RGD Reference Report - Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat. - Rat Genome Database

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Melanocortin receptor 4 deficiency affects body weight regulation, grooming behavior, and substrate preference in the rat.

Authors: Mul, JD  Van Boxtel, R  Bergen, DJ  Brans, MA  Brakkee, JH  Toonen, PW  Garner, KM  Adan, RA  Cuppen, E 
Citation: Mul JD, etal., Obesity (Silver Spring). 2012 Mar;20(3):612-21. doi: 10.1038/oby.2011.81. Epub 2011 Apr 28.
RGD ID: 6478803
Pubmed: PMID:21527895   (View Abstract at PubMed)
PMCID: PMC3286758   (View Article at PubMed Central)
DOI: DOI:10.1038/oby.2011.81   (Journal Full-text)

Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional Mc4r knockout model in the rat, resulting from an N-ethyl-N-nitrosourea mutagenesis-induced point mutation. In vitro observations revealed impaired membrane-binding and subsequent nonfunctionality of the receptor, whereas in vivo observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti-Related Protein(79-129) (AgRP(79-129)), an MC4R inverse agonist, or Melanotan-II (MTII), an MC4R agonist, did affect feeding behavior in wild-type rats but not in homozygous mutant rats, confirming complete loss of MC4R function in vivo. Finally, ICV administration of MTII induced excessive grooming behavior in wild-type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII-induced grooming behavior is exclusively regulated via MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MC4RHumanobesity  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rRatobesity  IMP DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rMouseobesity  ISOMc4r (Rattus norvegicus)DNA:nonsense mutation:cds:p.K314X (rat)RGD 
Mc4rm1HubrRatobesity  IMP DNA:nonsense mutation:cds:p.K314XRGD 
WI-Mc4rm1HubrRatobesity MODEL: spontaneousIMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AgrpRatpositive regulation of feeding behavior  IDA  RGD 
Mc4rRatregulation of feeding behavior  IMP  RGD 
Mc4rRatregulation of grooming behavior  IMP  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mc4rRathormone binding  IDA  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mc4rRatabnormal food preference  IMP  RGD 
Mc4rRatdecreased locomotor activity  IMP  RGD 
Mc4rm1HubrRatdecreased locomotor activity  IMP  RGD 
WI-Mc4rm1HubrRatdecreased locomotor activity  IMP  RGD 
Mc4rRatincreased body length  IMP  RGD 
Mc4rm1HubrRatincreased body length  IMP  RGD 
WI-Mc4rm1HubrRatincreased body length  IMP  RGD 
Mc4rRatincreased body weight  IMP  RGD 
Mc4rm1HubrRatincreased body weight  IMP  RGD 
WI-Mc4rm1HubrRatincreased body weight  IMP  RGD 
Mc4rRatincreased circulating leptin level  IMP  RGD 
Mc4rm1HubrRatincreased circulating leptin level  IMP  RGD 
WI-Mc4rm1HubrRatincreased circulating leptin level  IMP  RGD 
Mc4rRatincreased defecation amount  IMP  RGD 
Mc4rm1HubrRatincreased defecation amount  IMP  RGD 
WI-Mc4rm1HubrRatincreased defecation amount  IMP  RGD 
Mc4rRatincreased fat cell size  IMP  RGD 
Mc4rm1HubrRatincreased fat cell size  IMP  RGD 
WI-Mc4rm1HubrRatincreased fat cell size  IMP  RGD 
Mc4rRatincreased fluid intake  IMP  RGD 
Mc4rm1HubrRatincreased fluid intake  IMP  RGD 
WI-Mc4rm1HubrRatincreased fluid intake  IMP  RGD 
Mc4rRatincreased subcutaneous adipose tissue amount  IMP  RGD 
Mc4rm1HubrRatincreased subcutaneous adipose tissue amount  IMP  RGD 
WI-Mc4rm1HubrRatincreased subcutaneous adipose tissue amount  IMP  RGD 
Mc4rRatincreased white adipose tissue amount  IMP  RGD 
Mc4rm1HubrRatincreased white adipose tissue amount  IMP  RGD 
WI-Mc4rm1HubrRatincreased white adipose tissue amount  IMP  RGD 
Mc4rRatpolyphagia  IMP  RGD 
Mc4rm1HubrRatpolyphagia  IMP  RGD 
WI-Mc4rm1HubrRatpolyphagia  IMP  RGD 
Objects Annotated

Genes (Rattus norvegicus)
Agrp  (agouti related neuropeptide)
Mc4r  (melanocortin 4 receptor)
Mc4rm1Hubr  (melanocortin 4 receptor; ENU induced mutation 1, Hubr)

Genes (Mus musculus)
Mc4r  (melanocortin 4 receptor)

Genes (Homo sapiens)
MC4R  (melanocortin 4 receptor)

Strains
WI-Mc4rm1Hubr  (NA)


Additional Information