Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When rats are given access to a running-wheel in combination with food restriction, they will become hyperactive and decrease their food intake, a paradoxical phenomenon known as activity-based anorexia (ABA). Little is known about the regulation of the hypothalamic neuropeptides that are involved in the regulation of food intake and energy balance during the development of ABA. Therefore, rats were killed during the development of ABA, before they entered a state of severe starvation. Neuropeptide mRNA expression levels were analysed using quantitative real-time PCR on punches of separate hypothalamic nuclei. As is expected in a state of negative energy balance, expression levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) were increased 5-fold in the arcuate nucleus (ARC) of food-restricted running ABA rats vs 2-fold in sedentary food-restricted controls. The co-regulated expression of AgRP and NPY strongly correlated with relative body weight and white adipose tissue mass. Arcuate expression of pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) was reduced 2-fold in the ABA group. In second-order neurons of the lateral hypothalamic area (LHA), melanin-concentrating hormone (MCH) mRNA expression was upregulated 2-fold in food-restricted running rats, but not in food-restricted sedentary controls. Prepro-orexin, CART and corticotropin-releasing hormone expression levels in the LHA and the paraventricular nucleus (PVN) were unchanged in both food-restricted groups. From this study it was concluded that during the development of ABA, neuropeptides in first-order neurons in the ARC and MCH in the LHA are regulated in an adequate response to negative energy balance, whereas expression levels of the other studied neuropeptides in secondary neurons of the LHA and PVN are unchanged and are probably regulated by factors other than energy status alone.
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PMID:Hypothalamic neuropeptide expression following chronic food restriction in sedentary and wheel-running rats. 1621 17

Hypothalamic neurons that express neuropeptide Y (NPY) and agouti-related protein (AgRP) are thought to be critical regulators of feeding behavior and body weight. To determine whether NPY/AgRP neurons are essential in mice, we targeted the human diphtheria toxin receptor to the Agrp locus, which allows temporally controlled ablation of NPY/AgRP neurons to occur after an injection of diphtheria toxin. Neonatal ablation of NPY/AgRP neurons had minimal effects on feeding, whereas their ablation in adults caused rapid starvation. These results suggest that network-based compensatory mechanisms can develop after the ablation of NPY/AgRP neurons in neonates but do not readily occur when these neurons become essential in adults.
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PMID:NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. 1625 86

This paper discusses the hypothesis that a 'drive for activity" in the presence of physiological and endocrine changes consistent with starvation is a characteristic symptom of acute anorexia nervosa (AN). This 'drive for movement', along with alertness and lack of fatigue, so unlike the motor slowing and loss of energy observed in simple starvation has been recognized in AN throughout history, but has received little attention in the past fifty years. Clinical reports and experimental evidence suggest that 'restlessness' and a 'drive for activity' vary in intensity, they appears to be starvation-dependent and to wane with food intake. Central nervous system (CNS) systems known to be involved in mediating activity and arousal levels that are altered by the negative energy expenditure in AN are reviewed. Among these, the corticotropin-releasing hormone (CRH) system, the melanocyte stimulating hormone/agouti-related protein (MSH/AGRP) system and the norepinephrine/epinephrine (NE/EPI) and dopamine (DA) system may contribute to the 'drive for activity' and alertness in AN. AN appears to represent a disorder of gene/environment interaction. Future research will reveal whether in individuals predisposed to AN, the 'drive for activity' reflects the reactivation of mechanisms important in food scarcity, controlled by one or more evolutionary conserved genes including those regulating foraging behavior. Recognition of the 'drive for activity' as a diagnostic symptom of AN and its assessment prior to re-nutrition would permit clarification of its role in the etiology of AN.
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PMID:The 'drive for activity' and "restlessness" in anorexia nervosa: potential pathways. 1644 3

