| MAGED1, also named NRAGE or Dlxin-1, is regarded as an adaptor protein. MAGED1can interact with many proteins and play important roles in several intracellular signaling pathways. However, most conclusions are drawn on the basis of in vitro functional analysis. And the knowledge of the physiological roles of Magedl is limited.Up till now, only one Magedl knockout mouse has been reported. The deletion just appeared to cause defect in developmental apoptosis. A Magedl knockout mouse strain was also generated in our lab. Similar to those of the reported, the mice are viable, fertile, and normal in gross physical observation. However, the knockout mice were weightier and showed slightly higher levels of blood glucose in fasted status than wild-type mice although these phenotypes were variable among individuals. Compared with the wild-type littermates, the knockout mice exhibited normal or improved glucose tolerance and insulin sensitivity despite of low levels of insulin secretion, when their body weight was comparable. The data from Comprehensive Lab Animal Monitoring System showed that there was almost no difference in oxygen consumption and carbon dioxide production between the knockout and the wild-type mice with undistinguishable body weight. But the knockout mice had less food intake and were less active than wild-type mice. Cellular experiments demonstrated that immortalized Mefs of Magedl knockout mice had a stronger potential to differentiate into adipocytes than those of wild-type mice. In addition, the cells of knockout mice had higher protein levels of IRS-1and continuing phosphorylation of AKT under the stimulation of insulin, indicating that these cells had increased insulin sensitivity. Therefore, the increased adipogenesis observed in knockout Mefs was probably attributed to the improved insulin sensitivity. JNK has been demonstrated to regulate insulin pathway by negative feedback. Interestingly, insulin induced activation of JNK was downregulated in Magedl null cells, which indicated that low activity of JNK was probably responsible for the improved insulin sensitivity. The attenuated activation of JNK by insulin may be unique, because the phosphorylation of JNK caused by UV and TNF-a was comparable in the Maged1knockout and wild-type Mefs. During the further investigation, hypothermia and hyperleptinemia were found in the knockout mice when they were young. In random fed lean mice, administration of exogenous leptin results in anorexia and weight loss. The coexistence of hyperleptinemia and slow weight gain/obesity suggested that there was some kind of leptin resistance in the knockout mice. And more detailed mechanisms are needed to elucidate such late-onset obesity resulting from Maged1knockout.Besides the late-onset obesity, the most penetrated phenotype of Maged1was shortened circadian period. As we know, the circadian clock plays a central role in physiological adaption and anticipation of day to night alternations. In a genetic screen for novel regulators of circadian rhythms, the Magedl knockout mice were noted for shortened period and altered rest-activity bouts. These circadian phenotypes were proposed to result from a direct change in the core molecular clock network that reduced the robustness of the circadian clock. In vitro and in vivo evidences indicated that MAGED1bound to RORa and then affected the expression of core clock genes, Bmall, Rev-erba and E4bp4, through the Rev-Erba/RORA responsive elements (RORE). Although Magedl was a non rhythmic gene, it enhanced rhythmic input and buffered the irrelevant, perturbing stimuli or noise by binding RORa in a non-circadian way. Magedl was thus identified and defined as a novel circadian regulator, which was indispensable for the robustness of the circadian clock to better serve the organism. |
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