Cited by 87Regulation of Appetite and ObesityGenetic Associations and EpidemiologyHypothalamic control of reproductive hormones

Functional Inactivation of the Genome-Wide Association Study Obesity Gene Neuronal Growth Regulator 1 in Mice Causes a Body Mass Phenotype

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Lee, Angela W. S., Hengstler, Heidi, Schwald, Kathrin, Berriel-Diaz, Mauricio, Loreth, Desirée, Kirsch, Matthias, Kretz, Oliver, Haas, Carola A. +9 more·2012·PLoS ONE

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.

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  • There is a genetic correlation between ASD and social communication difficulties at age 8 in a non-ASD population sample (rG=0.375, p=0.0028).

    “we confirm the genetic correlation with social communication difficulties at age 8 in a non-ASD population sample reported previously based on a subset of the ASD sample 70 ( 𝑟 𝐺 = 0.375, p = 0.0028).”

    From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [70]

    The Materials and Methods passages on time-course analysis concern genotype effects in mice, not ASD or social communication in children (page unavailable). Searches for the age-8 social-communication finding, ASD, and the reported correlation and p-value found no passage addressing the claim. (LLM, conf=0.78)

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  1. [40]Lauritzen SL (2004) Graphical Models;. Atkinson AC, Copas JB, Pierce DA, Schervish MJ, Titterington DM, editors. Oxford University Press.
  2. [46]Rougon G, Hobert O (2003) New Insights into the Diversity and Function of Neuronal Immunoglobulin Superfamily Molecules. Annual Review of Neuroscience 26: 207– 238. 12598678
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  4. [58]Lauritzen S, Atkinson A, Copas J, Pierce D, Schervish M, et al (2004) Graphical Models. Oxford University Press.

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Authors
Lee, A. W. S., Hengstler, H., Schwald, K., Berriel-Diaz, M., Loreth, D., Kirsch, M., Kretz, O., Haas, C. A., de Angelis, M. H., Herzig, S., Brümmendorf, T., Klingenspor, M., Rathjen, F. G., Rozman, J., Nicholson, G., Cox, R. D., & Schäfer, M. K. E.
Affiliations
  • Mary Lyon Centre at MRC Harwell (GB)
  • University of Freiburg (DE)
  • University Medical Center Freiburg (DE)
  • German Cancer Research Center (DE)
  • Max Delbrück Center (DE)
  • Technical University of Munich (DE)
  • Helmholtz Munich (DE)
  • University of Oxford (GB)
Corresponding author
  • Lee, Angela W. S.
  • Cox, Roger D.
  • Schäfer, Michael K. E.
Venue
PLoS ONE
Published
2012-07-23
Volume
7
Issue
7
Pages
e41537
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2098560069
Cited by
84
References
59
Citations by year
2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 11 · 2019: 8 · 2018: 10 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 6 · 2012: 1
FWCI
2.42
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • mediaTUM (Technical University of Munich) (submittedVersion, cc-by)
  • Site cant be reached (submittedVersion, cc-by)
Funders
  • Wellcome Trust (081219)
  • Deutsche Forschungsgemeinschaft
  • Albert-Ludwigs-Universität Freiburg
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
NEGR1, obesity, body mass, weight management, dietary intake, hypothalamus, hypothalamic neurons, neurite outgrowth, cell-cell adhesion, lean body mass, energy expenditure, loss-of-function mutations, obesity susceptibility genes
MeSH terms
Alleles, Animals, Body Height, Body Weight, Cell Adhesion, Cell Line, Eating, Endoplasmic Reticulum, Energy Metabolism, Female, Genotype, Humans, Hypothalamus, Male, Membrane Proteins, Motor Activity, Nerve Tissue Proteins, Obesity, Phenotype, Cell Adhesion Molecules, Neuronal, Neurites, Gene Silencing, Mice, Genome-Wide Association Study, Gene Knockout Techniques, Diet, High-Fat

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