PARIS/ZNF746 DNA-binding domain deficiency promotes adipose tissue hyperplasia and hepatic lipid accumulation.

Zinc finger protein 746 (ZNF746), also known as PARKIN-interacting substrate (PARIS), is a KRAB-ZFP family transcriptional repressor implicated in Parkinson's disease and adipogenesis. Its unclear role in systemic metabolism led us to investigate PARIS-mediated metabolic function by generating mice with a knockout of Znf746 exon 7 (P7KO), containing the DNA-binding domain. Under a high-fat diet, P7KO mice exhibited larger gains in body and adipose tissue weight alongside improved insulin sensitivity and reduced adipocyte size compared with wild-type mice, suggesting hyperplastic expansion of white adipose tissue. P7KO mice also showed elevated anti-inflammatory markers in adipose tissues, in contrast to accumulation of lipids and upregulation of lipogenic genes, without changes in glucose transporter or lipid uptake genes, in the liver. These findings indicate a dual role for PARIS: suppressing adipose hyperplasia and restricting hepatic lipogenesis. Identification of the evolutionary conservation of PARIS among mammals, particularly the shared DNA-binding domain between mice and humans, support its translational relevance. Collectively, our results identify PARIS as a previously unrecognized regulator of metabolic homeostasis that coordinates lipid storage and utilization in a tissue-specific manner. Targeting PARIS may offer a novel therapeutic strategy for obesity-related metabolic disorders, such as type 2 diabetes and non-alcoholic fatty liver disease.