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A mouse model for a partially inactive obesity-associated human MC3R variant
Bonggi Lee1, Jashin Koo1, Joo Yun Jun1
1Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
Nature Communications
|January 29, 2016
Summary
Children with specific MC3R gene variants show increased fat mass. Mouse models confirm these variants influence weight, fat accumulation, and nutrient partitioning, suggesting a key role for MC3R in metabolism.
Area of Science:
- Genetics and Metabolism
- Endocrinology
- Molecular Biology
Background:
- Previous studies indicated children homozygous for MC3R variants (C17A+G241A) exhibit higher fat mass.
- The precise role of MC3R signaling in human adiposity and nutrient partitioning remains incompletely understood.
Purpose of the Study:
- To investigate the physiological impact of specific MC3R sequence variants (C17A+G241A) using humanized mouse models.
- To elucidate the role of MC3R signaling in adipose tissue development and nutrient partitioning.
Main Methods:
- Generation of homozygous knock-in mouse models expressing wild-type human MC3R (MC3R(hWT/hWT)) and double-mutant human MC3R (MC3R(hDM/hDM)).
- Comparative analysis of body weight, body composition (fat mass, fat-free mass), energy intake, feeding efficiency, and serum adiponectin levels.
- In vitro differentiation of mesenchymal stem cells (MSCs) from bone and adipose tissue to assess adipogenesis.
Main Results:
- MC3R(hDM/hDM) mice displayed increased weight, fat mass, energy intake, and feeding efficiency, alongside reduced length and fat-free mass compared to MC3R(hWT/hWT) mice.
- Despite increased fat mass, MC3R(hDM/hDM) mice showed no heightened adipose tissue inflammation or inflammatory markers.
- Elevated serum adiponectin levels were observed in both MC3R(hDM/hDM) mice and human subjects. MC3R(hDM/hDM) MSCs differentiated into adipocytes with greater triglyceride accumulation.
Conclusions:
- The MC3R C17A+G241A variants significantly impact nutrient partitioning, leading to increased metabolically healthy adipose tissue.
- These findings underscore the critical role of MC3R signaling in human metabolism.
- A novel role for MC3R in regulating adipose tissue development is suggested.
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