Agrp-IRES-CreERT2-P2A-tdTomato Mouse

The AGRP gene encodes Agouti-related protein (AgRP), a neuropeptide synthesized by AgRP/NPY neurons predominantly located in the arcuate nucleus of the hypothalamus, as well as in the kidneys and adrenal glands. The expression of AGRP is modulated by various factors, including nutritional status and hormonal signals. Notably, AGRP expression is markedly upregulated during periods of starvation and rapidly downregulated following refeeding. AgRP is exclusively synthesized in the ventromedial part of the arcuate nucleus within neuropeptide Y (NPY)-containing cells, where it is co-expressed with NPY. This neuropeptide plays a pivotal role in enhancing appetite, reducing metabolic rate, and decreasing energy expenditure, making it one of the most potent and enduring appetite stimulators. AgRP exerts its orexigenic effects by antagonizing melanocortin receptor 4 (MC4R), thereby promoting food intake and inhibiting energy expenditure, which is crucial for weight regulation. Mutations in the AGRP gene have been implicated in conditions such as late-onset obesity and anorexia nervosa, underscoring its significant role in energy homeostasis and body weight control.

The Agrp-IRES-CreERT2-P2A-tdTomato mouse model was generated by integrating the IRES-CreERT2-P2A-tdTomato gene expression cassette into the endogenous Agrp locus via gene editing technology. Under the control of the mouse endogenous Agrp gene regulatory elements, this mouse expresses tamoxifen-inducible CreERT2 recombinase. Additionally, the cassette includes a red fluorescent protein (tdTomato) for lineage tracing of Agrp-positive cells. In the absence of tamoxifen, CreERT2 recombinase remains cytoplasmic. Upon tamoxifen administration, CreERT2 translocates to the nucleus to mediate recombination. When Agrp-IRES-CreERT2-P2A-tdTomato mice are crossed with mice containing loxP sites, tamoxifen induction can trigger Cre recombinase-mediated sequence recombination between loxP sites in AgRP-positive neurons of the offspring.