Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol.
Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2(tm1a/tm1a)) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2(tm1a/tm1a) mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2(tm1a/tm1a) mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.
Centre for EndocrinologyQueen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
T V
TV
Novoselova
University of Cambridge Metabolic Research LaboratoriesMRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
R
R
Larder
University of Cambridge Metabolic Research LaboratoriesMRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
D
D
Rimmington
Wellcome Trust Sanger InstituteWellcome Trust Genome Campus, Hinxton, Cambridge, UK.
C
C
Lelliott
Wellcome Trust Sanger InstituteWellcome Trust Genome Campus, Hinxton, Cambridge, UK.
E H
EH
Wynn
Centre for EndocrinologyQueen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
R J
RJ
Gorrigan
Wellcome Trust Sanger InstituteWellcome Trust Genome Campus, Hinxton, Cambridge, UK.
P H
PH
Tate
Centre for EndocrinologyQueen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
L
L
Guasti
University of Cambridge Metabolic Research LaboratoriesMRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
S
S
O'Rahilly
Centre for EndocrinologyQueen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK a.j.clark@qmul.ac.uk.
A J L
AJ
Clark
Wellcome Trust Sanger InstituteWellcome Trust Genome Campus, Hinxton, Cambridge, UK.
D W
DW
Logan
University of Cambridge Metabolic Research LaboratoriesMRC Metabolic Disease Unit, Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.
A P
AP
Coll
Centre for EndocrinologyQueen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London, UK.
L F
LF
Chan
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D058261:Receptor Activity-Modifying Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D002784:Cholesterol; D003346:Corticotropin-Releasing Hormone; D010121:Oxytocin; D058261:Receptor Activity-Modifying Proteins; D012097:Repressor Proteins; D013973:Thyrotropin-Releasing Hormone; C582669:MRAP2 protein, mouse; C101750:Sim1 protein, mouse
AVP; CRH; MC4R; MRAP2; OXT; SIM1; TRH; accessory protein; melanocortin; metabolism; obesity