Schistosoma haematobium infection is associated with alterations in energy and purine-related metabolism in preschool-aged children.

Helminths are parasitic worms that infect over a billion people worldwide. The pathological consequences from infection are due in part, to parasite-induced changes in host metabolic pathways. Here, we analyse the changes in host metabolic profiles, in response to the first Schistosoma haematobium infection and treatment in Zimbabwean children. A cohort of 83 schistosome-negative children (2-5 years old) as determined by parasitological examination, guardian interviews and examination of medical records, was recruited at baseline. Children were followed up after three months for parasitological diagnosis of their first S. haematobium infection, by detection of parasite eggs excreted in urine. Children positive for infection were treated with the antihelminthic drug praziquantel, and treatment efficacy checked three months after treatment. Blood samples were taken at each time point, and capillary electrophoresis mass spectrometry in conjunction with multivariate analysis were used to compare the change in serum metabolite profiles in schistosome-infected versus uninfected children. Following baseline at the three-month follow up, 11 children had become infected with S. haematobium (incidence = 13.3%). Our results showed that infection with S. haematobium was associated with significant increases (>2-fold) in discriminatory metabolites, linked primarily with energy (G6P, 3-PG, AMP, ADP) and purine (AMP, ADP) metabolism. These observed changes were commensurate with schistosome infection intensity, and levels of the affected metabolites were reduced following treatment, albeit not significantly. This study demonstrates that early infection with S. haematobium is associated with alterations in host energy and purine metabolism. Taken together, these changes are consistent with parasite-related clinical manifestations of malnutrition, poor growth and poor physical and cognitive performance observed in schistosome-infected children.

Targeting Peripheral CB1 Receptors Reduces Ethanol Intake via a Gut-Brain Axis.

Endocannabinoids acting on the cannabinoid-1 receptor (CB1R) or ghrelin acting on its receptor (GHS-R1A) both promote alcohol-seeking behavior, but an interaction between the two signaling systems has not been explored. Here, we report that the peripheral CB1R inverse agonist JD5037 reduces ethanol drinking in wild-type mice but not in mice lacking CB1R, ghrelin peptide or GHS-R1A. JD5037 treatment of alcohol-drinking mice inhibits the formation of biologically active octanoyl-ghrelin without affecting its inactive precursor desacyl-ghrelin. In ghrelin-producing stomach cells, JD5037 reduced the level of the substrate octanoyl-carnitine generated from palmitoyl-carnitine by increasing fatty acid ß-oxidation. Blocking gastric vagal afferents abrogated the ability of either CB1R or GHS-R1A blockade to reduce ethanol drinking. We conclude that blocking CB1R in ghrelin-producing cells reduces alcohol drinking by inhibiting the formation of active ghrelin and its signaling via gastric vagal afferents. Thus, peripheral CB1R blockade may have therapeutic potential in the treatment of alcoholism.

Plasma metabolome analysis of patients with major depressive disorder.

AIM: This study sought to characterize the plasma metabolite profiling of patients with major depressive disorder (MDD). METHODS: Psychiatric assessments were made with the Structured Clinical Interview for DSM-IV Axis I Disorders. In the exploratory cohort, plasma metabolite profiles of 34 MDD patients and 31 mentally healthy controls were compared using capillary electrophoresis-mass spectrometry. Among the candidate metabolites, we focused on a metabolite showing the largest difference. The absolute concentrations were measured in two cohorts from a psychiatric primary care clinic to characterize the accuracy of the metabolite biomarker. RESULTS: Among 23 metabolites significantly lower in the MDD group than in healthy controls, we focused on phosphoethanolamine (PEA) as a candidate. The reduction of PEA levels in MDD was checked in independent clinical sample sets. An ion-chromatography-fluorescence detection method was developed to measure plasma PEA levels. In the preliminary cohort, we examined 34 MDD and 43 non-MDD subjects. The area under the receiver-operator curve (AUC) was 0.92, with sensitivity/specificity greater than 88%, at a cut-off of 1.46 µM. In the checking cohort, with 10 MDD and 13 non-MDD subjects, AUC was 0.89, with sensitivity/specificity of 86% and 100%, respectively, at a cut-off of 1.48 µM. Plasma PEA inversely correlated with MDD severity, depressed mood, loss of interest, and psychomotor retardation. CONCLUSION: These results suggest that plasma PEA level could be a candidate biomarker of MDD in the clinical setting. Further studies comparing MDD and mentally healthy controls are needed to confirm the utility of PEA as a biomarker for depression.

Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue.

We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3. Mice lacking GPR3 and maintained on normal chow had similar body weights during their first 5 months of life, but gained considerably more weight thereafter and displayed reduced total energy expenditure and lower core body temperature. By the age of 5 months GPR3 KO mice already had lower thermogenic gene expression and uncoupling protein 1 protein level and showed impaired glucose uptake into interscapular brown adipose tissue (iBAT) relative to WT littermates. These molecular deviations in iBAT of GPR3 KO mice preceded measurable differences in body weight and core body temperature at ambient conditions, but were coupled to a failure to maintain thermal homeostasis during acute cold challenge. At the same time, the same cold challenge caused a 17-fold increase in Gpr3 expression in iBAT of WT mice. Thus, GPR3 appears to have a key role in the thermogenic response of iBAT and may represent a new therapeutic target in age-related obesity.

Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences.

BACKGROUND: Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism. RESULTS: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (~600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway. CONCLUSION: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity.

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The backbone of both endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) is the ω-6 fatty acid arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated as an independent variable to reflect the dietary increase in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium-fat diets (35 en% fat) and high-fat diets (60 en%) for 14 weeks from weaning. Increasing LA from 1 en% to 8 en% elevated AA-phospholipids (PL) in liver and erythrocytes, tripled 2-AG + 1-AG and AEA associated with increased food intake, feed efficiency, and adiposity in mice. Reducing AA-PL by adding 1 en% long-chain ω-3 fats to 8 en% LA diets resulted in metabolic patterns resembling 1 en% LA diets. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. These animal diets modeled 20th century increases of human LA consumption, changes that closely correlate with increasing prevalence rates of obesity. In summary, dietary LA increased tissue AA, and subsequently elevated 2-AG + 1-AG and AEA resulting in the development of diet-induced obesity. The adipogenic effect of LA can be prevented by consuming sufficient EPA and DHA to reduce the AA-PL pool and normalize endocannabinoid tone.

Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects.

The enzyme fatty acid amide hydrolase (FAAH) catalyzes the in vivo degradation of the endocannabinoid anandamide, thus controlling its action at receptors. A novel FAAH inhibitor, AM3506, normalizes the elevated blood pressure and cardiac contractility of spontaneously hypertensive rats (SHR) without affecting these parameters in normotensive rats. These effects are due to blockade of FAAH and a corresponding rise in brain anandamide levels, resulting in CB1 receptor-mediated decrease in sympathetic tone. The supersensitivity of SHR to CB1 receptor-mediated cardiovascular depression is related to increased G protein coupling of CB1 receptors. Importantly, AM3506 does not elicit hyperglycemia and insulin resistance seen with other FAAH inhibitors or in FAAH⁻/⁻ mice, which is related to its inability to inhibit FAAH in the liver due to rapid hepatic uptake and metabolism. This unique activity profile offers improved therapeutic value in hypertension.

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity.

Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.

Transcriptional regulation of cannabinoid receptor-1 expression in the liver by retinoic acid acting via retinoic acid receptor-gamma.

