Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?

Harrold, Joanne A.; Elliott, Joanne; King, Peter; Widdowson, Peter; Williams, Gareth

doi:10.1016/s0006-8993(02)03245-6

Cited by 124 publications

(91 citation statements)

References 27 publications

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“…Since leptin production is elevated following chronic unpredictable stress (Gamaro et al, 2003), it is possible that increased leptin levels could be driving the decrease in eCB content in the hippocampus seen in this study. It is interesting in light of this argument that rats given free access to a highly palatable food for 10 weeks, which significantly elevates plasma leptin concentrations, exhibit a 30-50% decrease in CB 1 receptor density in the hippocampus (Harrold et al, 2002). It is also possible that changes in other neurotransmitter systems could be mediating the changes in eCB levels; however, due to the fact that stress stimulates excitatory transmission in the hippocampus (McEwen and Magarinos, 1997), one would actually expect an increase and not a decrease in eCB levels (Stella et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Hill

Patel

Carrier

et al. 2004

Neuropsychopharmacol

312

219

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Deficits in cognitive functioning and flexibility are seen following both chronic stress and modulation of endogenous cannabinoid (eCB) signaling. Here, we investigated whether alterations in eCB signaling might contribute to the cognitive impairments induced by chronic stress. Chronic stress impaired reversal learning and induced perseveratory behavior in the Morris water maze without significant effect on task acquisition. These cognitive impairments were reversed by exogenous cannabinoid administration, suggesting deficient eCB signaling underlies these phenomena. In line with this hypothesis, chronic stress downregulated CB 1 receptor expression and significantly reduced the content of the endocannabinoid 2-arachidonylglycerol within the hippocampus. CB 1 receptor density and 2-arachidonylglycerol content were unaffected in the limbic forebrain. These data suggest that stress-induced downregulation of hippocampal eCB signaling contributes to problems in behavioral flexibility and could play a role in the development of perseveratory and ruminatory behaviors in stress-related neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Hill

Patel

Carrier

et al. 2004

Neuropsychopharmacol

312

219

View full text Add to dashboard Cite

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“…16 By acting in these neural circuits, endocannabinoids may drive the appetite for palatable food as suggested in recent animal studies. 33 An experimental study of the treatment of dietinduced obesity in animals recently demonstrated the antiobesity effect of the specific CB1 receptor antagonist, SR141716A, that blocks endocannabinoid activation of CB1 receptors, and this strategy appears to have potential in humans as an obesity treatment. 34 In a previous study, we showed that the FAAH 385 A/A missense polymorphism was very significantly associated with problem drug use and abuse but not alcohol or tobacco abuse.…”

Section: Discussionmentioning

confidence: 99%

Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH)

et al. 2005

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BACKGROUND: The brain endogenous cannabinoid system modulates reward and craving pathways and consequently may affect body weight. A naturally occurring missense polymorphism in the gene encoding fatty acid amide hydrolase (FAAH), the primary enzyme for inactivation of endocannabinoids, is associated with problem drug use. AIMS: To investigate the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. SUBJECTS: A total of 2667 subjects of white, black and Asian ancestry were genotyped and stratified by a standardized clinicbased assessment of body mass index (BMI, weight in kilograms/(height in meters) 2 or kg/m 2 ). METHODS: Subjects were genotyped for the FAAH cDNA 385 C-A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements and World Health Organization ranges were used to stratify subjects. Statistical methods included the Fisher exact test, Mann-Whitney U-test and multivariable logistic regression analysis. RESULTS: The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P ¼ 0.005) and in black subjects (P ¼ 0.05) but not in a small group of Asians. The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared to heterozygote and wild-type groups (P ¼ 0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P ¼ 0.02) and obese (P ¼ 0.006) with the same trend in black subjects. CONCLUSIONS: These results suggest a role for the FAAH 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.

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“…26 In rats, a high-fat dietinduced downregulation of CB1 receptors, interpreted to indicate increased endocannabinoid activity, was detected in several regions of the limbic forebrain including the nucleus accumbens, but not in the hypothalamus. 35 Additionally, cannabinoids can increase the intake of palatable foodsby acting at sites in the brainstem, 36 which are known to have reciprocal neural connections with forebrain limbic structures. 37 The adipocyte-derived hormone leptin suppresses appetite indirectly by increasing the expression of anorexigenic mediators, such as alpha-MSH 38 and decreasing the expression of orexigenic factors, such as neuropeptide Y.…”

Section: Endocannabinoid Regulation Of Appetitive Behaviormentioning

confidence: 99%

The role of the endocannabinoid system in the control of energy homeostasis

et al. 2006

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The endocannabinoid system has recently emerged as an important regulator of energy homeostasis, involved in the control of both appetite and peripheral fat metabolism. We briefly review current understanding of the possible sites of action and cellular mechanisms involved in the central appetitive and peripheral metabolic effects of endocannabinoids. Studies in our laboratory, using leptin-deficient obese rodents and CB1 cannabinoid receptor (CB1)-deficient mice, have indicated that endocannabinoids acting via CB1 are involved in the hunger-induced increase in food intake and are negatively regulated by leptin in brain areas involved in appetite control, including the hypothalamus, limbic forebrain and amygdala. CB1 À/À mice are lean and are resistant to diet-induced obesity (DIO) despite similar energy intake to wild-type mice with DIO, suggesting that CB1 regulation of body weight involves additional peripheral targets. Such targets appear to include both adipose tissue and the liver. CB1 expressed in adipocytes has been implicated in the control of adiponectin secretion and lipoprotein lipase activity. Recent findings indicate that both endocannabinoids and CB1 are present in the liver and are upregulated in DIO. CB1 stimulation increases de novo hepatic lipogenesis through activation of the fatty acid biosynthetic pathway. Components of this pathway are also expressed in the hypothalamus where they have been implicated in the regulation of appetite. The fatty acid biosynthetic pathway may thus represent a common molecular target for the central appetitive and peripheral metabolic effects of endocannabinoids.

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Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?

Cited by 124 publications

References 27 publications

Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Downregulation of Endocannabinoid Signaling in the Hippocampus Following Chronic Unpredictable Stress

Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH)

The role of the endocannabinoid system in the control of energy homeostasis

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