Publications by authors named "Nicholas V DiPatrizio"

41 Publications

UPLC-MS/MS Method for Analysis of Endocannabinoid and Related Lipid Metabolism in Mouse Mucosal Tissue.

Front Physiol 2021 14;12:699712. Epub 2021 Jul 14.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States.

The endocannabinoid system is expressed in cells throughout the body and controls a variety of physiological and pathophysiological functions. We describe robust and reproducible UPLC-MS/MS-based methods for analyzing metabolism of the endocannabinoids, 2-arachidonoyl--glycerol and arachidonoyl ethanolamide, and related monoacylglycerols (MAGs) and fatty acid ethanolamides (FAEs), respectively, in mouse mucosal tissues (i.e., intestine and lung). These methods are optimized for analysis of activity of the MAG biosynthetic enzyme, diacylglycerol lipase (DGL), and MAG degradative enzymes, monoacylglycerol lipase (MGL) and alpha/beta hydrolase domain containing-6 (ABHD6). Moreover, we describe a novel UPLC-MS/MS-based method for analyzing activity of the FAE degradative enzyme, fatty acid amide hydrolase (FAAH), that does not require use of radioactive substrates. In addition, we describe pharmacological methods to inhibit MAG biosynthesis selectively in the mouse small-intestinal epithelium. These methods will be useful for profiling endocannabinoid metabolism in rodent mucosal tissues in health and disease.
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http://dx.doi.org/10.3389/fphys.2021.699712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317065PMC
July 2021

A high docosahexaenoic acid diet alters lung inflammation and recovery following repetitive exposure to aqueous organic dust extracts.

J Nutr Biochem 2021 Jun 12;97:108797. Epub 2021 Jun 12.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA; Pulmonary, Critical Care, Sleep and Allergy Division, University of Nebraska Medical Center, Omaha, Nebraska, USA. Electronic address:

Agricultural workers, especially those who work in swine confinement facilities, are at increased risk for developing pulmonary diseases including asthma, chronic obstructive pulmonary disease, and chronic bronchitis due to exposures to fumes, vapors, and organic dust. Repetitive exposure to agricultural dust leads to unresolved inflammation, a common underlying mechanism that worsens lung disease. Besides occupational exposure to dusts, diet also significantly contributes to inflammation and disease progression. Since DHA (docosahexaenoic acid), a polyunsaturated omega-3 fatty acid and its bioactive metabolites have key roles in inflammation resolution, we rationalized that individuals chronically exposed to organic dusts can benefit from dietary modifications. Here, we evaluated the role of DHA in modifying airway inflammation in a murine model of repetitive exposure to an aqueous extract of agricultural dust (three-week exposure to swine confinement dust extract, HDE) and after a one-week resolution/recovery period. We found that mice fed a high DHA diet had significantly increased bronchoalveolar lavage fluid (BALF) levels of DHA-derived resolvins and lower TNFα along with altered plasma levels of endocannabinoids and related lipid mediators. Following the one-week recovery we identified significantly reduced BALF cellularity and cytokine/chemokine release along with increased BALF amphiregulin and resolvins in DHA diet-fed versus control diet-fed mice challenged with HDE. We further report observations on the effects of repetitive HDE exposure on lung Ym1+ and Arg-1+ macrophages. Overall, our findings support a protective role for DHA and identify DHA-derived resolvins and endocannabinoids among the potential mediators of DHA in altering airway inflammation in chronic agricultural dust exposure.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108797DOI Listing
June 2021

Cannabinoid Receptor Subtype-1 Regulates Allergic Airway Eosinophilia During Lung Helminth Infection.

Cannabis Cannabinoid Res 2021 06 8;6(3):242-252. Epub 2021 Apr 8.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California, USA.

Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a T-helper type 2 (Th2) immune response in the host and can cause severe tissue damage and fibrosis if chronic. We recently reported that mice infected with the soil-transmitted helminth, , displayed elevated levels of endocannabinoids (eCBs) in the lung and intestine. eCBs are lipid-signaling molecules that control inflammation; however, their function in infection is not well defined. A combination of pharmacological approaches and genetic mouse models was used to investigate roles for the eCB system in inflammatory responses and lung injury in mice during parasitic infection with . Hemorrhaging of lung tissue in mice infected with was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CBRs) with the peripherally restricted CBR antagonist, AM6545. In addition, these mice exhibited an increase in nonfunctional alveolar space and prolonged airway eosinophilia compared to vehicle-treated infected mice. In contrast to mice treated with AM6545, infected cannabinoid receptor subtype-2-null mice (Cnr2) did not display any changes in these parameters compared to wild-type mice. Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CBRs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time.
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http://dx.doi.org/10.1089/can.2020.0167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217601PMC
June 2021

Endocannabinoids and the Gut-Brain Control of Food Intake and Obesity.

Nutrients 2021 Apr 7;13(4). Epub 2021 Apr 7.

Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA 92521, USA.

Gut-brain signaling controls food intake and energy homeostasis, and its activity is thought to be dysregulated in obesity. We will explore new studies that suggest the endocannabinoid (eCB) system in the upper gastrointestinal tract plays an important role in controlling gut-brain neurotransmission carried by the vagus nerve and the intake of palatable food and other reinforcers. A focus will be on studies that reveal both indirect and direct interactions between eCB signaling and vagal afferent neurons. These investigations identify () an indirect mechanism that controls nutrient-induced release of peptides from the gut epithelium that directly interact with corresponding receptors on vagal afferent neurons, and () a direct mechanism via interactions between eCBs and cannabinoid receptors expressed on vagal afferent neurons. Moreover, the impact of diet-induced obesity on these pathways will be considered.
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http://dx.doi.org/10.3390/nu13041214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067588PMC
April 2021

Impact of Circulating N-Acylethanolamine Levels with Clinical and Laboratory End Points in Hemodialysis Patients.

