| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
By using the loxTB/MC4-R mouse lacking MC4-Rs, we examined the implication of MC4-R-positive PVH (paraventricular nucleus of the hypothalamus) cells in regulating energy homeostasis in more detail.
In 2004,we reactivated MC4-Rs exclusively in the PVH in loxTB/MC4-R mice by using the Cre/loxP system. As a result, the morbid weight gain was markedly ameliorated. However, the distribution of Cre-immunoreactive cells in the PVH was not identical among the loxTB/MC4-R mice used in this experiment, and therefore the distribution pattern of reactivated MC4-R mRNA was also heterogeneous.
To reactivate MC4-Rs homogenously in the PVH, we generated a transgenic mouse line expressing Cre (Cre-recombinase) under the control of Sim-1 (single-minded 1) regulatory element (Sim1-Cre mice), as Sim-1 gene is broadly expressed within the PVH, contributing to the development of this hypothalamic nucleus. We crossed Sim-1-Cre mice with loxTB/MC4-R mice, and observed a heterogeneous pattern of MC4-R mRNA react
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ivation in the PVH by using in situ hybridization histochemistry. Of note, the loxTB/MC4-R Sim1-Cre mice displayed alleviated morbid weight gain. As expected from the gene expression pattern of Sim-1, the reactivation of MC4-R mRNA was also observed in the medial amygdala.
It has recently been demonstrated that MC4-Rs are expressed not only in the central nervous system but also in the peripheral organs. To observe the effect of neuron-specific MC4-R reactivation, we crossed loxTB/MC4-R mice with Nestin-Cre mice (Jackson Laboratories #003771) generated based on the same construct as that in Sim-1-Cre mice, resulting in the improvement of morbid weight gain.
We also attempted to determine whether the obesity phenotype resulting from MC4-R deficiency is due to increased energy intake or decreased energy expenditure. Whereas loxTB/MC4-R mice markedly overfed, loxTB/MC4-R Sim-1-Cre mice did not. No significant differences in oxygen consumption were observed between both mice.
Taken together, these observations indicate that MC4-Rs expressed in the PVH regulate energy homeostasis by suppressing food intake but not by increasing energy expenditure. It is also conceivable that the medial amygdala may also be involved in this process in term of the reactivation of MC4-R gene observed in loxTB/MC4-R Sim-1-Cre mice. The present study will appear in the journal Cell.
Relevant to this study, we also published a review article describing functional relation between the central melanocortin and serotonin systems that appeared in the journal Peptides. Less
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