Dmbx1 is a paired-class homeodomain transcription factor. We show here that mice deficient in Dmbx1 exhibit severe leanness associated with hypophagia and hyperactivity and that isolation of a Dmbx1(-/-) mouse from its cohabitants induces self-starvation, sometimes leading to death, features similar to those of anorexia nervosa in humans. Interestingly, overexpression of agouti in Dmbx1(-/-) mice failed to induce aspects of the A(y)/a phenotype, including hyperphagia, obesity, and diabetes mellitus. In Dmbx1(-/-) mice, administration of agouti-related protein increased cumulative food intake for the initial 6 h but significantly decreased it over 24- and 48-h periods. In addition, Dmbx1 was shown to be expressed at embryonic day 15.5 in the lateral parabrachial nucleus, the rostral nucleus of the tractus solitarius, the dorsal motor nucleus of the vagus, and the reticular nucleus in the brainstem, all of which receive melanocortin signaling, indicating involvement of Dmbx1 in the development of the neural network for the signaling. Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior.
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PMID:Dmbx1 is essential in agouti-related protein action. 1787 59

Hypothalamic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY) are thought to be important for regulation of feeding, especially under conditions of negative energy balance. The expression of NPY and AgRP increases during lactation and may promote the hyperphagia that ensues. We explored the role of AgRP neurons in reproduction and lactation, using a mouse model in which AgRP-expressing neurons were selectively ablated by the action of diphtheria toxin. We show that ablation of AgRP neurons in neonatal mice does not interfere with pregnancy, parturition, or lactation, suggesting that early ablation allows compensatory mechanisms to become established. However, ablation of AgRP neurons after lactation commences results in rapid starvation, indicating that both basal feeding and lactation-induced hyperphagia become dependent on AgRP neurons in adulthood. We also show that constitutive inactivation of Npy and Agrp genes does not prevent pregnancy or lactation, nor does it protect lactating dams from diphtheria toxin-induced starvation.
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PMID:Role of agouti-related protein-expressing neurons in lactation. 1797 21

Agouti-related protein (AgRP) is a key orexigenic neuropeptide expressed in the hypothalamic arcuate nucleus and a marker for neurons conveying hormonal signals of hunger to the brain. Mice homozygous for the anorexia (anx) mutation are characterized by decreased food intake, starvation, and death by 3-5 weeks of age. At this stage immunoreactivity for AgRP is increased in cell bodies but decreased in the nerve terminals. We studied when during early postnatal development the aberrant phenotype of the AgRP system becomes apparent in anx/anx mice and possible underlying mechanisms. AgRP and ionized calcium binding adapter molecule (Iba1), a marker for activated microglia, as well as Toll-like receptor 2 (TLR-2), were studied by immunohistochemistry at postnatal days P1, P5, P10, P12, P15 and P21 in anx/anx and wild-type mice. We found that the AgRP system in the anx/anx mouse develops similarly to the wild type until P12, when AgRP fibers in anx/anx mice cease to increase in density in the main projection areas. At P21, AgRP fiber density in anx/anx mice was significantly reduced vs. P15, in certain regions. At P21, many strongly AgRP-positive cell bodies were observed in the anx/anx arcuate nucleus vs. only few and weakly fluorescent ones in the wild type. The decrease in AgRP fiber density in anx/anx mice overlapped with an increase in Iba1 and TLR-2 immunoreactivities. Thus, the aberrant appearance of the AgRP system in the anx/anx mouse in the early postnatal development could involve a microglia-associated process and the innate immune system.
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PMID:Aberrant agouti-related protein system in the hypothalamus of the anx/anx mouse is associated with activation of microglia. 1809 36

Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize gamma-amino-butyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A(y)/a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A(y)/a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.
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PMID:Starvation after AgRP neuron ablation is independent of melanocortin signaling. 1827 80