Am J Nephrol 2021 18;52(1):59-68. Epub 2021 Feb 18.

Division of Nephrology, Hypertension and Kidney Transplantation, University of California Irvine School of Medicine, Irvine, California, USA,

Background: Patients with ESRD on maintenance hemodialysis (MHD) are particularly susceptible to dysregulation of energy metabolism, which may manifest as protein energy wasting and cachexia. In recent years, the endocannabinoid system has been shown to play an important role in energy metabolism with potential relevance in ESRD. N-acylethanolamines are a class of fatty acid amides which include the major endocannabinoid ligand, anandamide, and the endogenous peroxisome proliferator-activated receptor-α agonists, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA).

Methods: Serum concentrations of OEA and PEA were measured in MHD patients and their correlations with various clinical/laboratory indices were examined. Secondarily, we evaluated the association of circulating PEA and OEA levels with 12-month all-cause mortality.

Results: Both serum OEA and PEA levels positively correlated with high-density lipoprotein-cholesterol levels and negatively correlated with body fat and body anthropometric measures. Serum OEA levels correlated positively with serum interleukin-6 (IL-6) (rho = 0.19; p = 0.004). Serum PEA and IL-6 showed a similar but nonsignificant trend (rho = 0.12; p = 0.07). Restricted cubic spline analyses showed that increasing serum OEA and PEA both trended toward higher mortality risk, and these associations were statistically significant for PEA (PEA ≥4.7 pmol/mL; reference: PEA <4.7 pmol/mL) after adjustments in a Cox model (hazard ratio 2.99; 95% confidence interval 1.04, 8.64).

Conclusions: In MHD patients, OEA and PEA are significantly correlated with variables related to lipid metabolism and body mass. Additionally, higher serum levels of PEA are associated with mortality risk. Future studies are needed to examine the potential mechanisms responsible for these findings and their clinical implications.
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http://dx.doi.org/10.1159/000513381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987690PMC
February 2021

Considerations for Cannabis Use to Treat Pain in Sickle Cell Disease.

J Clin Med 2020 Dec 1;9(12). Epub 2020 Dec 1.

Hematology/Oncology, Department of Medicine, University of California, Irvine, CA 92868, USA.

Pain in Sickle Cell Disease (SCD) is a major comorbidity and unique with acute pain due to recurrent and episodic vaso-occlusive crises as well as chronic pain, which can span an individual's entire life. Opioids are the mainstay treatment for pain in SCD. Due to recent health crises raised by adverse effects including deaths from opioid use, pain management in SCD is adversely affected. Cannabis and its products are most widely used for pain in multiple conditions and also by patients with SCD on their own. With the availability of "Medical Cannabis" and approval to use cannabis as medicine across majority of States in the United States as well as over-the-counter preparations, cannabis products are being used increasingly for SCD. The reliability of many of these products remains questionable, which poses a major health risk to the vulnerable individuals seeking pain relief. Therefore, this review provides up to date insights into available categories of cannabis-based treatment strategies, their mechanism of action and pre-clinical and clinical outcomes in SCD. It provides evidence for the benefits and risks of cannabis use in SCD and cautions about the unreliable and unvalidated products that may be adulterated with life-threatening non-cannabis compounds.
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http://dx.doi.org/10.3390/jcm9123902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761429PMC
December 2020

Maternal transfer of environmentally relevant polybrominated diphenyl ethers (PBDEs) produces a diabetic phenotype and disrupts glucoregulatory hormones and hepatic endocannabinoids in adult mouse female offspring.

Sci Rep 2020 10 22;10(1):18102. Epub 2020 Oct 22.

Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA.

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardant chemicals and environmental contaminants with endocrine-disrupting properties that are associated with diabetes and metabolic syndrome in humans. However, their diabetogenic actions are not completely characterized or understood. In this study, we investigated the effects of DE-71, a commercial penta-mixture of PBDEs, on glucoregulatory parameters in a perinatal exposure model using female C57Bl/6 mice. Results from in vivo glucose and insulin tolerance tests and ex vivo analyses revealed fasting hyperglycemia, glucose intolerance, reduced sensitivity and delayed glucose clearance after insulin challenge, decreased thermogenic brown adipose tissue mass, and exaggerated hepatic endocannabinoid tone in F1 offspring exposed to 0.1 mg/kg DE-71 relative to control. DE-71 effects on F0 dams were more limited indicating that indirect exposure to developing offspring is more detrimental. Other ex vivo glycemic correlates occurred more generally in exposed F0 and F1, i.e., reduced plasma insulin and altered glucoregulatory endocrines, exaggerated sympathoadrenal activity and reduced hepatic glutamate dehydrogenase enzymatic activity. Hepatic PBDE congener analysis indicated maternal transfer of BDE-28 and -153 to F1 at a collective level of 200 ng/g lipid, in range with maximum values detected in serum of human females. Given the persistent diabetogenic phenotype, especially pronounced in female offspring after developmental exposure to environmentally relevant levels of DE-71, additional animal studies should be conducted that further characterize PBDE-induced diabetic pathophysiology and identify critical developmental time windows of susceptibility. Longitudinal human studies should also be conducted to determine the risk of long-lasting metabolic consequences after maternal transfer of PBDEs during early-life development.
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http://dx.doi.org/10.1038/s41598-020-74853-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582149PMC
October 2020

Cannabinoid CB Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice.

