Functional profiling of immediate early gene Egr1 in an anorexic mouse model

Abstract

A small population of neurons in the hypothalamus is known to promote food intake by releasing inhibitory agouti‑related peptide (ARP) and neuropeptide Y to broad postsynaptic areas. Acute ablation of ARP neurons in adult mice leads to rapid loss of appetite and the development of an anorexic phenotype. Recent studies have suggested that ablation of ARP neurons removes critical inhibition of postsynaptic neurons, resulting in hyperexcitation of selected downstream neurons. Left uncontrolled, this neuronal hyperactivation is hypothesized to induce starvation. However, the cellular mechanism underlying the control of excitability of postsynaptic neurons in response to the ablation of ARP neurons is poorly understood. The present study aimed to determine the functional correlation between ARP neurons and an immediate early gene, early growth response factor‑1 (Egr1), in postsynaptic neurons in the context of energy homeostasis. Egr1 expression levels were analyzed in different postsynaptic areas upon acute ablation of ARP neurons. As ARP neurons increase appetite by inhibiting the pro‑opiomelanocortin pathway, it was also investigated whether blockade of melanocortin signaling affects Egr1 expression in ARP neuron‑ablated mice. The results suggested that ablation of ARP neurons induced robust expression of Egr1 in numerous common postsynaptic targets of ARP and pro‑opiomelanocortin neurons. When ARP neurons were acutely ablated, it was demonstrated that Egr1 induction was attenuated by chronic blockade of the melanocortin signaling pathway in the arcuate nucleus, but not in other downstream regions. Further analysis of the Egr1 signaling cascade may aid in differentiating the functional involvement of postsynaptic targets of ARP neurons in the control of energy metabolism.