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bioRxiv · 10.64898/2025.12.30.697005

The inactivation of DHHC7 in mouse liver promotes diet-induced obesity through a hepatic Prg4-GPR146 axis

Sun, Y.·Liu, Y.·Wang, S.·Wu, H.·Hou, X.·Duan, J.·Pei, J.·Xu, Y.·Hu, X.·Chen, B.
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Abstract

The liver secretes hepatokines that coordinate whole-body metabolism. Posttranslational lipidation of signaling proteins by DHHC palmitoyltransferases controls membrane targeting and signaling, yet the role of hepatic palmitoylation in systemic metabolic regulation is largely unexplored. Using an inducible, liver-specific DHHC7 knockout (D7LKO) mouse, we report that loss of DHHC7 in hepatocytes potentiates adenylyl cyclase-PKA-CREB signaling through reducing palmitoylation of inhibitory G protein subunit (Gi), leading to transcriptional elevation and secretion of proteoglycan 4 (Prg4). Elevated circulating Prg4 acts on adipocytes by binding GPR146 via Prg4s N-terminal SMB domain, suppressing adipocyte PKA substrate phosphorylation and hormone-sensitive lipase (HSL) Ser563 phosphorylation, thereby impairing lipolysis. Under high-fat diet (HFD) feeding, D7LKO mice and mice with adenoviral hepatic Prg4 overexpression develop pronounced obesity characterized by increasing brown, subcutaneous, and visceral fat mass and adipocyte hypertrophy; strikingly, these animals show little impairment in glucose tolerance or circulating triglycerides but display elevated plasma cholesterol. Conditioned medium containing Prg4 recapitulates suppression of adipocyte HSL phosphorylation in vitro, and SMB-deleted Prg4 fails to bind GPR146 or inhibit HSL phosphorylation. Our findings define a liver palmitoylation- hepatokine axis that controls adipose lipolysis and predisposes to diet-induced fat accumulation, establishing Prg4-GPR146 as a mechanistic link between hepatic signaling and adipose energy mobilization.

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Sun, Y., Liu, Y., Wang, S., Wu, H., Hou, X., Duan, J., Pei, J., Xu, Y., Hu, X., Chen, B.. 2025-12-31. The inactivation of DHHC7 in mouse liver promotes diet-induced obesity through a hepatic Prg4-GPR146 axis. https://doi.org/10.64898/2025.12.30.697005

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