclerosis via CB2 activation (Taschler et al, 2011; Vujic et al, 2016). Taken in account the lower impact of the exposure to undernutrition observed in females in particular, and the lower risk of cardiovascular diseases described in females in general (Blenck et al, 2016), we can speculate that the CB2 receptor up-regulation may play a protective role in adverse metabolic conditions.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

Ramírez-López

Arco

Decara

et al. 2016

Front. Behav. Neurosci.

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Maternal malnutrition causes long-lasting alterations in feeding behavior and energy homeostasis in offspring. It is still unknown whether both, the endocannabinoid (eCB) machinery and the lipid metabolism are implicated in long-term adaptive responses to fetal reprogramming caused by maternal undernutrition. We investigated the long-term effects of maternal exposure to a 20% standard diet restriction during preconceptional and gestational periods on the metabolically-relevant tissues hypothalamus, liver, and perirenal fat (PAT) of male and female offspring at adulthood. The adult male offspring from calorie-restricted dams (RC males) exhibited a differential response to the CB1 antagonist AM251 in a chocolate preference test as well as increased body weight, perirenal adiposity, and plasma levels of triglycerides, LDL, VLDL, bilirubin, and leptin. The gene expression of the cannabinoid receptors Cnr1 and Cnr2 was increased in RC male hypothalamus, but a down-expression of most eCBs-metabolizing enzymes (Faah, Daglα, Daglβ, Mgll) and several key regulators of fatty-acid β-oxidation (Cpt1b, Acox1), mitochondrial respiration (Cox4i1), and lipid flux (Pparγ) was found in their PAT. The female offspring from calorie-restricted dams exhibited higher plasma levels of LDL and glucose as well as a reduction in chocolate and caloric intake at post-weaning periods in the feeding tests. Their liver showed a decreased gene expression of Cnr1, Pparα, Pparγ, the eCBs-degrading enzymes Faah and Mgll, the de novo lipogenic enzymes Acaca and Fasn, and the liver-specific cholesterol biosynthesis regulators Insig1 and Hmgcr. Our results suggest that the long-lasting adaptive responses to maternal caloric restriction affected cannabinoid-regulated mechanisms involved in feeding behavior, adipose β-oxidation, and hepatic lipid and cholesterol biosynthesis in a sex-dependent manner.

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Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice

Cited by 33 publications

References 44 publications

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

Exposure to a Highly Caloric Palatable Diet during the Perinatal Period Affects the Expression of the Endogenous Cannabinoid System in the Brain, Liver and Adipose Tissue of Adult Rat Offspring

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

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