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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    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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    Acta Pharmacologica Sinica 06/2012; 33(7):909-17. DOI:10.1038/aps.2012.50 · 2.91 Impact Factor
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