Brain apolipoprotein E: an important regulator of food intake in rats.
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 we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.
Cincinnati Obesity Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Ling
L
Shen
Patrick
P
Tso
Stephen C
SC
Woods
Deborah J
DJ
Clegg
Kyna L
KL
Barber
Katherine
K
Carey
Min
M
Liu
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects*; D005215:Fasting / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000906:Antibodies; D001057:Apolipoproteins E; D004041:Dietary Fats; D009479:Neuropeptides; D012333:RNA, Messenger; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones; D018021:Lithium Chloride