Alcoholism can result in fatty liver that can progress to steatohepatitis, cirrhosis, and liver cancer. Mice fed alcohol develop fatty liver through endocannabinoid activation of hepatic CB(1) cannabinoid receptors (CB(1)R), which increases lipogenesis and decreases fatty acid oxidation. Chronic alcohol feeding also up-regulates CB(1)R in hepatocytes in vivo, which could be replicated in vitro by co-culturing control hepatocytes with hepatic stellate cells (HSC) isolated from ethanol-fed mice, implicating HSC-derived mediator(s) in the regulation of hepatic CB(1)R (Jeong, W. I., Osei-Hyiaman, D., Park, O., Liu, J., Bátkai, S., Mukhopadhyay, P., Horiguchi, N., Harvey-White, J., Marsicano, G., Lutz, B., Gao, B., and Kunos, G. (2008) Cell Metab. 7, 227-235). HSC being a rich source of retinoic acid (RA), we tested whether RA and its receptors may regulate CB(1)R expression in cultured mouse hepatocytes. Incubation of hepatocytes with RA or RA receptor (RAR) agonists increased CB(1)R mRNA and protein, the most efficacious being the RARgamma agonist CD437 and the pan-RAR agonist TTNPB. The endocannabinoid 2-arachidonoylglycerol (2-AG) also increased hepatic CB(1)R expression, which was mediated indirectly via RA, because it was absent in hepatocytes from mice lacking retinaldehyde dehydrogenase 1, the enzyme catalyzing the generation of RA from retinaldehyde. The binding of RARgamma to the CB(1)R gene 5' upstream domain in hepatocytes treated with RAR agonists or 2-AG was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift and antibody supershift assays. Finally, TTNPB-induced CB(1)R expression was attenuated by small interfering RNA knockdown of RARgamma in hepatocytes. We conclude that RARgamma regulates CB(1)R expression and is thus involved in the control of hepatic fat metabolism by endocannabinoids.

Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain?

Endocannabinoids, endogenous lipid ligands of cannabinoid receptors, mediate a variety of effects similar to those of marijuana. Cannabinoid CB(1) receptors are highly abundant in the brain and mediate psychotropic effects, which limits their value as a potential therapeutic target. There is growing evidence for CB(1) receptors in peripheral tissues that modulate a variety of functions, including pain sensitivity and obesity-related hormonal and metabolic abnormalities. In this review we propose that selective targeting of peripheral CB(1) receptors has potential therapeutic value because it would help to minimize addictive, psychoactive effects in the case of CB(1) agonists used as analgesics, or depression and anxiety in the case of CB(1) antagonists used in the management of cardiometabolic risk factors associated with the metabolic syndrome.

The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels.

The novel endocannabinoid-like lipid N-arachidonoyl L-serine (ARA-S) causes vasodilation through both endothelium-dependent and -independent mechanisms. We have analyzed the vasorelaxant effect of ARA-S in isolated vascular preparations and its effects on Ca(2+)-activated K(+) currents in human embryonic kidney cells stably transfected with the alpha-subunit of the human, large conductance Ca(+)-activated K(+) (BK(Ca)) channel [human embryonic kidney (HEK) 293hSlo cells]. ARA-S caused relaxation of rat isolated, intact and denuded, small mesenteric arteries preconstricted with (R)-(-)-1-(3-hydroxyphenyl)-2-methylaminoethanol hydrochloride (pEC(50), 5.49 and 5.14, respectively), whereas it caused further contraction of vessels preconstricted with KCl (pEC(50), 5.48 and 4.82, respectively). Vasorelaxation by ARA-S was inhibited by 100 nM iberiotoxin. In human embryonic kidney cells stably transfected with the alpha-subunit of the human BK(Ca) channel cells, ARA-S and its enantiomer, N-arachidonoyl-D-serine, enhanced the whole-cell outward K(+) current with similar potency (pEC(50), 5.63 and 5.32, respectively). The potentiation was not altered by the beta(1) subunit or mediated by ARA-S metabolites, stimulation of known cannabinoid receptors, G proteins, protein kinases, or Ca(2+)-dependent processes; it was lost after patch excision or after membrane cholesterol depletion but was restored after cholesterol reconstitution. BK(Ca) currents were also enhanced by N-arachidonoyl ethanolamide (pEC(50), 5.27) but inhibited by another endocannabinoid, O-arachidonoyl ethanolamine (pIC(50), 6.35), or by the synthetic cannabinoid O-1918 [(-)-1,3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol] (pIC(50), 6.59), which blocks ARA-S-induced vasodilation. We conclude the following. 1) ARA-S directly activates BK(Ca) channels. 2) This interaction does not involve cannabinoid receptors or cytosolic factors but is dependent on the presence of membrane cholesterol. 3) Direct BK(Ca) channel activation probably contributes to the endothelium-independent component of ARA-S-induced mesenteric vasorelaxation. 4) O-1918 is a BK(Ca) channel inhibitor.

