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: 8.47). 07/2008; 57(8):2092-8. DOI: 10.2337/db08-0291
Source: PubMed

ABSTRACT 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 · 4.91 Impact Factor
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    • "Recently, we demonstrated that apoE acts as a satiation factor in the hypothalamus. Intracerebroventricular (icv) administration of apoE significantly decreased food intake without causing malaise, whereas icv infusion of apoE antibody stimulated feeding, implying that endogenous apoE reduces food intake (Shen et al., 2008). One of the mechanisms mediating apoE's anorectic action in the hypothalamus is increased PI3K/Akt signaling, which is the same signaling pathway activated by insulin (Niswender et al., 2003). "
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    ABSTRACT: Cerebrospinal fluid (CSF) provides an invaluable analytical window to the central nervous system (CNS) because it reflects the dynamically changing complement of CNS constituents. We describe an improved method for sampling CSF in rats that is easy to perform. It has a 96% success rate of CSF collection and consistently yields large volumes (150-200 μl) of CSF. The blood contamination rate is also low (6%) as determined by both visual inspection and the lack of molecular detection of apolipoprotein B, a plasma-derived protein, which is absent in the CNS. This improved method of CSF sampling can have broad applicability in physiological and pharmacological evaluation for diverse CNS targets. We used this technique to provide proof of principle by examining the effect of intraperitoneal insulin on the level of apolipoprotein E (apoE) in the CSF. Insulin (0.5 and 1 U/kg) led to a significant increase of insulin in both plasma and CSF at 2 h after intraperitoneal administration and decreased blood glucose for at least 2h. ApoE concentrations in CSF, but not in plasma, were also significantly increased, and its time-course was inversely correlated with the alterations in blood glucose over 2 h. These results provide a pharmacological validation of the novel CSF sampling and validation procedure for sampling rat CSF.
    Journal of neuroscience methods 06/2012; 209(1):106-12. DOI:10.1016/j.jneumeth.2012.05.034 · 1.96 Impact Factor
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    ABSTRACT: Apolipoprotein E (apoE) is a protein mainly synthesized in the liver and brain. To further understand the role of brain apoE in the management of daily food intake, we have examined the circadian pattern of hypothalamic apoE gene and protein expression in freely-fed (FF) and food-restricted (RF, food provided 4 h daily between 1000 h and 1400 h) rats sacrificed at 3-h intervals throughout the light-dark cycle. In FF rats, hypothalamic apoE mRNA and protein levels fluctuated with peaks occuring during the dark phase and the nadirs occuring during the light phase. This pattern was altered in RF rats, which had a marked increase in hypothalamic apoE mRNA and protein levels during the 4-h feeding period in the light phase. Although corticosterone (CORT) levels temporally coincided with the increasing phase of apoE in the hypothalamus in both FF and RF rats, depletion of CORT by adrenalectomy (ADX) did not significantly influence the hypothalamic apoE levels during either period, implying that the circadian pattern of hypothalamic apoE is regulated by factors other than circulating CORT. The finding that hypothalamic apoE and food intake are positively associated during the normal circadian cycle as well as in the period of restricted feeding suggests that hypothalamic apoE is food-entrained and likely involved in the physiological regulation of daily food intake.
    Brain research 05/2009; 1273:66-71. DOI:10.1016/j.brainres.2009.04.004 · 2.83 Impact Factor
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