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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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    • "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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