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

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  • Bonggi Lee

    (Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
    Present address: College of Pharmacy, Pusan National University, Gumjung-Gu, Busan, South Korea)

  • Jashin Koo

    (Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive
    Present address: KBIO, 123, Osongsaengmyeong-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk 28160, Korea)

  • 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
    Present address: Section on Eukaryotic DNA Replication and Gene Regulation, Program in Genomics of Differentiation, NICHD, National Institutes of Health, 6 Center Drive, Bethesda, Maryland 20892, USA)

  • 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)

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.

Suggested Citation

  • 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 Sheraf, 2016. "A mouse model for a partially inactive obesity-associated human MC3R variant," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10522
    DOI: 10.1038/ncomms10522
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    Cited by:

    1. Tushar P. Patel & Joo Yun Jun & Arnold Y. Seo & Noah J. Levi & Diana M. Elizondo & Jocelyn Chen & Adrian M. Wong & Nicol Tugarinov & Elizabeth K. Altman & Daniel B. Gehle & Sun Min Jung & Pooja Patel , 2025. "Melanocortin 3 receptor regulates hepatic autophagy and systemic adiposity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    2. Julian C. Lui & Adalbert Raimann & Hironori Hojo & Lijin Dong & Paul Roschger & Bijal Kikani & Uwe Wintergerst & Nadja Fratzl-Zelman & Youn Hee Jee & Gabriele Haeusler & Jeffrey Baron, 2022. "A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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