Role of cold-inducible RNA-binding protein in hypothalamic regulation of feeding behavior during fasting and cold exposure.

Appetite regulation is a complex process that is critical for maintaining energy balance and is governed by intricate molecular and cellular mechanisms in the hypothalamus. RNA-binding proteins play vital roles in the post-transcriptional regulation of mRNA and influence feeding behavior and energy metabolism. This study explored the role of cold-inducible RNA-binding protein (Cirbp) in hypothalamic neurons under metabolic stress conditions, such as fasting and cold exposure. Next-generation sequencing (NGS) of the hypothalami from fasted mice identified 67 differentially expressed RNA-binding proteins, with Cirbp and RNA-binding motif protein 3 (Rbm3) being significantly upregulated. Immunohistochemical analysis confirmed increased Cirbp expression in the arcuate nucleus (ARC) and dorsomedial hypothalamus during fasting, indicating responsiveness to metabolic cues. Ribo-Tag analysis of agouti-related protein (AgRP) neurons demonstrated elevated Cirbp expression levels in response to fasting, linking it to hunger-regulating pathways. Intracerebroventricular injection of Cirbp antisense oligodeoxynucleotides (AS ODN) reduced Cirbp expression, leading to a decrease in food intake and a reduction in body weight, highlighting the functional role of Cirbp in appetite regulation. Cold exposure also induced Cirbp expression in the ARC, which correlated with an increase in food intake. Blockade of Cirbp by AS ODN treatment attenuated cold-induced food intake, indicating that Cirbp plays a specific role in regulating feeding behavior during cold stress. This suggests that Cirbp is a key mediator in hypothalamic responses to metabolic stress, influencing feeding behavior through its regulatory functions in AgRP neurons. Further exploration of Cirbp mechanisms may offer insights into therapeutic strategies for energy balance disorders, such as obesity and anorexia.