title: A mouse model for a partially inactive obesity-associated human MC3R variant.
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 (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.
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Bonggi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Jashin
authors.initials: J
authors.lastname: Koo
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Joo
authors.initials: J
authors.lastname: Yun Jun
authors.affiliation: Mouse Metabolism Core Laboratory, NIDDK, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Heritable Disorders Branch, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Cell Biology and Metabolism Program, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Arnold Y
authors.initials: AY
authors.lastname: Seo
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Dezmond C
authors.initials: DC
authors.lastname: Taylor-Douglas
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Adler-Wailes
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Faye
authors.initials: F
authors.lastname: Chen
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Gardner
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Koutzoumis
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Roya
authors.initials: R
authors.lastname: Sherafat Kazemzadeh
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Robin B
authors.initials: RB
authors.lastname: Roberson
authors.affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004435:Eating; D004734:Energy Metabolism; D005223:Fats / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D020738:Leptin / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D005223:Fats; D020738:Leptin; C505392:MC3R protein, human; C470053:Mc3r protein, mouse; D044104:Receptor, Melanocortin, Type 3
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