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

Bonggi Lee, Jashin Koo, Joo Yun Jun, Oksana Gavrilova, Yongjun Lee, Arnold Y. Seo, Dezmond C. Taylor-Douglas, Diane C. Adler-Wailes, Faye Chen, Ryan Gardner, Dimitri Koutzoumis, Roya Sherafat Kazemzadeh, Robin B. Roberson and Jack A. Yanovski ()
Additional contact information
Bonggi Lee: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Jashin Koo: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Joo Yun Jun: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Oksana Gavrilova: Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, 10 Center Drive
Yongjun Lee: Heritable Disorders Branch, NICHD, National Institutes of Health, 10 Center Drive
Arnold Y. Seo: Cell Biology and Metabolism Program, NICHD, National Institutes of Health
Dezmond C. Taylor-Douglas: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Diane C. Adler-Wailes: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Faye Chen: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Ryan Gardner: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Dimitri Koutzoumis: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Roya Sherafat Kazemzadeh: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Robin B. Roberson: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
Jack A. Yanovski: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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 (MC3RhWT/hWT) and double-mutant (C17A+G241A) human (MC3RhDM/hDM) MC3R, that MC3RhDM/hDM have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced length and fat-free mass compared with MC3RhWT/hWT. MC3RhDM/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 MC3RhDM/hDM mice and MC3RhDM/hDM human subjects. MC3RhDM/hDM bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiate into adipocytes that accumulate more triglyceride than MC3RhWT/hWT MSCs. MC3RhDM/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.

Date: 2016
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DOI: 10.1038/ncomms10522

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