NLRC5 affects diet-induced adiposity in female mice and co-regulates peroxisome proliferator-activated receptor PPARγ target genes

• Published in: iScience 2023-04, Vol.26 (4), p.106313-106313, Article 106313
• Main Authors: Bauer, Sarah, Aeissen, Vanessa, Bubeck, Alena M., Kienes, Ioannis, Ellwanger, Kornelia, Scheurenbrand, Mona, Rexhepi, Fjolla, Ramanathan, Sheela, Rosenstiel, Philip, Fricke, W. Florian, Kufer, Thomas A.
• Format: Article
• Language: English
• Subjects: Diet; Immunology; Molecular mechanism of gene regulation
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106313

Nucleotide-binding and oligomerization domain containing 5 (NLRC5) is the key transcriptional regulator of major histocompatibility (MHC) class I genes. Recent observations suggest a role for NLRC5 in metabolic traits and in transcriptional regulation beyond MHC class I genes. To understand the function of NLRC5 in metabolic disease, we subjected Nlrc5−/− mice to high-fat diet (HFD) feeding. Female Nlrc5−/− mice presented with higher weight gain and more adipose tissue (AT) compared to wild-type (WT) animals. Mechanistically, we demonstrate that NLRC5 enhanced the expression of peroxisome proliferator-activated receptor (PPAR) γ target genes in human cells. We identify Sin3A and negative elongation factor (NELF) B as two novel NLRC5 interaction partners and show that Sin3A partly modulates the synergistic transcriptional effect of NLRC5 on PPARγ. Collectively, we show that NLRC5 contributes to weight gain in mice, which involves transcriptional enhancement of PPARγ targets by NLRC5 that is co-regulated by Sin3A. [Display omitted] •Female Nlrc5−/− mice on HFD gain more weight compared to WT animals•NLRC5 interacts with PPARγ and synergistically co-regulates PPARγ target genes•NLRC5 interacts with Sin3A and NELFB•Sin3A fine-tunes NLRC5-mediated transcription of PPARγ targets Diet; Immunology; Molecular mechanism of gene regulation