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

Sarah Bauer; Vanessa Aeissen; Alena M Bubeck; Ioannis Kienes; Kornelia Ellwanger; Mona Scheurenbrand; Fjolla Rexhepi; Sheela Ramanathan; Philip Rosenstiel; W Florian Fricke; Thomas A Kufer

doi:10.1016/j.isci.2023.106313

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

iScience. 2023 Mar 2;26(4):106313. doi: 10.1016/j.isci.2023.106313. eCollection 2023 Apr 21.

Affiliations

¹ Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, 70599 Stuttgart, Germany.
² Department of Microbiome and Applied Bioinformatics, Institute of Nutritional Science, University of Hohenheim, 70599 Stuttgart, Germany.
³ Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
⁴ Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.

Abstract

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.

Keywords: Diet; Immunology; Molecular mechanism of gene regulation.