NIH Research Festival
FARE Award Winner
The human melanocortin 3 receptor (MC3R) is known to play an important role in regulating appetite, energy expenditure, possibly playing a pivotal role in human metabolic function. To characterize mutations in association with metabolic function, we generated homozygous knock-in mouse models replacing murine Mc3r with wild type human MC3R (MC3RhWT/hWT) and a double mutant (C17A + G241A) hypofunctioning human MC3R (MC3RhDM/hDM) that we found was associated with pediatric obesity. MC3RhDM/hDM had significantly greater fat mass but less fat-free mass compared to MC3RhWT/hWT at 7 week old. Dual-energy x-ray absorptiometry showed MC3RhDM/hDM mice had significantly lower bone area and bone mineral contents compared to MC3RhWT/hWT. Therefore, we hypothesized that multipotent mesenchymal stem cells (MSCs) from MC3RhDM/hDM mice are predisposed towards adipocyte differentiation and away from osteoblast differentiation. Bone-derived MSCs were differentiated into either adipocytes or osteoblasts, and the accumulation of triglycerides for adipocytes and calcium for osteoblasts were measured by Oil Red O and Alizarin Red S staining. MC3RhDM/hDM MSCs had ~40% increased capacity to differentiate into triglyceride-storing adipocytes than MC3RhWT/hWT MSCs, and mRNAs of adipocyte markers were correspondingly increased. In contrast, MC3RhDM/hDM MSCs have ~50% less capacity to differentiate into osteoblasts than MC3RhWT/hWT MSCs, and mRNA of osteoblast markers were correspondingly reduced. These data suggest that MC3R activity may regulate MSC fate, with low activity facilitating differentiation into lipid storing cells. These findings are the first to identify a role for MC3R in differentiation and suggest a novel mechanism through which MC3R signaling regulates energy homeostasis and metabolism.
Scientific Focus Area: Stem Cell Biology
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