A recent study has shown that dietary fats promote obesity not only because of their caloric value but also due to damage in hypothalamic neuronal circuitries that control whole body energy homeostasis. The transcription factor IRX3 can modulate FTO expression, thus, playing a role in the development of obesity. However, the effect of high fat diet (HDF) consumption on the regulation of IRX3 expression in the hypothalamus is poorly understood. Previous results obtained in the process 2014/07496-4 entitled (Role of the transcription factor IRX3 in inducing hypothalamic neurogenesis in adult mice), demonstrate that IRX3 is co-localized with AgRP and POMC neurons. We also observed that the consumption of HFD resulted in a reduction of IRX3 expression in the hypothalamus, which was followed by an increase in FTO expression. Fasting is also capable of modulating IRX3 expression in the hypothalamus. In HFD fed mice, the inhibition of hypothalamic IRX3 by bilateral arcuate nucleus injection using a lentivirus was accompanied by 1.6-fold increase in body mass, particularly due to an increased fat mass (measured by DEXA). These mice also presented an increase in caloric intake and no changes in spontaneous physical activity and whole body oxygen consumption. The hypothalamic IRX3 inhibition increases the FTO expression as soon as AgRP and CART. The inhibition of IRX3 expression in the hypothalamus worsens diet-induced body mass gain. Considering the results above described, we would like to understand the impact of selective inhibition of IRX3 expression either in AgRP or POMC neurons using male mice heterozygous for Cre recombinase under the control of AgRP and POMC promoters.
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