Endocannabinoids May Mediate the Ability of (n-3) Fatty Acids to Reduce Ectopic Fat and Inflammatory Mediators in Obese Zucker Rats

Batetta, Barbara; Griinari, Mikko; Carta, Gianfranca; Murru, Elisabetta; Ligresti, Alessia; Cordeddu, Lina; Giordano, Elena; Sanna, Francesca; Bisogno, Tiziana; Uda, Susumu; Collu, Maria; Bruheim, Inge; Marzo, Vincenzo Di; Banni, Sebastiano

doi:10.3945/jn.109.104844

Cited by 218 publications

(227 citation statements)

References 53 publications

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“…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. Finally, there is an in vitro study showing that n-3 PUFA can reduce the levels of both anandamide and 2-AG in differentiated mouse adipocytes, whereas n-6 PUFAs (that is, arachidonic acid) were found to increase endocannabinoid levels.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

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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“…Correspondingly, ω-3 PUFAenriched diet during pregnancy lowers 2-AG and AEA levels in the fetus (48). ω-3 PUFA intake is also beneficial for insulin secretion and sensitivity (49)(50)(51). Here, we hypothesized that lowering eCB levels during pregnancy and lactation might be reflected in a mixed cell-pancreatic phenotype and improved hormonal responses to glucose in the offspring.…”

Section: -Ag Signaling Modulates β Cell Survival In Pancreatic Pseudmentioning

confidence: 99%

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Malenczyk

Keimpema

Piscitelli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids are implicated in the control of glucose utilization and energy homeostasis by orchestrating pancreatic hormone release. Moreover, in some cell niches, endocannabinoids regulate cell proliferation, fate determination, and migration. Nevertheless, endocannabinoid contributions to the development of the endocrine pancreas remain unknown. Here, we show that α cells produce the endocannabinoid 2-arachidonoylglycerol (2-AG) in mouse fetuses and human pancreatic islets, which primes the recruitment of β cells by CB 1 cannabinoid receptor (CB 1 R) engagement. Using subtractive pharmacology, we extend these findings to anandamide, a promiscuous endocannabinoid/endovanilloid ligand, which impacts both the determination of islet size by cell proliferation and α/β cell sorting by differential activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) and CB 1 Rs. Accordingly, genetic disruption of TRPV1 channels increases islet size whereas CB 1 R knockout augments cellular heterogeneity and favors insulin over glucagon release. Dietary enrichment in ω-3 fatty acids during pregnancy and lactation in mice, which permanently reduces endocannabinoid levels in the offspring, phenocopies CB 1 R −/− islet microstructure and improves coordinated hormone secretion. Overall, our data mechanistically link endocannabinoids to cell proliferation and sorting during pancreatic islet formation, as well as to life-long programming of hormonal determinants of glucose homeostasis.A nandamide (AEA) and 2-arachydonoylglycerol (2-AG), major endocannabinoids (eCBs), are involved in the regulation of energy homeostasis through coordinated actions in peripheral organs (adipose tissue, liver, and pancreas) and brain (hypothalamus, ventral striatum) (1). eCB signals are particularly significant to coordinate the regulated release of insulin and glucagon from mature pancreatic islets (2-6). Genetic evidence from CB 1 cannabinoid receptor −/− (CB 1 R −/− ) mice supports these findings because CB 1 R −/− mice are lean, resistant to high fat diet-induced obesity and diabetes (4, 7-9). Whether eCBs impact the formation of the endocrine pancreas and predispose it to long-lasting changes in hormone release postnatally remains unknown.Because eCBs broadly affect cell proliferation, fate, motility, and differentiation (e.g., in sperm, hematopoietic and T cells, and neurons) (10-13), it is likely that they play a role in the cellular organization of developing pancreatic islets, possibly by affecting the spatial segregation of α and β cells. A contribution of eCBs to cell diversification and positioning in the developing pancreas is supported by the temporal control of their levels in fetal tissues (14) and circulation (15). Moreover, α and β cells in mature pancreatic islets express the molecular machinery for eCB metabolism together with CB 1 Rs and transient receptor potential cation channels, particularly subfamily V member 1 (TRPV1) (2,16,17). Understanding these developmental processes is also relevant to po...

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“…Supplemental -3 fatty acid intake (including DHA) can reduce cell and tissue levels of AA and AA-derived downstream metabolites, including AEA and/or AG potentially due to substrate competition among biosynthetic enzymes ( 12,16,23,24,32,46,47 ). Alternatively, diets low in -3 and rich in -6 fatty acids (including AA) have been shown to increase AA-derived AEA and AG in mouse and piglet brain ( 24,31 ).…”

Section: -3 -6 and -9 Metabolitesmentioning

confidence: 99%

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

Wood

Williams

Pandarinathan

et al. 2010

Journal of Lipid Research

123

110

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The endocannabinoid system includes two G-protein coupled cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids), and the enzymes and transporters that help regulate cannabinergic tone ( 1 ). Endocannabinoid signaling is ubiquitous in mammals, being particularly critical in brain , where it modulates neurotransmitter release and exhibits neuroprotective effects ( 2, 3 ). Although the fi rst two endocannabinoids identifi ed, N -arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (AG), have been extensively characterized, the (patho)physiological impact of endocannabinoid signaling has prompted the search for additional endocannabinoids and their related metabolites/ biosynthetic precursors, creating an evolving network of chemical species collectively termed the endocannabinoid metabolome, few of which have been functionally annotated ( 1,(3)(4)(5)(6)(7)(8)(9). Although the translational and diagnostic aspects of endocannabinoid signaling are well appreciated ( 10, 11 ), factors that infl uence and regulate the endocannabinoid metabolome profi le among various tissues and compartments remains incompletely described and understood ( 1, 10 ), as are the metabolome's relationship to lipid pathways outside of the endocannabinoid signaling system ( 3, 9 ). Abstract

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Endocannabinoids May Mediate the Ability of (n-3) Fatty Acids to Reduce Ectopic Fat and Inflammatory Mediators in Obese Zucker Rats

Cited by 218 publications

References 53 publications

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

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

Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture

Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma

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