A mouse model for a partially inactive obesity-associated human MC3R variant

• Published in: Nature communications 2016-01, Vol.7 (1), p.10522-10522, Article 10522
• Main Authors: Lee, Bonggi, Koo, Jashin, Yun Jun, Joo, Gavrilova, Oksana, Lee, Yongjun, Seo, Arnold Y., Taylor-Douglas, Dezmond C., Adler-Wailes, Diane C., Chen, Faye, Gardner, Ryan, Koutzoumis, Dimitri, Sherafat Kazemzadeh, Roya, Roberson, Robin B., Yanovski, Jack A.
• Format: Article
• Language: English
• Subjects: 13/100; 13/51; 14; 42/109; 59/57; 631/1647/334/1874/345; 631/443/319/1642/393; 631/80/86; 64/60; 692/308; 82/80; Adipocytes - metabolism; Adiponectin - metabolism; Adipose Tissue - metabolism; Animals; Body composition; Body fat; Disease Models, Animal; Eating; Energy Metabolism; Fats - metabolism; Gene Knock-In Techniques; Humanities and Social Sciences; Humans; Leptin - metabolism; Metabolism; Mice; multidisciplinary; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - physiopathology; Proteins; Receptor, Melanocortin, Type 3 - genetics; Receptor, Melanocortin, Type 3 - metabolism; Science; Science (multidisciplinary); Signal transduction
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10522

We previously reported children homozygous for two MC3R sequence variants (C17A+G241A) have greater fat mass than controls. Here we show, using homozygous knock-in mouse models in which we replace murine Mc3r with wild-type human ( MC3R hWT/hWT ) and double-mutant (C17A+G241A) human ( MC3R hDM/hDM ) MC3R , that MC3R hDM/hDM have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3R hWT/hWT . MC3R hDM/hDM mice do not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. Serum adiponectin levels are increased in MC3R hDM/hDM mice and MC3R hDM/hDM human subjects. MC3R hDM/hDM bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3R hWT/hWT MSCs. MC3R hDM/hDM impacts nutrient partitioning to generate increased adipose tissue that appears metabolically healthy. These data confirm the importance of MC3R signalling in human metabolism and suggest a previously-unrecognized role for the MC3R in adipose tissue development. The melanocortin receptor, MC3R, regulates organismal energy homeostasis. Here, Lee et al . create knock-in mice with the a mutated version of the human MC3R receptor found in obese children, and show these mice have more fat and smaller bone, yet are by and large metabolically healthy.