Nutrients 2020 Sep 20;12(9). Epub 2020 Sep 20.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521, USA.

The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut-brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CBRs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CBR antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CBR-deficient mice (IntCB-/-) to investigate if intestinal CBRs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB-/- mice when compared to control mice for up to 6 h. Together, these data suggest that CBRs in the murine intestinal epithelium are required for acute WD preferences.
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http://dx.doi.org/10.3390/nu12092874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551422PMC
September 2020

Bile acid composition regulates GPR119-dependent intestinal lipid sensing and food intake regulation in mice.

Gut 2020 09 28;69(9):1620-1628. Epub 2020 Feb 28.

Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA

Objectives: Lipid mediators in the GI tract regulate satiation and satiety. Bile acids (BAs) regulate the absorption and metabolism of dietary lipid in the intestine, but their effects on lipid-regulated satiation and satiety are completely unknown. Investigating this is challenging because introducing excessive BAs or eliminating BAs strongly impacts GI functions. We used a mouse model (Cyp8b1 mice) with normal total BA levels, but alterations in the composition of the BA pool that impact multiple aspects of intestinal lipid metabolism. We tested two hypotheses: BAs affect food intake by (1) regulating production of the bioactive lipid oleoylethanolamide (OEA), which enhances satiety; or (2) regulating the quantity and localisation of hydrolysed fat in small intestine, which controls gastric emptying and satiation.

Design: We evaluated OEA levels, gastric emptying and food intake in wild-type and Cyp8b1 mice. We assessed the role of the fat receptor GPR119 in these effects using Gpr119 mice.

Results: Cyp8b1 mice on a chow diet showed mild hypophagia. Jejunal OEA production was blunted in Cyp8b1 mice, thus these data do not support a role for this pathway in the hypophagia of Cyp8b1 mice. On the other hand, Cyp8b1 deficiency decreased gastric emptying, and this was dependent on dietary fat. GPR119 deficiency normalised the gastric emptying, gut hormone levels, food intake and body weight of Cyp8b1 mice.

Conclusion: BAs regulate gastric emptying and satiation by determining fat-dependent GPR119 activity in distal intestine.
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http://dx.doi.org/10.1136/gutjnl-2019-319693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423635PMC
September 2020

Circulating Endocannabinoids and Mortality in Hemodialysis Patients.

Am J Nephrol 2020 14;51(2):86-95. Epub 2020 Jan 14.

Anatomy and Neurobiology, University of California Irvine School of Medicine, Irvine, California, USA.

Background: Mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) remains exceptionally high. While traditional risk factors such as obesity are paradoxically associated with better survival, nontraditional risk factors including cachexia increase the likelihood of poor outcomes. There is accumulating evidence that the endocannabinoid (ECB) system plays a major role in energy preservation and storage, factors which can prevent the deleterious effects of cachexia. Hence, in this study, we evaluated the association of circulating ECB levels with mortality in MHD patients.

Methods: Serum concentrations of anandamide (AEA) and 2-arachidonoyl-sn-glycerol (2-AG), major ECB ligands, were measured in MHD patients. Their correlation with various clinical/laboratory indices and association with 12-month all-cause mortality were examined.

Results: Serum 2-AG levels positively correlated with body mass index, serum triglycerides and body anthropometric measures. Meanwhile, serum AEA levels correlated positively with serum interleukin-6, and negatively with serum very low-density lipoprotein levels. While increased serum 2-AG levels were associated with reduced risk of all-cause mortality (hazard ratio [HR] 0.52, 95% CI 0.28-0.98), there was no clear association between serum AEA levels and mortality (HR 0.91, 95% CI 0.48-1.72).

Conclusions: In MHD patients, the circulating levels of ECB ligand, 2-AG, may play an important role in determining body mass and risk of mortality. These observations were unique to 2-AG as similar findings were not obtained with serum AEA. Future studies need to investigate the mechanisms responsible for these associations and examine the modulation of the ECB system as a potential target for therapy in ESRD.
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http://dx.doi.org/10.1159/000505444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158229PMC
February 2021

Serum Endocannabinoid Levels in Patients With End-Stage Renal Disease.

J Endocr Soc 2019 Oct 5;3(10):1869-1880. Epub 2019 Aug 5.

Tibor Rubin Veterans Affairs Medical Center, Long Beach, California.

Context: Previous studies have shown that the endocannabinoid system plays a major role in energy metabolism through the actions of its main mediators, 2-arachidonoyl--glycerol (2-AG) and anandamide (AEA).

Objective: We examined serum levels of major endocannabinoid mediators and their association with clinical parameters in patients with end-stage renal disease (ESRD).

Design And Setting: Serum concentrations of 2-AG and AEA were measured in patients on maintenance hemodialysis (MHD) and controls, and correlations with various clinical and laboratory indices were examined. 2-AG was also measured in age and sex-matched healthy subjects for comparison of levels in patients undergoing MHD.

Main Outcome Measure: Serum 2-AG.

Results: Serum 2-AG levels were significantly elevated in patients with ESRD compared with healthy controls. Higher levels of 2-AG were found in patients on MHD compared to healthy subjects, and similar findings were seen in a second set of subjects in independent analyses. Among 96 patients on MHD, 2-AG levels correlated significantly and positively with serum triglycerides ( = 0.43; < 0.0001), body mass index ( = 0.40; < 0.0001), and body anthropometric measures and negatively with serum high-density lipoprotein cholesterol ( = -0.33; = 0.001) following adjustment for demographic and clinical variables.

