Role of neuropeptide Y and proopiomelanocortin in fluoxetine-induced anorexia

Laboratory in Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764, Korea.
Archives of Pharmacal Research (Impact Factor: 2.05). 07/2005; 28(6):716-21. DOI: 10.1007/BF02969363
Source: PubMed


Fluoxetine is an anorexic agent known to reduce food intake and weight gain. However, the molecular mechanism by which fluoxetine induces anorexia has not been well-established. We examined mRNA expression levels of neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the brain regions of rats using RT-PCR and in situ hybridization techniques after 2 weeks of administering fluoxetine daily. Fluoxetine persistently suppressed food intake and weight gain during the experimental period. The pair-fed group confirmed that the reduction in body weight in the fluoxetine treated rats resulted primarily from decreased food intake. RT-PCR analyses showed that mRNA expression levels of both NPY and POMC were markedly reduced by fluoxetine treatment in all parts of the brain examined, including the hypothalamus. POMC mRNA in situ signals were significantly decreased, NPY levels tended to increase in the arcuate nucleus (ARC) of fluoxetine treated rats (compared to the vehicle controls). In the pair-fed group, NPY mRNA levels did not change, but the POMC levels decreased (compared with the vehicle controls). These results reveal that the chronic administration of fluoxetine decreases expression levels in both NPY and POMC in the brain, and suggests that fluoxetine-induced anorexia may not be mediated by changes in the ARC expression of either NPY or POMC. It is possible that a fluoxetine raised level of 5-HT play an inhibitory role in the orectic action caused by a reduced expression of ARC POMC (alpha-MSH).

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    • "It is well known that 5-HT plays an inhibitory role in the control of ingestive behavior, and that the administration of fluoxetine suppresses food intake and weight gain under free-feeding and food-restricted conditions [58]. In addition, it has been shown that fluoxetine reduces mRNA expression levels of Npy in rat brain [59]. Feeding behavior is also regulated by npy in zebrafish (Fig. 2D). "
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    ABSTRACT: The increasing number of people suffering from metabolic syndrome and obesity is becoming a serious problem not only in developed countries, but also in developing countries. However, there are few agents currently approved for the treatment of obesity. Those that are available are mainly appetite suppressants and gastrointestinal fat blockers. We have developed a simple and rapid method for the measurement of the feeding volume of Danio rerio (zebrafish). This assay can be used to screen appetite suppressants and enhancers. In this study, zebrafish were fed viable paramecia that were fluorescently-labeled, and feeding volume was measured using a 96-well microplate reader. Gene expression analysis of brain-derived neurotrophic factor (bdnf), knockdown of appetite-regulating genes (neuropeptide Y, preproinsulin, melanocortin 4 receptor, agouti related protein, and cannabinoid receptor 1), and the administration of clinical appetite suppressants (fluoxetine, sibutramine, mazindol, phentermine, and rimonabant) revealed the similarity among mechanisms regulating appetite in zebrafish and mammals. In combination with behavioral analysis, we were able to evaluate adverse effects on locomotor activities from gene knockdown and chemical treatments. In conclusion, we have developed an assay that uses zebrafish, which can be applied to high-throughput screening and target gene discovery for appetite suppressants and enhancers.
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    • "Rats in each cage were assigned together either for fluoxetine or for vehicle, randomly. The chronic dosage of fluoxetine used in this study significantly suppressed food intake in adult rats (Myung et al., 2005), and was proved to maintain the serum fluoxetine levels corresponding to an effective therapeutic dose for depressed patients (Dulawa et al., 2004). "
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    ABSTRACT: This study was conducted to examine if fluoxetine, a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor, would reverse adverse behavioral effects of neonatal maternal separation in female rats. Sprague-Dawley pups were separated from dam daily for 3h during postnatal day (PND) 1-14 (maternal separation; MS) or left undisturbed (non-handled; NH). Female NH and MS pups received intraperitoneal injection of fluoxetine (10mg/kg) or vehicle daily from PND 35 until the end of the whole experimental period. Rats were either subjected to behavioral tests during PND 44-54, or sacrificed for neurochemical analyses during PND 43-45. Daily food intake and weight gain of both NH and MS pups were suppressed by fluoxetine, with greater effects in MS pups. MS experience increased immobility and decrease swimming in forced swim test. Swimming was increased, although immobility was not significantly decreased, in MS females by adolescence fluoxetine. However, adolescence fluoxetine increased immobility during forced swim test and decreased time spent in open arms during elevated plus maze test in NH females. Fluoxetine normalized MS-induced decrease of the raphe 5-HT levels and increased 5-HT metabolism in the hippocampus in MS females, and increased the hypothalamic 5-HT both in NH and MS. Fluoxetine decreased the raphe 5-HT and increased the plasma corticosterone in NH females. Results suggest that decreased 5-HTergic activity in the raphe nucleus is implicated in the pathophysiology of depression-like behaviors, and increased 5-HTergic activities in the raphe-hippocampus axis may be a part of anti-depressant efficacy of fluoxetine, in MS females. Also, an extra-hypothalamic 5-HTergic activity may contribute to the increased anorectic efficacy of fluoxetine in MS females. Additionally, decreased 5-HT in the raphe and elevated plasma corticosterone may be related with fluoxetine-induced depression- and/or anxiety-like behaviors in NH females.
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    • "However, 5-HTP injections did not increase the expression of proopiomelanocortin (POMC), functional precursor of α-MSH, in the arcuate nucleus (our unpublished observation). We have previously reported that the arcuate POMC expression is decreased by chronic treatment with selective 5-HT reuptake inhibitor fluoxetine known to increase the brain 5-HT level (Myung et al., 2005). Thus, it is concluded that the increased pERK1/2 in the PVN of 5-HTP injected rats is less likely due to an activation of melanocortin pathways. "
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