We used microarray and quantitative real-time PCR (qRT-PCR) analyses in adult female zebrafish (Danio rerio) to identify metabolic pathways regulated by starvation in the liver and brain. The transcriptome of whole zebrafish brain showed little response to 21 days of starvation. Only agouti-related protein 1 (agrp1) significantly responded, with increased expression in brains of starved fish. In contrast, a 21-day period of starvation significantly downregulated 466 and upregulated 108 transcripts in the liver, indicating an overall decrease in metabolic activity, reduced lipid metabolism, protein biosynthesis, proteolysis, and cellular respiration, and increased gluconeogenesis. Starvation also regulated expression of many components of the unfolded protein response, the first such report in a species other than yeast (Saccharomyces cerevisiae) and mice (Mus musculus). The response of the zebrafish hepatic transcriptome to starvation was strikingly similar to that of rainbow trout (Oncorhynchus mykiss) and less similar to mouse, while the response of common carp (Cyprinus carpio) differed considerably from the other three species.
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PMID:Effect of starvation on transcriptomes of brain and liver in adult female zebrafish (Danio rerio). 1872 27

We have developed a mouse model in which a specific population of inhibitory neurons can be selectively ablated by the action of diphtheria toxin (DT). The model involves targeting the human DT receptor to the agouti-related protein (Agrp) locus so that systemic administration of DT kills all of the AgRP-expressing neurons, resulting in starvation of the mice. Ablation of AgRP neurons results in robust (5- to 10-fold) activation of Fos gene expression in many brain regions that are innervated by AgRP neurons, including the arcuate nucleus (ARC), the paraventricular nucleus, the medial preoptic area, the lateral septum, and nucleus of the solitary tract. As expected, there is robust increase in GFAP staining (astrocytes) as well as IBA1 and CD11b staining (microglia) in the ARC in response to AgRP neuron ablation. There is also a dramatic increase of these markers in most, but not all, postsynaptic targets of AgRP axons. We used a genetic approach to reduce melanocortin signaling, which attenuated Fos activation in some brain regions after ablation of AgRP neurons. We suggest that loss of inhibitory signaling onto target neurons results in unopposed excitation that is responsible for the activation of Fos and that dysregulation of these neuronal circuits is responsible for starvation. Furthermore, glial cell activation in target areas of AgRP neurons appears to be a result of excitotoxicity.
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PMID:Ablation of neurons expressing agouti-related protein activates fos and gliosis in postsynaptic target regions. 1878 2

Ghrelin is a 28 amino acid acylated peptide originally characterised for its capacity to stimulate growth hormone secretion. Ghrelin is also an orexigenic and adipogenic hormone and is thought to be a signal to increase locomotor activity in anticipation of a scheduled meal. Although ghrelin is considered to be up-regulated during fasting, there are still conflicting data regarding the impact of starvation on ghrelin secretion. To test whether the secretory pattern of acylated ghrelin is altered during fasting, plasma levels were monitored every 20 min for 6 h in freely-behaving rats at the light/dark cycle transition, when animals initiate feeding and activity and use preferentially free fatty acids (FFA) as a source of energy. Rats were fed ad lib. or fasted at dark onset for 24, 48 or 72 h, with or without refeeding rate. The anticipatory rise in ghrelin levels, as well as home-cage activity at the onset of darkness, was significantly reduced from 48 h of fasting compared to ad lib. conditions. A delayed ghrelin peak, sensitive to renutrition, was observed in fasted animals. Although their motivation to eat appeared to be intact, rats fasted for 72 h showed the smallest compensatory refeeding rate after fasting, possibly reflecting altered gut function. Expression of agouti-related protein and neuropeptide Y, was significantly increased in 48- and 72-h fasted animals. Thus, following fasting, a blunted acylated ghrelin secretion at dark onset (i.e. a period when animals depend on FFA as a source of energy) is associated with reduced locomotor activity and refeeding and an up-regulation of anabolic neuropeptides. Such changes could be interpreted as compensatory mechanisms for helping to conserve energy under conditions where food is not available.
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PMID:Meal anticipatory rise in acylated ghrelin at dark onset is blunted after long-term fasting in rats. 2172 14


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