Conclusions: In patients on MHD, levels of serum 2-AG, a major endocannabinoid mediator, were increased. In addition, increasing serum 2-AG levels correlated with increased serum triglycerides and markers of body mass. Future studies will need to evaluate the potential mechanisms responsible for these findings.
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http://dx.doi.org/10.1210/js.2019-00242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767629PMC
October 2019

Endocannabinoid System and the Kidneys: From Renal Physiology to Injury and Disease.

Cannabis Cannabinoid Res 2019 13;4(1):10-20. Epub 2019 Mar 13.

University of California-Irvine, School of Medicine, Orange, California.

As the prevalence of kidney disease continues to rise worldwide, there is accumulating evidence that kidney injury and dysfunction, whether acute or chronic, is associated with major adverse outcomes, including mortality. Meanwhile, effective therapeutic options in the treatment of acute kidney injury (AKI) and chronic kidney disease (CKD) have been sparse. Many of the effective treatments that are routinely utilized for different pathologies in patients without kidney disease have failed to demonstrate efficacy in those with renal dysfunction. Hence, there is an urgent need for discovery of novel pathways that can be targeted for innovative and effective clinical therapies in renal disease states. There is now accumulating evidence that the endocannabinoid (EC) system plays a prominent role in normal renal homeostasis and function. In addition, numerous recent studies have described mechanisms through which alteration in the EC system can contribute to kidney damage and disease. These include a potential role for cannabinoid receptors in tubulo-glomerular damage and fibrosis, which are common features of AKI, interstitial nephritis, glomerulopathy, and other conditions leading to AKI and CKD. These findings suggest that manipulating the EC system may be an effective therapeutic strategy for the treatment of kidney disease and injury. However, further mechanistic studies are needed to fully delineate the role of this system in various conditions affecting the kidneys. Furthermore, while most of the current literature is focused on the role of the EC system as a whole in renal pathophysiology, future studies will also need to clarify the contribution of each component of this system, including the EC mediators, in the pathogenesis of kidney disease and their potential role as part of a therapeutic strategy.
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http://dx.doi.org/10.1089/can.2018.0060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653784PMC
March 2019

Cannabinoid CB Receptors Inhibit Gut-Brain Satiation Signaling in Diet-Induced Obesity.

Front Physiol 2019 11;10:704. Epub 2019 Jun 11.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States.

Gut-brain signaling controls feeding behavior and energy homeostasis; however, the underlying molecular mechanisms and impact of diet-induced obesity (DIO) on these pathways are poorly defined. We tested the hypothesis that elevated endocannabinoid activity at cannabinoid CB receptor (CBRs) in the gut of mice rendered DIO by chronic access to a high fat and sucrose diet for 60 days inhibits nutrient-induced release of satiation peptides and promotes overeating. Immunoreactivity for CBRs was present in enteroendocrine cells in the mouse's upper small-intestinal epithelium that produce and secrete the satiation peptide, cholecystokinin (CCK), and expression of mRNA for CBRs was greater in these cells when compared to non-CCK producing cells. Oral gavage of corn oil increased levels of bioactive CCK (CCK-8) in plasma from mice fed a low fat no-sucrose diet. Pretreatment with the cannabinoid receptor agonist, WIN55,212-2, blocked this response, which was reversed by co-administration with the peripherally-restricted CBR neutral antagonist, AM6545. Furthermore, monoacylglycerol metabolic enzyme function was dysregulated in the upper small-intestinal epithelium from DIO mice, which was met with increased levels of a variety of monoacylglycerols including the endocannabinoid, 2-arachidonoyl--glycerol. Corn oil failed to affect levels of CCK in DIO mouse plasma; however, pretreatment with AM6545 restored the ability for corn oil to stimulate increases in levels of CCK, which suggests that elevated endocannabinoid signaling at small intestinal CBRs in DIO mice inhibits nutrient-induced CCK release. Moreover, the hypophagic effect of AM6545 in DIO mice was reversed by co-administration with the CCK receptor antagonist, devazepide. Collectively, these results provide evidence that hyperphagia associated with DIO is driven by a mechanism that includes CBR-mediated inhibition of gut-brain satiation signaling.
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http://dx.doi.org/10.3389/fphys.2019.00704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597959PMC
June 2019

Impact of maternal western diet-induced obesity on offspring mortality and peripheral endocannabinoid system in mice.

PLoS One 2018 1;13(10):e0205021. Epub 2018 Oct 1.

University of California Riverside, School of Medicine, Division of Biomedical Sciences, Riverside CA, United States of America.

Over two-thirds of adults in the United States are obese or overweight, which is largely due to chronic overconsumption of diets high in fats and sugars (i.e., Western diet). Recent studies reveal that maternal obesity may predispose offspring to development of obesity and other metabolic diseases; however, the molecular underpinnings of these outcomes are largely unknown. The endocannabinoid system is an important signaling pathway that controls feeding behavior and energy homeostasis, and its activity becomes upregulated in the upper small intestinal epithelium of Western diet-induced obese mice, which drives overeating. In the current investigation, we examined the impact of chronic maternal consumption of Western diet on the expression and function of the endocannabinoid system in several peripheral organs important for food intake and energy homeostasis in offspring. Female C57BL/6Tac mice were fed a Western diet or low-fat/no-sucrose control chow for 10 weeks, then males were introduced for mating. Dams were maintained on their respective diets through weaning of pups, at which time pups were maintained on low-fat/no-sucrose chow for 10 weeks. Neonates born from dams fed Western diet, when compared to those born from mice fed control chow, unexpectedly displayed increases in mortality that occurred exclusively within six days following birth (greater than 50% mortality). Males comprised a larger fraction of surviving offspring from obese dams. Furthermore, surviving offspring displayed transient increases in body mass for first two days post weaning, and no marked changes in feeding patterns and endocannabinoid levels in upper small intestinal epithelium, pancreas, and plasma, or in expression of key endocannabinoid system genes in the upper small intestinal epithelium and pancreas at 10 weeks post-weaning. Collectively, these results suggest that maternal diet composition greatly influences survival of neonate C57BL/6Tac mice, and that surviving offspring from dams chronically fed a Western diet do not display marked changes in body mass, eating patterns, or expression and function of the endocannabinoid system in several peripheral organs important for feeding behavior and energy homeostasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166980PMC
March 2019

