Brain Apolipoprotein E: an Important Regulator of Food Intake in Rats

Cincinnati Obesity Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Diabetes (Impact Factor: 8.1). 07/2008; 57(8):2092-8. DOI: 10.2337/db08-0291
Source: PubMed


The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies.
Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied.
Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding.
These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.

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    • "These functions include antiatherogenic effects through promotion of cholesterol efflux in macrophages [2] [3], neuronal repair and synaptogenic activity [4] [5], as well as adipocyte differentiation and lipid storage in adipose tissue [6]. Interestingly, APOE is also expressed in the hypothalamus and olfactory bulb, suggesting involvement in appetite and regulation of food intake [7] [8]. "
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    ABSTRACT: ScopeOf the three human apolipoprotein E (APOE) alleles, the ε3 allele is most common, which may be a result of adaptive evolution. In this study, we investigated whether the APOE genotype affects body weight and energy metabolism through regulation of fatty acid utilization.Methods and resultsTargeted replacement mice expressing the human APOE3 were significantly heavier on low- and high-fat diets compared to APOE4 mice. Particularly on high-fat feeding, food intake and dietary energy yields as well as fat mass were increased in APOE3 mice. Fatty acid mobilization determined as activation of adipose tissue lipase and fasting plasma nonesterified fatty acid levels were significantly lower in APOE3 than APOE4 mice. APOE4 mice, in contrast, exhibited higher expression of proteins involved in fatty acid oxidation in skeletal muscle.Conclusion Our data suggest that APOE3 is associated with the potential to more efficiently harvest dietary energy and to deposit fat in adipose tissue, while APOE4 carriers tend to increase fatty acid mobilization and utilization as fuel substrates especially under high-fat intake. The different handling of dietary energy may have contributed to the evolution and worldwide distribution of the ε3 allele.
    Molecular Nutrition & Food Research 11/2014; 59(2). DOI:10.1002/mnfr.201400636 · 4.60 Impact Factor
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    • "Perhaps the most striking results were observed with ApoE, a component of plasma lipoprotein that is involved in cholesterol metabolism and lipid transport [46]. ApoE is synthesized in the hypothalamus and plays a major role in regulation of feeding behavior [47]. Our qRT-PCR analysis showed that parental adolescent binge EtOH exposure almost completely abolished ApoE mRNA expression in both the male and female F1 generation offspring (Fig. 4B). "
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    ABSTRACT: Adolescent binge alcohol exposure has long-lasting effects on the expression of hypothalamic genes that regulate the stress response, even in the absence of subsequent adult alcohol exposure. This suggests that alcohol can induce permanent gene expression changes, potentially through epigenetic modifications to specific genes. Epigenetic modifications can be transmitted to future generations therefore, and in these studies we investigated the effects of adolescent binge alcohol exposure on hypothalamic gene expression patterns in the F1 generation offspring. It has been well documented that maternal alcohol exposure during fetal development can have devastating neurological consequences. However, less is known about the consequences of maternal and/or paternal alcohol exposure outside of the gestational time frame. Here, we exposed adolescent male and female rats to a repeated binge EtOH exposure paradigm and then mated them in adulthood. Hypothalamic samples were taken from the offspring of these animals at postnatal day (PND) 7 and subjected to a genome-wide microarray analysis followed by qRT-PCR for selected genes. Importantly, the parents were not intoxicated at the time of mating and were not exposed to EtOH at any time during gestation therefore the offspring were never directly exposed to EtOH. Our results showed that the offspring of alcohol-exposed parents had significant differences compared to offspring from alcohol-naïve parents. Specifically, major differences were observed in the expression of genes that mediate neurogenesis and synaptic plasticity during neurodevelopment, genes important for directing chromatin remodeling, posttranslational modifications or transcription regulation, as well as genes involved in regulation of obesity and reproductive function. These data demonstrate that repeated binge alcohol exposure during pubertal development can potentially have detrimental effects on future offspring even in the absence of direct fetal alcohol exposure.
    PLoS ONE 02/2014; 9(2):e89320. DOI:10.1371/journal.pone.0089320 · 3.23 Impact Factor
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    • "ApoE is considered to be a major apolipoprotein for cholesterol transport and clearance in the brain18,19,20,21. The data from QT-PCR showed that apart from the liver, the peripheral tissues exhibited a low level of ApoE mRNA, which was in accordance with the fact that the liver is the primary organ for ApoE secretion29. Contrary to the low expression of ApoE mRNA in all the studied peripheral tissues except the liver, high levels of ApoE mRNA were found in the hippocampus and cerebral cortex. "
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    ABSTRACT: Diabetes is associated with elevated serum total cholesterol level and disrupted lipoprotein subfractions. The aim of this study was to examine alterations in the tissue cholesterol contents closely related to diabetic complications. Intraperitoneal injection of streptozotocin was used to induce type 1 diabetes in adult male Sprague-Dawley rats. On d 35 after the injection, liver, heart, intestine, kidney, pancreas, cerebral cortex and hippocampus were isolated from the rats. The content of total and free cholesterol in the tissues was determined using HPLC. The ATP-binding cassette protein A1 (ABCA1) protein and ApoE mRNA were measured using Western blot and QT-PCR analyses, respectively. In diabetic rats, the level of free cholesterol was significantly decreased in the peripheral tissues, but significantly elevated in hippocampus, as compared with those in the control rats. Diabetic rats showed a trend of decreasing the total cholesterol level in the peripheral tissues, but significant change was only found in kidney and liver. In diabetic rats, the level of the ABCA1 protein was significantly increased in the peripheral tissues and cerebral cortex; the expression of ApoE mRNA was slightly decreased in hippocampus and cerebral cortex, but the change had no statistical significance. Type 1 diabetes decreases the free cholesterol content in the peripheral tissues and increases the free cholesterol content in hippocampus. The decreased free cholesterol level in the peripheral tissues may be partly due to the increased expression of the ABCA1 protein.
    Acta Pharmacologica Sinica 06/2012; 33(7):909-17. DOI:10.1038/aps.2012.50 · 2.91 Impact Factor
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