NREP deficiency reshapes liver-adipose lipid metabolism and the inflammatory microenvironment of adipose tissue

Obesity and associated metabolic disorders, including metabolic syndrome, represent a major global health challenge, but their underlying molecular mechanisms remain incompletely understood. Here, we investigated the role of the neuronal regeneration related protein (NREP) gene in body weight regulation, systemic adipose accumulation and inflammatory remodeling of metabolic tissues. Using an integrative multi omics approach, we analyzed human hepatic transcriptome datasets, generated a CRISPR/Cas9 NREP knockout mouse model. Body weight, adipose and hepatic histology, circulating lipid profiles, liver and inguinal white adipose tissue transcriptomes, and selected metabolic genes were assessed. Gene-set enrichment and mMCP-counter analyses were used to explore inflammatory pathways and estimated immune and stromal cell populations. Clinical data analysis revealed significantly higher hepatic NREP expression in over weight individuals and in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Genetic ablation of NREP in mice resulted in reduced body weight, sex dependent remodeling of adipose tissue, and pronounced alterations in the serum lipidome. Transcriptomic profiling demonstrated that NREP deficiency reprograms hepatic lipid metabolic networks by promoting fatty acid oxidation and suppressing de novo lipogenesis. Differentially expressed genes were significantly enriched for long‑chain fatty acid metabolism, PPAR signaling, and pathways associated with tissue fibrosis. Simultaneously, NREP ablation reduced the enrichment of inflammation and immune related pathways in adipose tissue, improved the metabolic microenvironment, and induced a high turnover lipid metabolic state in peripheral adipose tissues. These findings identify NREP as a potential regulator of metabolic-inflammatory coupling, establish NREP as a key modulator of body weight and lipid metabolism, and provide mechanistic insights into the pathophysiology of obesity and related metabolic disorders.