Host- and Helminth-Derived Endocannabinoids That Have Effects on Host Immunity Are Generated during Infection.

Infect Immun 2018 11 25;86(11). Epub 2018 Oct 25.

Division of Biomedical Sciences, University of California, Riverside, Riverside, California, USA

Helminths have coevolved with their hosts, resulting in the development of specialized host immune mechanisms and parasite-specific regulatory products. Identification of new pathways that regulate helminth infection could provide a better understanding of host-helminth interaction and may identify new therapeutic targets for helminth infection. Here we identify the endocannabinoid system as a new mechanism that influences host immunity to helminths. Endocannabinoids are lipid-derived signaling molecules that control important physiologic processes, such as feeding behavior and metabolism. Following murine infection with , an intestinal nematode with a life cycle similar to that of hookworms, we observed increased levels of endocannabinoids (2-arachidonoylglycerol [2-AG] or anandamide [AEA]) and the endocannabinoid-like molecule oleoylethanolamine (OEA) in infected lung and intestine. To investigate endocannabinoid function in helminth infection, we employed pharmacological inhibitors of cannabinoid subtype receptors 1 and 2 (CBR and CBR). Compared to findings for vehicle-treated mice, inhibition of CBR but not CBR resulted in increased worm burden and egg output, associated with significantly decreased expression of the T helper type 2 cytokine interleukin 5 (IL-5) in intestinal tissue and splenocyte cultures. Strikingly, bioinformatic analysis of genomic and transcriptome sequencing (RNA-seq) data sets identified putative genes encoding endocannabinoid biosynthetic and degradative enzymes in many parasitic nematodes. To test the novel hypothesis that helminth parasites produce their own endocannabinoids, we measured endocannabinoid levels in by mass spectrometry and quantitative PCR and found that parasites produced endocannabinoids, especially at the infectious larval stage. To our knowledge, this is the first report of helminth- and host-derived endocannabinoids that promote host immune responses and reduce parasite burden.
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http://dx.doi.org/10.1128/IAI.00441-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204704PMC
November 2018

Plasma fatty acid ethanolamides are associated with postprandial triglycerides, ApoCIII, and ApoE in humans consuming a high-fructose corn syrup-sweetened beverage.

Am J Physiol Endocrinol Metab 2018 08 10;315(2):E141-E149. Epub 2018 Apr 10.

Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, California.

Epidemiological and clinical research studies have provided ample evidence demonstrating that consumption of sugar-sweetened beverages increases risk factors involved in the development of obesity, Type 2 diabetes, and cardiovascular disease (CVD). Our previous study demonstrated that when compared with aspartame (Asp), 2 wk of high-fructose corn syrup (HFCS)-sweetened beverages provided at 25% of daily energy requirement was associated with increased body weight, postprandial (pp) triglycerides (TG), and fasting and pp CVD risk factors in young adults. The fatty acid ethanolamide, anandamide (AEA), and the monoacylglycerol, 2-arachidonoyl- sn-glycerol (2-AG), are two primary endocannabinoids (ECs) that play a role in regulating food intake, increasing adipose storage, and regulating lipid metabolism. Therefore, we measured plasma concentrations of ECs and their analogs, oleoylethanolamide (OEA), docosahexaenoyl ethanolamide (DHEA), and docosahexaenoyl glycerol (DHG), in participants from our previous study who consumed HFCS- or Asp-sweetened beverages to determine associations with weight gain and CVD risk factors. Two-week exposure to either HFCS- or Asp-sweetened beverages resulted in significant differences in the changes in fasting levels of OEA and DHEA between groups after the testing period. Subjects who consumed Asp, but not HFCS, displayed a reduction in AEA, OEA, and DHEA after the testing period. In contrast, there were significant positive relationships between AEA, OEA, and DHEA vs. ppTG, ppApoCIII, and ppApoE in those consuming HFCS, but not in those consuming Asp. Our findings reveal previously unknown associations between circulating ECs and EC-related molecules with markers of lipid metabolism and CVD risk after HFCS consumption.
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http://dx.doi.org/10.1152/ajpendo.00406.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335011PMC
August 2018

Plasma endocannabinoid levels in lean, overweight, and obese humans: relationships to intestinal permeability markers, inflammation, and incretin secretion.

Am J Physiol Endocrinol Metab 2018 10 13;315(4):E489-E495. Epub 2018 Feb 13.

University of Adelaide School of Medicine , Adelaide , Australia.

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.
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http://dx.doi.org/10.1152/ajpendo.00355.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230711PMC
October 2018

Identification of a Widespread Palmitoylethanolamide Contamination in Standard Laboratory Glassware.

