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Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol.

ABSTRACT: Endocannabinoids are implicated in appetite and body weight regulation. In rodents, anandamide stimulates eating by actions at central CB1 receptors, and hypothalamic endocannabinoids may be under the negative control of leptin. However, changes to brain endocannabinoid levels in direct relation to feeding or changing nutritional status have not been investigated. We measured anandamide and 2-arachidonoyl glycerol (2-AG) levels in feeding-associated brain regions of rats, during fasting, feeding of a palatable food, or after satiation. Endocannabinoid levels were compared to those in rats fed ad libitum, at a point in their daily cycle when motivation to eat was absent. Fasting increased levels of anandamide and 2-AG in the limbic forebrain and, to a lesser extent, of 2-AG in the hypothalamus. By contrast, hypothalamic 2-AG declined as animals ate. No changes were detected in satiated rats. Endocannabinoid levels in the cerebellum, a control region not directly involved in the control of food intake, were unaffected by any manipulation. As 2-AG was most sensitive to variation during feeding, and to leptin regulation in a previous study, we examined the behavioural effects of 2-AG when injected into the nucleus accumbens shell, a limbic forebrain area strongly linked to eating motivation. 2-AG potently, and dose-dependently, stimulated feeding. This effect was attenuated by the CB1 receptor antagonist SR141716. These findings provide the first direct evidence of altered brain levels of endocannabinoids, and of 2-AG in particular, during fasting and feeding. The nature of these effects supports a role for endocannabinoids in the control of appetitive motivation.

SUBMITTER: Kirkham TC

PROVIDER: S-EPMC1573386 | biostudies-other | 2002 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundThe hypothalamus plays a central role in regulating appetite and metabolism. However, the gene networks within the hypothalamus that regulate feed intake and metabolism, and the effects of fasting on those pathways are not completely understood in any species. The present experiment evaluated global hypothalamic gene expression in newly hatched chicks using microarray analysis to elucidate genes and pathways regulated by feeding, fasting, and delayed feeding. Ten groups of chicks were sampled over four days post-hatch, including fed, fasted, and 48 h fasted followed by access to feed for 4 h, 24 h, and 48 h. Hypothalamic samples were collected for microarray analysis (n = 4). Expression patterns of selected genes were confirmed by quantitative real-time PCR. Pathway analysis of the microarray results predicted a network of genes involved in neuropeptide or neurotransmitter signaling. To confirm the functionality of this predicted gene network, hypothalamic neurons from fed and fasted chicks were isolated and cultured in the presence of neuropeptide Y, somatostatin, alpha-melanocyte stimulating hormone, norepinephrine, and L-phospho-serine. Results confirmed functional relationships among members of the predicted gene network. Moreover, the effects observed were dependent upon the nutritional state of the animals (fed vs. fasted).ResultsDifferences in gene expression (> or = 1.6 fold) were detected in 1,272 genes between treatments, and of those, 119 genes were significantly (P < 0.05) different. Pathway Miner analysis revealed that six genes (SSTR5, NPY5R, POMC, ADRB2, GRM8, and RLN3) were associated within a gene network. In vitro experiments with primary hypothalamic neurons confirmed that receptor agonists involved in this network regulated expression of other genes in the predicted network, and this regulation within the network was influenced by the nutritional status and age of the chick.ConclusionsMicroarray analysis of the hypothalamus during different nutritional states revealed that many genes are differentially regulated. We found that functional interactions exist among six differentially regulated genes associated within a putative gene network from this experiment. Considering that POMC, an important gene in controlling metabolism, was central to this network, this gene network may play an important role in regulation of feeding and metabolism in birds.

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Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol.

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