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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabis exerts its actions by mimicking 'endocannabinoid' neuromodulators at CB1 receptors in brain and peripheral tissues. The endocannabinoids both stimulate appetite by increasing food craving and enjoyment and promote the deposition of energy as fat in adipose tissues. These findings have raised the possibility of CB1 antagonists as a novel class of anti-obesity agents.
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PMID:Endocannabinoids and the neurochemistry of gluttony. 1862 29

In the Western world, consumption of soft drinks has increased the last three decades and is partly responsible for the epidemic-like increase in obesity. Soft drinks, originally sweetened by sucrose, are now sweetened by other caloric sweeteners, such as fructose. In this study, we investigated the short-term effect of sucrose, glucose or fructose solutions on food intake and body weight in rats, and on peripheral and central appetite signals. Rats received water containing either of the sugars and standard rat chow for two weeks. Rats receiving water alone and standard chow were controls. All rats offered the sugar solutions increased their total caloric intake. The increased caloric intake occurred despite the fact that the rats offered either of the sugar solutions consumed less chow. As a consequence of the increased caloric intake, the sugar-drinking rats had elevated serum levels of free fatty acids, triglycerides and cholesterol. In addition, consuming sugar solutions resulted in increased serum leptin, decreased serum PYY and down-regulated hypothalamic NPY mRNA. Serum ghrelin was increased in rats receiving fructose solution. Moreover, consumption of sucrose or fructose solution resulted in up-regulated hypothalamic CB1 mRNA. Hypothalamic POMC mRNA was down-regulated in rats receiving glucose or fructose. In conclusion, consumption of glucose, sucrose or fructose solution results in caloric overconsumption and body weight gain through activation of hunger signals and depression of satiety signals as well as activation of reward components. The weight-promoting effect of these sugar solutions may possibly be ameliorated by the down-regulation of NPY mRNA and increased serum leptin.
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PMID:Effects of sucrose, glucose and fructose on peripheral and central appetite signals. 1862 77

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.
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PMID:Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. 1902 4

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.
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PMID:Endocannabinoids and the control of energy homeostasis. 1869 38

Cardiometabolic risk factors affect more than 47 million adults in the United States today. Although certain risk factors (e.g., obesity, dyslipidemia, hypertension, and hyperglycemia) contribute independently to the global risk, dyslipidemia is one of the most important risk factors for cardiovascular disease. Successful treatment requires a well-coordinated multifaceted approach, with commitment to a long-term program for disease management. Although initial attempts should focus on dietary changes and increased physical activity, most patients also need effective, safe, and well-monitored pharmacotherapy. Experimental studies have shown that overactivation of the endocannabinoid system-a physiologic signaling system involved in regulating energy intake, fatty acid synthesis and storage, and glucose and lipid metabolism-is associated with obesity, dyslipidemia, and insulin resistance. In clinical trials, selective blockade of CB1 receptors has resulted in substantial weight loss and significant improvement in lipid profiles. The effects of rimonabant, the first selective CB1 receptor blocker, were evaluated in 6600 obese or overweight adults who participated in one of 4 multicenter, placebo-controlled, randomized clinical trials for at least 1 year. Significant improvement in lipid profiles (specifically HDL and triglyceride levels and ratio of total cholesterol to HDL cholesterol) was seen in the 2503 patients taking rimonabant 20 mg/day, independent of its substantial effects on weight loss. No significant changes in LDL or total cholesterol were observed. Results of clinical trials with rimonabant are promising. Additional long-term controlled studies with appropriate follow-up are warranted to confirm the clinical potential of this drug, particularly its effects on dyslipidemia and other cardiovascular endpoints.
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PMID:The endocannabinoid system and cardiometabolic risk: effects of CB1 receptor blockade on lipid metabolism. 1871 60

We developed a high-throughput approach to knockout (KO) and phenotype mouse orthologs of the 5,000 potential drug targets in the human genome. As part of the phenotypic screen, dual-energy X-ray absorptiometry (DXA) technology estimates body-fat stores in eight KO and four wild-type (WT) littermate chow-fed mice from each line. Normalized % body fat (nBF) (mean KO % body fat/mean WT littermate % body fat) values from the first 2322 lines with viable KO mice at 14 weeks of age showed a normal distribution. We chose to determine how well this screen identifies body-fat phenotypes by selecting 13 of these 2322 KO lines to serve as benchmarks based on their published lean or obese phenotype on a chow diet. The nBF values for the eight benchmark KO lines with a lean phenotype were > or =1 s.d. below the mean for seven (perilipin, SCD1, CB1, MCH1R, PTP1B, GPAT1, PIP5K2B) but close to the mean for NPY Y4R. The nBF values for the five benchmark KO lines with an obese phenotype were >2 s.d. above the mean for four (MC4R, MC3R, BRS3, translin) but close to the mean for 5HT2cR. This screen also identifies novel body-fat phenotypes as exemplified by the obese kinase suppressor of ras 2 (KSR2) KO mice. These body-fat phenotypes were confirmed upon studying additional cohorts of mice for KSR2 and all 13 benchmark KO lines. This simple and cost-effective screen appears capable of identifying genes with a role in regulating mammalian body fat.
Obesity (Silver Spring) 2008 Oct
PMID:High-throughput screening of mouse knockout lines identifies true lean and obese phenotypes. 1871 66