Cannabis Cannabinoid Res 2017 1;2(1):123-132. Epub 2017 Jun 1.

Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.

Fatty acid ethanolamides (FAEs) are a family of lipid mediators that participate in a host of biological functions. Procedures for the quantitative analysis of FAEs include organic solvent extraction from biological matrices (e.g., blood), followed by purification and subsequent quantitation by liquid chromatography-mass spectrometry (LC/MS) or gas chromatography-mass spectrometry. During the validation process of a new method for LC/MS analysis of FAEs in biological samples, we observed unusually high levels of the FAE, palmitoylethanolamide (PEA), in blank samples that did not contain any biological material. We investigated a possible source of this PEA artifact via liquid chromatography coupled to tandem mass spectrometry, as well as accurate mass analysis. We found that high levels of a contaminant indistinguishable from PEA is present in new 5.75″ glass Pasteur pipettes, which are routinely used by laboratories to carry out lipid extractions. This artifact might account for discrepancies found in the literature regarding PEA levels in human blood serum and other tissues. It is recommended to take into account this pitfall by analyzing potential contamination of the disposable glassware during the validation process of any method used for analysis of FAEs.
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http://dx.doi.org/10.1089/can.2017.0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510777PMC
June 2017

Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.

Physiol Behav 2017 03 5;171:32-39. Epub 2017 Jan 5.

University of California Riverside, Riverside, CA, USA; School of Medicine, Riverside, CA, USA; Division of Biomedical Sciences, Riverside, CA, USA. Electronic address:

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CBRs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CBRs with the peripherally-restricted neutral cannabinoid CB receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CBRs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CBRs.
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http://dx.doi.org/10.1016/j.physbeh.2016.12.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296283PMC
March 2017

Endocannabinoids in the Gut.

Cannabis Cannabinoid Res 2016 Feb 24;1(1):67-77. Epub 2016 Feb 24.

Cannabis has been used medicinally for centuries to treat a variety of disorders, including those associated with the gastrointestinal tract. The discovery of our bodies' own "cannabis-like molecules" and associated receptors and metabolic machinery - collectively called the endocannabinoid system - enabled investigations into the physiological relevance for the system, and provided the field with evidence of a critical function for this endogenous signaling pathway in health and disease. Recent investigations yield insight into a significant participation for the endocannabinoid system in the normal physiology of gastrointestinal function, and its possible dysfunction in gastrointestinal pathology. Many gaps, however, remain in our understanding of the precise neural and molecular mechanisms across tissue departments that are under the regulatory control of the endocannabinoid system. This review highlights research that reveals an important - and at times surprising - role for the endocannabinoid system in the control of a variety of gastrointestinal functions, including motility, gut-brain mediated fat intake and hunger signaling, inflammation and gut permeability, and dynamic interactions with gut microbiota.
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http://dx.doi.org/10.1089/can.2016.0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940133PMC
February 2016

Obesity development in neuron-specific lipoprotein lipase deficient mice is not responsive to increased dietary fat content or change in fat composition.

Metabolism 2016 07 4;65(7):987-97. Epub 2016 Feb 4.

Division of Endocrinology, Metabolism, & Diabetes, Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

We have previously reported that mice with neuron-specific LPL deficiency (NEXLPL-/-) become obese by 16weeks of age on chow. Moreover, these mice had reduced uptake of triglyceride (TG)-rich lipoprotein-derived fatty acids and lower levels of n-3 long chain polyunsaturated fatty acids (n-3 PUFAs) in the hypothalamus. Here, we asked whether increased dietary fat content or altered dietary composition could modulate obesity development in NEXLPL-/- mice. Male NEXLPL-/- mice and littermate controls (WT) were randomly assigned one of three synthetic diets; a high carbohydrate diet (HC, 10% fat), a high-fat diet (HF, 45% fat), or a HC diet supplemented with n-3 PUFAs (HCn-3, 10% fat, Lovaza, GSK®). After 42weeks of HC feeding, body weight and fat mass were increased in the NEXLPL-/- mice compared to WT. WT mice fed a HF diet displayed typical diet-induced obesity, but weight gain was only marginal in HF-fed NEXLPL-/- mice, with no significant difference in body composition. Dietary n-3 PUFA supplementation did not prevent obesity in NEXLPL-/- mice, but was associated with differential modifications in hypothalamic gene expression and PUFA concentration compared to WT mice. Our findings suggest that neuronal LPL is involved in the regulation of body weight and composition in response to either the change in quantity (HF feeding) or quality (n-3 PUFA-enriched) of dietary fat. The precise role of LPL in lipid sensing in the brain requires further investigation.
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http://dx.doi.org/10.1016/j.metabol.2016.01.015DOI Listing
July 2016

Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways.

Am J Physiol Regul Integr Comp Physiol 2015 Oct 19;309(8):R805-13. Epub 2015 Aug 19.

Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California; Department of Pharmacology, University of California, Irvine, School of Medicine, Irvine, California; Department of Biological Chemistry, University of California, Irvine, School of Medicine, Irvine, California; and Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy

The endocannabinoids are lipid-derived signaling molecules that control feeding and energy balance by activating CB1-type cannabinoid receptors in the brain and peripheral tissues. Previous studies have shown that oral exposure to dietary fat stimulates endocannabinoid signaling in the rat small intestine, which provides positive feedback that drives further food intake and preference for fat-rich foods. We now describe an unexpectedly broader role for cholinergic signaling of the vagus nerve in the production of the endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), in the small intestine. We show that food deprivation increases levels of 2-AG and its lipid precursor, 1,2-diacylglycerol, in rat jejunum mucosa in a time-dependent manner. This response is abrogated by surgical resection of the vagus nerve or pharmacological blockade of small intestinal subtype-3 muscarinic acetylcholine (m3 mAch) receptors, but not inhibition of subtype-1 muscarinic acetylcholine (m1 mAch). We further show that blockade of peripheral CB1 receptors or intestinal m3 mAch receptors inhibits refeeding in fasted rats. The results suggest that food deprivation stimulates 2-AG-dependent CB1 receptor activation through a mechanism that requires efferent vagal activation of m3 mAch receptors in the jejunum, which, in turn, may promote feeding after a fast.
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http://dx.doi.org/10.1152/ajpregu.00239.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666947PMC
October 2015

Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice.