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid omega-Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease.

Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis), due to a decrease in mitochondria beta-oxidation with an increase in both peroxisomal beta-oxidation, and microsomal omega-oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs). How steatosis increases PPARalpha activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid beta-oxidation and omega-oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA), monounsaturated (MUFA), or saturated (SFA) may be determined by the interplay of PPARs and HNF4alpha with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the omega-oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPARalpha. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid omega-hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA) CYP4A and long-chain fatty acid (LCFA) CYP4Fomega-hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to steatohepatitis.

Endocannabinoids and the control of energy homeostasis.

Endocannabinoids (ECBs) are ubiquitous lipid mediators that act through the same G protein-coupled receptors (CB1 and CB2) that recognize plant-derived cannabinoids. As regulators of metabolism, ECBs are anabolic: they increase the intake, promote the storage, and decrease the expenditure of energy. Recent work indicates that activation of peripheral CB1 receptors by ECBs plays a key role in the hormonal/metabolic changes associated with obesity/metabolic syndrome and may be targeted for its pharmacotherapy.

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice.

Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB1 (CB1-/-) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CB1 receptors in the metabolic consequences of a high-fat diet, using liver-specific CB1 knockout (LCB1-/-) mice. LCB1(-/-) mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1(-/-) mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CB1 agonist-induced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine palmitoyltransferase-1 and total energy expenditure were absent in both CB1(-/-) and LCB1(-/-) mice. We conclude that endocannabinoid activation of hepatic CB1 receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CB1 receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB1 blockade during treatment of obesity-associated conditions.

Sustained weight loss after Roux-en-Y gastric bypass is characterized by down regulation of endocannabinoids and mitochondrial function.

OBJECTIVE: To determine the physiologic importance of endocannabinoids and mitochondrial function in the long-term outcome using a rat model of Roux-en-Y gastric bypass (RYGB) surgery. BACKGROUND: Sixteen million people are morbidly obese and RYGB surgery is the most effective treatment. Endocannabinoids are implicated in appetite stimulation and regulation of peripheral energy metabolism. We hypothesize that down-regulation of endocannabinoids and alterations in mitochondrial function and hormones favoring catabolism contribute to sustained RYGB-induced weight loss. METHODS: Diet-induced obese Sprague-Dawley rats were randomized to sham-operated obese controls, RYGB, and sham-operated obese pair-fed rats. Body weight and food intake were recorded, and food efficiency was calculated. Endocannabinoid levels in skeletal muscle and liver, muscle mitochondrial respiratory complex I-V content, and hormones concentrations were determined 14 and 28 days postsurgery, reflecting rapid and sustained weight loss periods after RYGB, respectively. RESULTS: Compared with pair-fed controls, RYGB rats had significant reduction in body weight and food efficiency (P < 0.001). Increased cholecystokinin, reduced insulin, leptin, adiponectin, T3, and down-regulation of mitochondrial complex I were evident on day 14 postsurgery. On day 28, leptin, insulin, and T3 remained low, whereas adiponectin and cholecystokinin were normal. Along with complex I, the endocannabinoids anandamide in muscle (P = 0.003) and 2-arachidonoylglycerol in liver were significantly down-regulated (P < 0.001). CONCLUSIONS: The attenuated caloric intake, reduced food efficiency, and normalization of hormonal levels on day 28 post-RYGB were associated with significant down-regulation of endocannabinoids anandamide and 2-arachidonoylglycerol in muscle and liver, respectively. These results suggest a role for endocannabinoids in the mechanism of sustained weight loss and RYGB success, and may have implications for treatment of morbid obesity.

Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.

