Abstract
To date, genome-wide association studies (GWAS) have identified at least 32 novel loci for obesity and body mass-related traits. However, the causal genetic variant and molecular mechanisms of specific susceptibility genes in relation to obesity are yet to be fully confirmed and characterised. Here, we examined whether the candidate gene NEGR1 encoding the neuronal growth regulator 1, also termed neurotractin or Kilon, accounts for the obesity association. To characterise the function of NEGR1 for body weight control in vivo, we generated two novel mutant mouse lines, including a constitutive NEGR1-deficient mouse line as well as an ENU-mutagenised line carrying a loss-of-function mutation (Negr1-I87N) and performed metabolic phenotypic analyses. Ablation of NEGR1 results in a small but steady reduction of body mass in both mutant lines, accompanied with a small reduction in body length in the Negr1-I87N mutants. Magnetic resonance scanning reveals that the reduction of body mass in Negr1-I87N mice is due to a reduced proportion of lean mass. Negr1-I87N mutants display reduced food intake and physical activity while normalised energy expenditure remains unchanged. Expression analyses confirmed the brain-specific distribution of NEGR1 including strong expression in the hypothalamus. In vitro assays show that NEGR1 promotes cell-cell adhesion and neurite growth of hypothalamic neurons. Our results indicate a role of NEGR1 in the control of body weight and food intake. This study provides evidence that supports the link of the GWAS candidate gene NEGR1 with body weight control.
Highlights
Neuronal growth regulator 1 (NEGR1), termed neurotractin [1] or Kilon [2], is among the genes in the expanding list of common obesity loci recently identified in three independent human genome-wide association studies (GWAS) studies [3,4,5]
The body mass phenotype of both Negr1-KO and Negr1-I87N mutants develops after weaning, suggesting that there is not a defect in suckling or feeding during the immediate postnatal period
Body mass reduction in Negr1-I87N mutants is due to reduced lean mass
Summary
Neuronal growth regulator 1 (NEGR1), termed neurotractin [1] or Kilon [2], is among the genes in the expanding list of common obesity loci recently identified in three independent human genome-wide association studies (GWAS) studies [3,4,5]. The three associated single nucleotide polymorphisms (SNPs; rs3101336, rs2568958 and rs2815752) lie approximately 60 kb upstream of NEGR1, flanking two regions of deletion polymorphisms that segregate on distinct haplotypes. These deletions remove conserved elements upstream of NEGR1 and are associated with increased body mass index (BMI) [5]. Many of the GWAS hits have pointed to a role of the central nervous system (CNS) in obesity and have identified proven functional obesity genes such as MC4R, SH2B1 and BDNF. The function of other neural-specific candidate genes such as NEGR1, TMEM18 and KCTD15 are yet to be proven in vivo
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