Prostaglandin E 2 activates melanin-concentrating hormone neurons to drive diet-induced obesity

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 (PGE ), a key hypothalami...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-08, Vol.120 (31), p.e2302809120
Main Authors: Fang, Lisa Z, Linehan, Victoria, Licursi, Maria, Alberto, Christian O, Power, Jacob L, Parsons, Matthew P, Hirasawa, Michiru
Format: Article
Language:English
Subjects:
Animals
Diet, High-Fat - adverse effects
Fatty Liver
Female
Hypothalamus
Inflammation
Inflammation Mediators
Male
Melanins - genetics
Mice
Neurons
Obesity - genetics
Prostaglandins
Rats
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Summary: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 (PGE ), 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 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 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2302809120