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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 ([CB.sub.1]R) 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 [CB.sub.1]R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by [CB.sub.1]R 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 [CB.sub.1]R in peripheral tissues, including the liver, as verified through the use of [CB.sub.1]R -deficient mice with or without transgenic expression of [CB.sub.1]R in the liver. These results suggest that targeting peripheral [CB.sub.1]R has therapeutic potential for alleviating cardiometabolic risk in obese patients., Introduction Endocannabinoids are endogenous lipid mediators that interact with the same G protein-coupled receptors--[CB.sub.1]R and [CB sub.2]R--that recognize plant-derived cannabinoids, and they regulate a broad range of physiological functions. [CB.sub.1]Rs [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2008.10.001 Byline: George Kunos (1), Douglas Osei-Hyiaman (1), Sandor Batkai (1), Keith A. Sharkey (2), Alexandros Makriyannis (3) Abstract: Endocannabinoids, endogenous lipid ligands of cannabinoid receptors, mediate a variety of effects similar to those of marijuana. Cannabinoid CB.sub.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.sub.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.sub.1 receptors has potential therapeutic value because it would help to minimize addictive, psychoactive effects in the case of CB.sub.1 agonists used as analgesics, or depression and anxiety in the case of CB.sub.1 antagonists used in the management of cardiometabolic risk factors associated with the metabolic syndrome. Author Affiliation: (1) Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA (2) Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada (3) Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA

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 [CB.sub.1] (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 [CB.sub.1] receptors in the metabolic consequences of a high-fat diet, using liver-specific [CB.sub.1] 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. [CB.sub.1] 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 [CB.sub.1] 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 [CB.sub.1] 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 [CB.sub.1] blockade during treatment of obesity-associated conditions., Introduction Endocannabinoids increase food intake through their interaction with the leptin-regulated central neural appetitive circuitry (1), (2), and pharmacological blockade of [CB.sub.1] receptors has shown promise in the treatment of [...]

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 leptinregulated 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 receptors; metabolic syndrome; appetite; lipogenesis; cardiovascular risk factors

The endocannabinoid anandamide exerts neurobehavioral, cardiovascular, and immune-regulatory effects through cannabinoid receptors (CB). Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation, and hypertension. In this study, we compared the cardiac performance of FAAH knockout (FAA[H.sup.-/-]) mice and their wild-type (FAA[H.sup.+/+]) littermates and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads, and baroreflex sensitivity were similar in FAA[H.sup.-/-] and FAA[H.sup.+/+] mice. FAA[H.sup.-/-] mice displayed increased sensitivity to anandamide-induced, C[B.sub.1]-mediated hypotension and decreased cardiac contractility compared with FAA[H.sup.+/+] littermates. In contrast, the hypotensive potency of synthetic C[B.sub.1] agonist HU-210 and the level of expression of myocardial C[B.sub.1] were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAA[H.sup.-/-] mice compared with FAA[H.sup.+/+] mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to C[B.sub.1] agonists. contractility; hypertension; cannabinoids; endocannabinoids

Author(s): George Kunos [1]; Douglas Osei-Hyiaman [1]; Sandor Batkai [1]; Bin Gao [1] The 25,000 people who die each year of cirrhosis in the United States succumb to a disease [...]

Endocannabinoids, endogenous lipid ligands of cannabinoid receptors, mediate a variety of effects similar to those of marijuana. Cannabinoid CB1 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 CB1 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 CB1 receptors has potential therapeutic value because it would help to minimize addictive, psychoactive effects in the case of CB1 agonists used as analgesics, or depression and anxiety in the case of CB1 antagonists used in the management of cardiometabolic risk factors associated with the metabolic syndrome. [Copyright &y& Elsevier]

Summary: 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 β 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. [Copyright &y& Elsevier]

The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released ‘on demand’ by neurons in the brain. Anandamide is also generated by macrophages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE-PLD). Here we document a biosynthetic pathway for anandamide in mouse brain and RAW264.7 macrophages that involves the phospholipase C (PLC)-catalyzed cleavage of NAPE to generate a lipid, phosphoanandamide, which is subsequently dephosphorylated by phosphatases, including PTPN220 previously described as a protein tyrosine phosphatase. Bacterial endotoxin (LPS)-induced synthesis of anandamide in macrophages is mediated exclusively by the PLC/phosphatase pathway, which is up-regulated by LPS, whereas NAPE-PLD is down-regulated by LPS and functions as a salvage pathway of anandamide synthesis when the PLC/phosphatase pathway is compromised. Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC/phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target. [ABSTRACT FROM AUTHOR]

Age at menopause has been found to be associated positively with bone mineral density, and age at menarche has been found to be associated negatively with bone mineral density. However, there have been few studies on the relations of timing of menopause and length of the reproductive period with bone mineral density. The purpose of this study was to examine the relations of timing of menopause and reproductive years (calculated as age at menopause minus age at menarche) with mineral density of the second metacarpal bone in postmenopausal Japanese women. The study population consisted of 1, 035 naturally menopausal women aged 40–70 years who were screened in 1996–1997. Using computed x-ray densitometry, the authors measured bone mineral density by analyzing radiographic films of the right second metacarpal bone. Using the women with early menopause (age <49 years) as the reference group and adjusting for age, subjects with late menopause were at decreased risk for low bone mineral density (odds ratio (OR) = 0.69, 95% confidence interval (Cl) 0.49–0.97). After adjustment for additional covariates (grip strength, physical activity, body mass index, smoking, and calcium intake), the association was unchanged (OR = 0.70, 95% Cl 0.50–0.99). Postmenopausal women with more reproductive years (>40 years) were at decreased risk for low bone mineral density compared with those with fewer reproductive years, after adjustment for age (OR = 0.73, 95% Cl 0.40–1.30) and potentially confounding factors (OR = 0.76, 95% Cl 0.41–1.37); thep-value for trend was not statistically significant. In multiple linear regression analysis, early menopause and fewer reproductive years were independent predictors of low bone mineral density. In this study, postmenopausal Japanese women who had a late menopause and more reproductive years were at decreased risk for low bone mineral density, and may therefore be less prone to osteoporosis. Am J Epidemiol 1998; 148: 1055-61. [ABSTRACT FROM PUBLISHER]

Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication that can follow liver surgery or transplantation. We have investigated the involvement of the endocannabinoid system in hepatic I/R injury using an in vivo mouse model. Here we report that I/R triggers several-fold increases in the hepatic levels of the endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG), which originate from hepatocytes, Kupffer and endothelial cells. Concomitant activation of CB2 cannabinoid receptors by endocannabinoids protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNFá, MIP-1á and MIP-2 levels, and tissue expression of ICAM-1, as indicated by the increased I/R-induced tissue damage and pro-inflammatory phenotype in CB2-/-mice or following CB2 blockade in wild-type mice. We also show that the CB1 cannabinoid receptor agonist, HU-210, reduces ischemic damage by centrally mediated hypothermia, while CB1 receptor knockout mice show increased I/R-induced tissue damage and pro-inflammatory phenotype following injury. Surprisingly, in contrast to knockouts, the CB1 receptor antagonists SR141716 and AM251 show a tendency to reduce ischemic damage. These findings indicate that targeting CB2 and CB1 cannabinoid receptors may represent a novel protective strategy in hepatic I/R injury. Furthermore, CB1 antagonists might exert additional anti-inflammatory effects not mediated via CB1 receptors. [ABSTRACT FROM AUTHOR]

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.

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.

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.