PLoS One 2015 11;10(8):e0135113. Epub 2015 Aug 11.

Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, School of Medicine, Aurora, CO 80045, United States of America.

Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer's disease. Lipoprotein lipase (LPL) hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS). Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/-) and 10 mo in heterozygous mice (NEXLPL+/-). In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid β accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA) in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532501PMC
May 2016

Feeding-induced oleoylethanolamide mobilization is disrupted in the gut of diet-induced obese rodents.

Biochim Biophys Acta 2015 Sep 27;1851(9):1218-26. Epub 2015 May 27.

Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA; Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address:

The gastrointestinal tract plays a critical role in the regulation of energy homeostasis by initiating neural and hormonal responses to the ingestion of nutrients. In addition to peptide hormones, such as cholecystokinin (CKK) and peptide YY (PYY), the lipid-derived mediator oleoylethanolamide (OEA) has been implicated in the control of satiety. Previous studies in humans and rodent models have shown that obesity is associated with changes in CCK, PYY and other gut-derived peptide hormones, which may contribute to decreased satiety and increased energy intake. In the present study, we show that small-intestinal OEA production is disrupted in the gut of diet-induced obese (DIO) rats and mice. In lean rodents, feeding or duodenal infusion of Intralipid® or pure oleic acid stimulates jejunal OEA mobilization. This response is strikingly absent in DIO rats and mice. Confirming previous reports, we found that feeding rats or mice a high-fat diet for 7 days is sufficient to suppress jejunal OEA mobilization. Surprisingly, a similar effect is elicited by feeding rats and mice a high-sucrose low-fat diet for 7 days. Collectively, our findings suggest that high fat-induced obesity is accompanied by alterations in the post-digestive machinery responsible for OEA biosynthesis, which may contribute to reduced satiety and hyperphagia.
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http://dx.doi.org/10.1016/j.bbalip.2015.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516666PMC
September 2015

Modulation of sweet taste sensitivities by endogenous leptin and endocannabinoids in mice.

J Physiol 2015 Jun 16;593(11):2527-45. Epub 2015 Apr 16.

Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan.

Key Points: Potential roles of endogenous leptin and endocannabinoids in sweet taste were examined by using pharmacological antagonists and mouse models including leptin receptor deficient (db/db) and diet-induced obese (DIO) mice. Chorda tympani (CT) nerve responses of lean mice to sweet compounds were increased after administration of leptin antagonist (LA) but not affected by administration of cannabinoid receptor antagonist (AM251). db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid levels in the taste organ, and enhanced expression of a biosynthesizing enzyme of endocannabinoids in taste cells. The effect of LA was gradually decreased and that of AM251 was increased during the course of obesity in DIO mice. These findings suggest that circulating leptin, but not local endocannabinoids, is a dominant modulator for sweet taste in lean mice and endocannabinoids become more effective modulators of sweet taste under conditions of deficient leptin signalling.

Abstract: Leptin is an anorexigenic mediator that reduces food intake by acting on hypothalamic receptor Ob-Rb. In contrast, endocannabinoids are orexigenic mediators that act via cannabinoid CB1 receptors in hypothalamus, limbic forebrain, and brainstem. In the peripheral taste system, leptin administration selectively inhibits behavioural, taste nerve and taste cell responses to sweet compounds. Opposing the action of leptin, endocannabinoids enhance sweet taste responses. However, potential roles of endogenous leptin and endocannabinoids in sweet taste remain unclear. Here, we used pharmacological antagonists (Ob-Rb: L39A/D40A/F41A (LA), CB1 : AM251) and examined the effects of their blocking activation of endogenous leptin and endocannabinoid signalling on taste responses in lean control, leptin receptor deficient db/db, and diet-induced obese (DIO) mice. Lean mice exhibited significant increases in chorda tympani (CT) nerve responses to sweet compounds after LA administration, while they showed no significant changes in CT responses after AM251. In contrast, db/db mice showed clear suppression of CT responses to sweet compounds after AM251, increased endocannabinoid (2-arachidonoyl-sn-glycerol (2-AG)) levels in the taste organ, and enhanced expression of a biosynthesizing enzyme (diacylglycerol lipase α (DAGLα)) of 2-AG in taste cells. In DIO mice, the LA effect was gradually decreased and the AM251 effect was increased during the course of obesity. Taken together, our results suggest that circulating leptin, but not local endocannabinoids, may be a dominant modulator for sweet taste in lean mice; however, endocannabinoids may become more effective modulators of sweet taste under conditions of deficient leptin signalling, possibly due to increased production of endocannabinoids in taste tissue.
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http://dx.doi.org/10.1113/JP270295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461413PMC
June 2015

Intestinal lipid-derived signals that sense dietary fat.

J Clin Invest 2015 Mar 2;125(3):891-8. Epub 2015 Feb 2.

