Affiliation:
1. Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John’s A1B 3V6, Canada
Abstract
Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E
2
(PGE
2
), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE
2
on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE
2
depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na
+
/K
+
-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.
Funder
Gouvernement du Canada | Canadian Institutes of Health Research
Research Development Corporation Newfoundland and Labrador
Heart and Stroke Foundation of Canada
Publisher
Proceedings of the National Academy of Sciences