NLRC5 affects adiposity in high-fat diet-fed female mice and co-regulates peroxisome proliferator-activated receptor ? targets
BAUER S. 1, AEISSEN V. 1, BUBECK A. 2, KIENES I. 1, ELLWANGER K. 1,5, SCHEURENBRAND M. 2, REXHEPI F. 3, RAMANATHAN S. 3, ROSENSTIEL P. 4, FRICKE W. 2, KUFER T. 1
1 Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany; 2 Department of Microbiome and Applied Bioinformatics, Institute of Nutritional Science, University of Hohenheim, Stuttgart, Germany; 3 Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sheerbrooke, Canada; 4 Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Kiel, Germany; 5 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany
The pattern recognition receptor (PRR)-related protein nucleotide-binding and oligomerization domain containing 5 (NLRC5) is a key transcriptional regulator of major histocompatibility (MHC) class I genes. However, recent observations implicate a role for NLRC5 in metabolic traits as well as in transcriptional regulation beyond MHC class I genes. So far, no link between these two novel roles of NLRC5 was established. In order to address the role of NLRC5 in metabolic disease, we subjected female Nlrc5-/- mice to high fat diet (HFD) feeding and performed phenotypic, morphological and biochemical analyses. Nlrc5-/- mice presented with higher weight gain, more AT and larger adipocytes compared to wildtype (WT) animals. Microbiome analysis revealed only minor alterations of the fecal microbiome by diet:genotype interactions. Mechanistically, we show that NLRC5 enhances expression of peroxisome proliferator-activated receptor (PPAR) γ target genes in human cells. Using yeast two-hybrid (Y2H) screening, we identify Sin3A and negative elongation factor (NELF) B as two novel NLRC5 interaction partners and show that Sin3A modulates the synergistic transcriptional effect of NLRC5 on PPARγ. Taken together, we provide evidence that NLRC5 contributes to weight gain in mice, which mechanistically involves transcriptional enhancement of PPARγ target genes by NLRC5 that is co-regulated by the transcriptional regulator Sin3A.