Fat is a vital macronutrient, and its intake is closely monitored by an array of molecular sensors distributed throughout the alimentary canal. In the mouth, dietary fat constituents such as mono- and diunsaturated fatty acids give rise to taste signals that stimulate food intake, in part by enhancing the production of lipid-derived endocannabinoid messengers in the gut. As fat-containing chyme enters the small intestine, it causes the formation of anorexic lipid mediators, such as oleoylethanolamide, which promote satiety. These anatomically and functionally distinct responses may contribute to the homeostatic control and, possibly, the pathological dysregulation of food intake.
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http://dx.doi.org/10.1172/JCI76302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362267PMC
March 2015

Is fat taste ready for primetime?

Physiol Behav 2014 Sep 12;136:145-54. Epub 2014 Mar 12.

Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, United States. Electronic address:

Mounting evidence suggests that gustation is important for the orosensory detection of dietary fats, and might contribute to preferences that humans, rodents, and possibly other mammals exhibit for fat-rich foods. In contrast to sweet, sour, salty, bitter, and umami, fat is not widely recognized as a primary taste quality. Recent investigations, however, provide a wealth of information that is helping to elucidate the specific molecular, cellular, and neural mechanisms required for fat detection in mammals. The latest evidence supporting a fat taste will be explored in this review, with a particular focus on recent studies that suggest a surprising role for gut-brain endocannabinoid signaling in controlling intake and preference for fats based on their proposed taste properties.
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http://dx.doi.org/10.1016/j.physbeh.2014.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162865PMC
September 2014

Endocannabinoid signaling in the gut mediates preference for dietary unsaturated fats.

FASEB J 2013 Jun 5;27(6):2513-20. Epub 2013 Mar 5.

Department of Anatomy and Neurobiology, University of California-Irvine School of Medicine, Irvine, CA 92697-1275, USA.

Dietary fat exerts a potent stimulatory effect on feeding. This effect is mediated, at least in part, by a cephalic mechanism that involves recruitment of the vagus nerve and subsequent activation of endocannabinoid signaling in the gut. Here, we used a sham-feeding protocol in rats to identify fatty-acid constituents of dietary fat that might be responsible for triggering small-intestinal endocannabinoid signaling. Sham feeding rats with a corn oil emulsion increased endocannabinoid levels in jejunum, relative to animals that received either mineral oil (which contains no fatty acids) or no oil. Sham-feeding emulsions containing oleic acid (18:1) or linoleic acid (18:2) caused, on average, a nearly 2-fold accumulation of jejunal endocannabinoids, whereas emulsions containing stearic acid (18:0) or linolenic acid (18:3) had no such effect. In a 2-bottle-choice sham-feeding test, rats displayed strong preference for emulsions containing 18:2, which was blocked by pretreatment with the peripherally restricted CB1 cannabinoid receptor antagonists, AM6546 and URB447. Our results suggest that oral exposure to the monoenoic and dienoic fatty acid component of dietary fat selectively initiates endocannabinoid mobilization in the gut, and that this local signaling event is essential for fat preference.
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http://dx.doi.org/10.1096/fj.13-227587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659363PMC
June 2013

Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome.

Nat Commun 2012 ;3:1080

Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, USA.

Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerol-producing enzyme, diacylglycerol lipase-α (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as a molecular substrate for fragile X syndrome, which might be targeted by therapy.
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http://dx.doi.org/10.1038/ncomms2045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657999PMC
February 2013

Selective cannabinoid-1 receptor blockade benefits fatty acid and triglyceride metabolism significantly in weight-stable nonhuman primates.

Am J Physiol Endocrinol Metab 2012 Sep 3;303(5):E624-34. Epub 2012 Jul 3.

Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9052, USA.

The goal of this study was to determine whether administration of the CB₁ cannabinoid receptor antagonist rimonabant would alter fatty acid flux in nonhuman primates. Five adult baboons (Papio Sp) aged 12.1 ± 4.7 yr (body weight: 31.9 ± 2.1 kg) underwent repeated metabolic tests to determine fatty acid and TG flux before and after 7 wk of treatment with rimonabant (15 mg/day). Animals were fed ad libitum diets, and stable isotopes were administered via diet (d₃₁-tripalmitin) and intravenously (¹³C₄-palmitate, ¹³C₁-acetate). Plasma was collected in the fed and fasted states, and blood lipids were analyzed by GC-MS. DEXA was used to assess body composition and a hyperinsulinemic euglycemic clamp used to assess insulin-mediated glucose disposal. During the study, no changes were observed in food intake, body weight, plasma, and tissue endocannabinoid concentrations or the quantity of liver-TG fatty acids originating from de novo lipogenesis (19 ± 6 vs. 16 ± 5%, for pre- and posttreatment, respectively, P = 0.39). However, waist circumference was significantly reduced 4% in the treated animals (P < 0.04), glucose disposal increased 30% (P = 0.03), and FFA turnover increased 37% (P = 0.02). The faster FFA flux was consistent with a 43% reduction in these fatty acids used for TRL-TG synthesis (40 ± 3 vs. 23 ± 4%, P = 0.02) and a twofold increase in TRL-TG turnover (1.5 ± 0.9 vs. 3.1 ± 1.4 μmol·kg⁻¹·h⁻¹, P = 0.03). These data support the potential for a strong effect of CB₁ receptor antagonism at the level of adipose tissue, resulting in improvements in fasting turnover of fatty acids at the whole body level, central adipose storage, and significant improvements in glucose homeostasis.
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http://dx.doi.org/10.1152/ajpendo.00072.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468508PMC
September 2012
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