Prolactin acts on proopiomelanocortin neurons to regulate hepatic lipid metabolism.

OBJECTIVE

To elucidate the central mechanism of pituitary-derived prolactin (PRL) in hepatic lipid homeostasis and identify therapeutic targets for metabolic dysfunction-associated fatty liver disease (MASLD).

METHODS

High-fat diet (HFD)-fed mice induced MASLD. PRL⁻/⁻ mice, POMC neuron-specific PRL receptor (PRLR) conditional knockout mice, AAV-mediated PRLR knockdown, and central/peripheral PRL administration were used to explore PRL's central regulatory role. Metabolic phenotyping, histological/biochemical assays, immunofluorescence, electrophysiology, RNA-seq, 6-OHDA-induced sympathetic denervation, and primary hepatocyte experiments were performed to evaluate phenotypes, neuronal activity and underlying mechanisms.

RESULTS

PRL deficiency exacerbated HFD-induced hepatic lipid deposition, and central intracerebroventricular PRL alleviated hepatic steatosis in HFD-fed PRL⁻/⁻ and wild-type mice more rapidly than peripheral intraperitoneal PRL. PRLR was highly expressed in hypothalamic arcuate nucleus POMC neurons, which PRL selectively activated by enhancing neuronal excitability. POMC-specific PRLR knockout abrogated PRL's anti-steatotic effects and aggravated HFD-induced hepatic lipid accumulation. Mechanistically, central PRL enhanced hepatic sympathetic outflow to suppress de novo lipogenesis via the FASN pathway.

CONCLUSION

PRL acts on hypothalamic POMC neurons to enhance hepatic sympathetic activity, suppressing FASN-mediated lipogenesis and maintaining lipid homeostasis. This novel PRL-driven brain-liver circuit highlights central PRL signaling as a promising MASLD therapeutic target.