BACKGROUND & AIMS: Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure. METHODS: The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks. RESULTS: Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor alpha, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor alpha compared with wild-type controls. CONCLUSIONS: These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.

Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.

Alcohol-induced fatty liver, a major cause of morbidity, has been attributed to enhanced hepatic lipogenesis and decreased fat clearance of unknown mechanism. Here we report that the steatosis induced in mice by a low-fat, liquid ethanol diet is attenuated by concurrent blockade of cannabinoid CB1 receptors. Global or hepatocyte-specific CB1 knockout mice are resistant to ethanol-induced steatosis and increases in lipogenic gene expression and have increased carnitine palmitoyltransferase 1 activity, which, unlike in controls, is not reduced by ethanol treatment. Ethanol feeding increases the hepatic expression of CB1 receptors and upregulates the endocannabinoid 2-arachidonoylglycerol (2-AG) and its biosynthetic enzyme diacylglycerol lipase beta selectively in hepatic stellate cells. In control but not CB1 receptor-deficient hepatocytes, coculture with stellate cells from ethanol-fed mice results in upregulation of CB1 receptors and lipogenic gene expression. We conclude that paracrine activation of hepatic CB1 receptors by stellate cell-derived 2-AG mediates ethanol-induced steatosis through increasing lipogenesis and decreasing fatty acid oxidation.

Endocannabinoids and liver disease. IV. Endocannabinoid involvement in obesity and hepatic steatosis.

Endocannabinoids are endogenous lipid mediators that interact with the same receptors as plant-derived cannabinoids to produce similar biological effects. The well-known appetitive effect of smoking marijuana has prompted inquiries into the possible role of endocannabinoids in the control of food intake and body weight. This brief review surveys recent evidence that endocannabinoids and their receptors are involved at multiple levels in the control of energy homeostasis. Endocannabinoids are orexigenic mediators and are part of the leptin-regulated central neural circuitry that controls energy intake. In addition, they act at multiple peripheral sites including adipose tissue, liver, and skeletal muscle to promote lipogenesis and limit fat elimination. Their complex actions could be viewed as anabolic, increasing energy intake and storage and decreasing energy expenditure, as components of an evolutionarily conserved system that has insured survival under conditions of starvation. In the era of plentiful food and limited physical activity, pharmacological inhibition of endocannabinoid activity offers benefits in the treatment of obesity and its hormonal/metabolic consequences.

Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis.

In this study, we have investigated the role of the cannabinoid CB(2) (CB(2)) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB(2) receptor in TNF-alpha-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB(2) receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-alpha, MIP-1alpha, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB(2) receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB(2) receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.

Endocannabinoid system in cancer cachexia.

PURPOSE OF REVIEW: More than 60% of advanced cancer patients suffer from anorexia and cachexia. This review focuses on the possible mechanisms by which the endocannabinoid system antagonizes cachexia-anorexia processes in cancer patients and how it can be tapped for therapeutic applications. RECENT FINDINGS: Cannabinoids stimulate appetite and food intake. Hepatocytes express functional cannabinoid type 1 receptors, activation of which increases the expression of lipogenic genes (e.g those encoding sterol regulatory element binding protein 1c, acetyl-coenzyme A carboxylase-1, and fatty acid synthase in the liver and hypothalamus) and increase de-novo fatty acid synthesis, which contributes to development of diet-induced obesity. Both ghrelin and cannabinoids stimulate AMP-activated protein kinase in the hypothalamus, whereas they inhibit it in the liver and adipose tissues. Both anandamide and synthetic cannabinoid type 1 receptor agonists such as HU210 and the plant-derived cannabinoid tetrahydro-cannabinol also significantly inhibit tumor necrosis factor-alpha. SUMMARY: Cannabinoid type 1 receptor activation stimulates appetite and promotes lipogenesis and energy storage. Further study of cancer-cachexia pathophysiology and the role of endocannabinoids will help us to develop cannabinoids without psychotropic properties, which will help cancer patients suffering from cachexia and improve outcomes of clinical antitumor therapy.