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

Abstract

OBJECTIVE: 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, such as apolipoprotein E (apoE) we present here, offers exciting possibilities for future development of successful anti-obesity therapies.

RESEARCH DESIGN AND METHODS: Changes in feeding behavior following intracerebroventricular (icv) injection of apoE, along with regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides, were studied.

RESULTS: Icv apoE significantly decreased food intake without causing malaise, whereas icv 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 high-fat diet-induced obese rats had significantly reduced hypothalamic apoE mRNA levels, compared with their lean controls, 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 apoE's inhibitory function on feeding.

CONCLUSIONS: These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.