The discovery of cannabinoids, with the well-known stimulatory effect of Cannabis sativa on appetite, has offered a new drug target for obesity treatment. Cannabinoids act on two different receptors: CB1 receptors which are sited in the brain and many peripheral tissues, and CB2 receptors which are primarily found in immune system cells. Cannabinoid receptor antagonists act centrally by blocking CB1 receptors, thereby reducing food intake. Moreover, they probably also act peripherally by increasing thermogenesis and therefore energy expenditure, as has been suggested by animal experiments. Despite these promising mechanisms of action, recent clinical studies examining the effect of the two CB1 receptor antagonists rimonabant and taranabant showed that the attained weight loss did not exceed that attained with other currently approved anti-obesity medications. Moreover, potentially severe psychiatric adverse effects limit their clinical use. As several new CB1 receptor antagonists are presently undergoing development, it remains to be elucidated to what extent they differ in terms of efficacy and safety. This review primarily discusses how close cannabinoid receptor antagonists are to the ideal anti-obesity drug, with respect to their mechanisms of action, clinical effectiveness and safety.
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PMID:A critical review of the cannabinoid receptor as a drug target for obesity management. 1872 Dec 31

The cannabinoid CB1 receptor has been implicated in the regulation of appetite and the consumption of palatable foods. This experiment aimed to explore the involvement of the CB1 receptor in the early and late stages of high fat diet-induced obesity in C57BL/6 mice. The C57Bl/6 mice were placed on a high fat (HF) or low fat/high carbohydrate (LF) diet for 3 or 20 weeks. Quantitative autoradiography revealed that binding of [3H] CP-55,940 (CB1 receptor ligand) was elevated following 3 weeks of HF feeding in areas including the medial/ventral anterior olfactory nucleus (22.1%), agranular insular cortex (24.0%) and the hypothalamus (31.5%) compared to LF controls. This increased level of binding was correlated with an increase in plasma leptin in the hypothalamus, raising the possibility that this hormone may exert inhibitory control over endocannabinoid signalling at this stage of obesity. Mice fed a HF diet for 20 weeks were obese, hyperphagic and had decreased CB1 receptor binding levels in the substantia nigra (12.8%) and ventral tegmental area (17.1%) compared to LF controls. The low [3H] CP-55,940 binding density seen in these reward-related areas in the late stage of obesity may be indicative of increased endocannabinoid release due to the chronic HF diet consumption.
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PMID:Temporal and site-specific brain alterations in CB1 receptor binding in high fat diet-induced obesity in C57Bl/6 mice. 1875 50

The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, therefore drugs interfering with this overactivation by blocking CB1 receptor are considered as valuable candidates for the treatment of obesity and related cardiometabolic risk factors.
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PMID:[Endocannabinoid system and energy metabolism: physiology and pathophysiology]. 1877 54

This experiment reports on the ability of rimonabant to alter the reinforcing properties of food in the genetically obese Zucker (fa/fa) rat, a strain that exhibits higher levels of endocannabinoids in brain regions that correspond to heightened food intake. We characterized food reinforcement in obese and lean Zucker rats by placing behavior under progressive ratio schedules of sucrose reinforcement. Then, doses of rimonabant (1-10 mg/kg), a CB1 receptor antagonist, were administered. Obese Zuckers had slightly higher breakpoints for sucrose under baseline conditions compared with leans, and also demonstrated significantly higher response rates than leans. Rimonabant dose-dependently decreased breakpoints and response rates for both groups, though only obese Zuckers demonstrated suppressed behavior under the 1 mg/kg dose. The 10 mg/kg dose of rimonabant reduced breakpoints equally for both groups (by about 60%). This dose of rimonabant also reduced food intake by 20% in lean Zuckers, and by 30% in obese Zuckers. These findings extend the literature that rimonabant reduces food reinforcer efficacy, and suggest that obese Zuckers may exhibit a heightened sensitivity to rimonabant. The findings also suggest that the effort required to obtain food reinforcement may also play a role in the efficacy of rimonabant.
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PMID:Effects of rimonabant on behavior maintained by progressive ratio schedules of sucrose reinforcement in obese Zucker (fa/fa) rats. 1879 50


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